gold standard for diagnosis, the lack of clearly defined objective end points limits the utility of even this diagnostic tool.
Despite the inconsistent evidence supporting the role for specific excipients in adverse drug reactions, the possibility that dyes in foods and medications may induce reactions should not be considered
implausible. Many of the dyes used to color medications were historically referred to as coal tar colors, based on the fact that their original synthesis was from coal tar. It is interesting to note that the origins of the modern chemical and pharmaceutical industry are from that same source. Synthetic dye manufacture served as the genesis for the modern German chemical industry in the mid-19th century. The dyes that were deployed initially to dye clothing were retasked in medicine, first to dye tissue for histology and then as the backbones for many modern pharmaceuticals.14,15
It is not contested that virtually all medications are potential sources of reactions, particularly allergic reactions. Reactions to specific medications are taken as a given, supported generally
only by a temporal relationship between administration and development of objective findings or symptoms. Because of the lack of a gold-standard test to confirm specific drug allergy
other than rechallenge, we accept most diagnoses of drug allergy based on less stringent diagnostic criteria.16 Rarely, if ever, does the claim of drug allergy require a double-blind challenge
with the suspected offending agent.
Despite their similar origins and common elements of chemical structure, there is limited consensus on whether medical and food dyes can induce similar reactions. However, there is nothing
chemically distinct about the classes of agents used as dyes that would predict immunological responses any different from agents designated as drugs. Consistent with this perspective is a study showed that FD&C Blue No. 2 (indigo carmine) behaved like a drug in that it interacted with the cytochrome P450 system, inhibiting CYP2A6 in a noncompetitive manner.17 We would anticipate
a low frequency of hypersensitivity reactions in both groups of compounds. The major difference is in the realm of exposure, which regarding dyes is almost ubiquitous, being found in many prescription drugs, OTC, drugs, foods, and personal care products.
Simply being aware that dyes in medications and other ingested products may trigger generalized pruritus, with or without typical urticaria or dermatitis, may prompt alternative management strategies.
A given excipient may be avoided by simply switching to a different manufacturer, a different strength of the preparation, or a different formulation, as shown in case 2, where the patient switched from a doxepin pills/capsules to a dye-free liquid formation.
An invaluable resource in managing patients with suspect excipient
allergy is the US National Library of Medicine Web site (http://dailymed.nlm.nih.gov), which provides medication package inserts
that are brand-specific and dose-specific. While certified color additives are typically listed under inactive ingredients in OTC and prescription medications, this is strictly voluntary for all certified color additives with the exception of FD&C Yellow No. 5 and Yellow No. 6.18 It is important to know that drug manufacturers
are allowed to change any of the excipients, without informing anyone, as long as US Food and Drug Administration–approved ingredients are GRAS (generally recognized as safe).19
In summary, we have identified a cadre of patients with pruritic
dermatoses, many of long standing, whose skin symptoms appear to be triggered by dyes in medications. Substitution of different preparations of the same medications resulted in clearance or improvement of pruritus and dermatitis. Further study is warranted to better define patients who are affected and to develop diagnostic approaches.
The authors have no relevant conflicts of interest to disclose.
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- Supramaniam G, Warner JO. Artificial food additive intolerance in patients with angio-oedema and urticaria. Lancet. 1986;2(8512):907-909.
- Randhawa S, Bahna SL. Hypersensitivity reactions to food additives. Curr Opin Allergy Clin Immunol. 2009;9(3):278-283.
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- Beer JJ. Coal tar dye manufacture and the origins of the Modern Industrial Research Laboratory. Isis. 1958;49(2):123-131.
- Findlay A. The Treasures of Coal Tar. New York, NY: Van Nostrand Company; 1917.
- Mirakian R, Ewan PW, Durham SR, et al; BSACI. BSACI guidelines for the management of drug allergy. Clin Exp Allergy. 2009;39(1):43-61.
- Kuno N, Mizutani T. Influence of synthetic and natural food dyes on activities of CYP2A6,
UGT1A6, and UGT2B7. J Toxicol Environ Health A. 2005;68(16):1431-1444.
- Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for human use. http://www.fda.gov/ForIndustry/ColorAdditives/ColorAdditivesinSpecificProducts/InDrugs/default.htm. Accessed April 13, 2012.
- Kumar A, Rawlings RD, Beaman DC. The mystery ingredients: sweeteners, flavorings, dyes, and preservatives in analgesic/antipyretic, antihistamine/decongestant, cough and cold, antidiarrheal, and liquid theophylline preparations. Pediatrics. 1993;91(5):927-933.
Robert A. Swerlick MDrswerli@emory.edu