Inactive Ingredients in Oral Medication May Cause Adverse Reactions
Did you know that 92.8% of all oral drug agents possess at least one potential allergen? This is what a team of investigators from MIT have discovered in a recent data analysis that evaluated thousands of ingredients in approved medications. What may surprise you, however, is that the drug itself is not responsible for the adverse reaction. Rather, it is the inactive ingredients, known as excipients, that elicit these reactions. Read on to learn more about excipients and what recent research has discovered about the safety of medications and their inactive ingredients.
What are excipients?
All oral drug agents consist of two fundamental parts: the active pharmaceutical ingredient (API) and a mixture of excipients. An excipient is an inactive substance that is not intended or expected to have a direct biological or therapeutic effect. Rather, excipients are added to alter the physical properties of an oral solid dosage form (tablet or capsule) to facilitate absorption, to improve stability, taste, and appearance, or to render the medication tamper resistant. Excipients account for the majority (about two thirds) of an oral medication. Moreover, in the data analysis mentioned above, the investigators determined that the average oral drug product contains 8.8 excipients.
Excipients and adverse reactions
In the past, the safety of excipients were overlooked and no specific safety tests were generally conducted. However, this fact has been changed over times, especially since clinical reports documenting adverse reactions caused by excipients have been increasing. It is currently being recognized that the toxicity of an excipient is not negligible. Excipients can trigger allergic reactions, have interactions with the API or between other excipients, and be a source of contaminants.
To learn more about the undesired effects of excipients, the MIT researchers conducted a comprehensive analysis of 18 of the most commonly prescribed active ingredients (54 unique medications). They used the National Library of Medicine's Pillbox database, DailyMed, and the web resources of the manufacturers to learn more about inactive ingredients. The researchers found that greater than 90% of all oral medications contain at least one adverse reaction-associated inactive ingredient (ARAII) that can trigger an allergy or intolerance in sensitive patients. The authors identified 38 inactive ingredients that have been described as a trigger of allergic symptoms following oral exposure, either “through direct allergenic potential or through contamination introduced through these ingredients.”
Some of the most common inactive ingredients that act as allergens or can be contaminated with allergens include the following:
Colorants (brilliant blue, sunset yellow FCF, allura red)
Let’s discuss the first example, lactose, which is present in 45% of all oral drugs. This can be problematic since 75% of the world population is lactose intolerant. While the lactose content of a medication may be too low to elicit a reaction in one patient, it could significantly impact an individual with severe lactose intolerance. Moreover, it is important to note that even very low concentrations of specific allergens (i.e. submilligram range) can cause severe reactions.
Adverse reactions to excipients can range from life-threatening anaphylaxis to less severe but still bothersome reactions, such as abdominal pain or bloating. The researchers suggest that intolerance to inactive ingredients, such as gastrointestinal disturbances, are likely underestimated. Patients older than 65 years, almost one third of whom take five or more different medications each day, are especially vulnerable. Plus, these effects can become amplified if a patient takes multiple drugs or doses with ingredients to which they are sensitive.
What you can do
The U.S. Pharmacopeia (USP), which sets standards for medicine that are enforceable by the FDA, has guidelines for the labeling of inactive ingredients. These guidelines require manufacturers to disclose every single ingredient in all medications, including excipients. This information can be found on the package of a prescription drug or in the drug's package insert. For over-the-counter drugs, inactive ingredients must be listed on the outside of the box. Since you most likely receive your prescription medication in a pharmacy vial with no accompanying documents from the manufacturer, you may have to ask your pharmacist for the package insert to learn what excipients are used in your medication.
Another way to find out which excipients are in your medication is to type in the drug name on the website DailyMed. DailyMed is the official provider of FDA label information (package inserts) and has a searchable database of package inserts. However, these materials are written for healthcare professionals, not consumers. To simplify your search, skip to the section of the package insert titled "Description" to find the list of inactive ingredients.
It’s also important to note that the generic version of a drug may contain slightly different inactive ingredients than the brand name version. Thus, if you switch from brand name to generic and need to avoid a particular ingredient, read the generic label or ask your pharmacist, just to be safe.
Cassandra Pardini, PharmD, MPR, “Not so Inactive: Excipients in Medications May Trigger Adverse Reactions in Some Patients”, April 11, 2019
Troy Brown, RN, Medscape, “Inactive Ingredients in Medications Cause Trouble for Some”, March 14, 2019
Consumer Reports, “Q&A: How can I find out which ingredients are in a medication?”
Reker D, Blum SM, Steiger C, et al. Inactive ingredients in oral medications. Sci. Transl. Med. 13 March 2019; 483. DOI: 10.1126/scitranslmed.aau6753.
Inactive ingredients in pills and capsules may cause allergic, adverse reactions [news release]. Eurekalert! Web site. March 13, 2019. https://www.eurekalert.org/pub_releases/2019-03/bawh-iii030819.php Accessed March 20, 2019.