Identifying Color Additives in Regulated Drug Products
Problem: Some patients are sensitive to the color additives approved by the US Food and Drug Administration (FDA) for use in medications. Even though allergies to these approved color additives are relatively infrequent, a few in particular have been linked to intolerances and allergic reactions:
Red dyes, particularly FD&C red #4 (carmine, only approved for use in externally applied drugs) and FD&C red #40 (Allura Red)
Yellow dyes, particularly FD&C yellow #5 (tartrazine) and FD&C yellow #6 (Sunset Yellow)
Blue dyes, particularly FD&C blue #1 (Brilliant Blue)
FD&C (short for Federal Food, Drug, and Cosmetic Act) in front of the colorant name and number (e.g., FD&C yellow #6) indicates that it has been approved for use in food, drugs, and cosmetics, and D&C (e.g., D&C red #33) indicates it has been approved for use in drugs and cosmetics. These approved colorants can be found in many medications. Patients who are allergic to these approved color additives and unknowingly take or apply medications that contain them may experience hypersensitivity reactions that range from mild (e.g., stomach cramps, skin reactions, and rashes), to moderate (e.g., facial swelling, hives, skin lesions, wheezing), to severe (e.g., anaphylactic reactions).
ISMP recently received a report about a medication that contained D&C red #33 that, due to labeling confusion, was almost dispensed for a patient with a red dye allergy. While the product’s principal display panel on the immediate container clearly listed FD&C yellow #6, the D&C red #33 color additive was only listed in the package insert.
Ibuprofen oral suspension was prescribed for a 7-year-old child with a known red dye allergy. Pharmacy staff discovered that the package insert for a prescription-only 473 mL bottle of ibuprofen oral suspension (100 mg/5 mL) from Perrigo specified that the product contained D&C red #33, but this inactive ingredient was not listed on the bottle’s principal display panel. However, another color additive, FD&C yellow #6, was listed there (Figure 1), leading the pharmacy technician and pharmacist to initially and incorrectly assume that this was the only color additive in the product. Fortunately, a pharmacy staff member read the package insert and noticed that the product also contained D&C red #33 before the product was dispensed for the child.
It is easy to see how pharmacy staff and other clinicians might be misled and incorrectly assume that all color additives are listed on the principal display panel since the FD&C yellow #6 is listed there. The reason for the confusion is muddled in a myriad of labeling regulations for both prescription and over-the-counter (OTC) medications.
Why was the inactive ingredient, D&C red #33, missing from the bottle label?
According to the Code of Federal Regulations Title 21–Food and Drugs, prescription drugs for other than oral use are required to include the names of all inactive ingredients in the product labeling, with the exception that color additives may be designated as coloring without naming specific color components, unless required by other regulations [21 CFR 201.100(a)(5)]. Prescription medications for oral use are not required to list all of the inactive ingredients in the product labeling; not on the immediate container label, not on the outside wrapper (e.g., carton label, if present), nor in the package insert. Since the event described above involved a prescription-only bulk bottle of ibuprofen oral suspension, the inactive ingredient D&C red #33 was not required on the container label.
For over-the-counter medications, including varying strengths, concentrations, and volumes of ibuprofen, the regulations require the listing of each inactive ingredient in the Drug Facts section on the outside container or wrapper of the retail package, or on the immediate container label. Thus, OTC ibuprofen oral suspensions available to consumers include information about all the color additives in the product in the “Inactive Ingredients” section of the Drug Facts label.
Why did the inactive ingredient, D&C red #33, appear in the package insert?
Even though companies are not required to include all the inactive ingredients on oral prescription medication labeling, most companies voluntarily list these ingredients, including specific color additives, in the “Description” section of the package insert.
Why was the inactive ingredient, FD&C yellow #6, listed on the principal display panel on the ibuprofen bottle?
The Code of Federal Regulations Title 21–Food and Drugs also establishes specific labeling requirements for certain inactive ingredients, particularly those that are likely to be allergens. According to Section 201.20, the label for OTC products administered orally, nasally, rectally, or vaginally that contain FD&C yellow #6 must declare its presence using the name “FD&C Yellow #6.” Also, the labeling of both OTC and prescription drug products containing FD&C yellow #6 must declare its presence. Thus, the statement, “Contains FD&C yellow #6,” appears on the label of the bulk bottle of ibuprofen oral suspension.
Interestingly, the regulation associated with declaring FD&C yellow #6 use on the label and/or labeling of both OTC and prescription products was suspended in 1988 pending further agency action (Department of Health and Human Services, Food and Drug Administration. 21 CFR Parts 74 and 201. FD&C Yellow No. 6 Label Declaration. Federal Register. December 6, 1988:49138). At this time, it appears that companies would not be required to comply with declaring the use of the FD&C yellow #6 color additive. However, as required elsewhere in the regulations, OTC products should list all specific color additives as inactive ingredients on the Drug Facts label, and prescription products would be expected to continue the voluntary listing of inactive ingredients, including color additives, in the “Description” section of the package insert.
Are there regulations associated with FD&C yellow #5?
According to Section 201.20, the labeling for both OTC and prescription drug products administered orally, nasally, rectally, vaginally, or for use in the area of the eye that contain FD&C yellow #5 also must declare its presence using the names “FD&C Yellow No. 5 and tartrazine.” Additionally, for prescription drugs administered orally, nasally, rectally, vaginally, or for use in the area of the eye that contain FD&C yellow #5, a warning statement in the “Precautions” section of the package insert is required: “This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.”
Safe Practice Recommendations: Query patients upon admission or at each encounter about any food, drug, and environmental intolerances or allergies they may have, asking a scripted question or using a prompt to help identify a color additive intolerance or allergy. If the patient has experienced an adverse reaction to a color additive or food dye, obtain and document information about the specific reaction so it can be distinguished as either an allergy or an intolerance. If a patient has a known color additive or food dye intolerance or allergy, be sure it is listed in a standardized, clearly visible location on all drug-related pages or screens of the electronic health record (EHR) or medical record. All allergies to color additives or food dyes also should be properly coded to allow for clinical decision support, when possible, during allergy screening.
If a patient has a known allergy to a food dye or color additive, an allergen in a medication’s inactive ingredients may not be readily apparent, as even the product’s appearance might not serve as a clue regarding color additives. Practitioners will need to become label detectives, reading the “Description” and “Precautions” sections of the package insert as well as the Drug Facts label to determine all the inactive ingredients of a product, including color additives. After you have read the package insert or Drug Facts label, if you are not sure whether a certain medication contains the color additive, call the manufacturer for more drug information. If a patient cannot take a medication critical to their recovery or health due to the color additive in the medication, compounding pharmacies might be able to provide the medication without the allergen.