An oral drug product contains both the active pharmaceutical ingredient (API) as well as a mixture of inactive ingredients, or excipients.1 Inactive ingredients are used to alter the physical properties of a medication, while the API is intended to produce the desired pharmaceutical effect of the agent. Excipients may be added to a medication to improve absorption, alter taste, increase stability, or render the medication tamper resistant.
Although there are thousands of known inactive ingredients that have been tested and have established safety at the population level, numerous case reports have been published suggesting some excipients may cause adverse reactions in some patients.2 Because of this, a team of investigators from both Brigham and Women’s Hospital and the Massachusetts Institute of Technology analyzed data on thousands of inactive ingredients in approved medications to further characterize them and enhance our knowledge of their safety.
During their analysis, the study authors found that inactive ingredients account for the majority of an oral medication.1 In fact, when analyzing the most frequently prescribed oral agents, it was found that the inactive ingredient portion of the medication typically accounted for 75 ± 26% of the total mass of the product. Furthermore, data analysis showed that 41.3% of all drug products contain >250mg of inactive ingredients. The study authors added, “Such doses are further multiplied by polypharmacy (simultaneous usage of multiple medications), which is particularly prevalent in older adults.” It is also important to note that information regarding the mass content of individual inactive ingredients contained in an agent is not typically accessible to patients or healthcare providers.
In their review, the study authors also highlighted the complexity of the formulation landscape due to the number of inactive ingredients contained in one oral drug product as well as the diversity of available formulations of the same API.1,2 Using the Pillbox database, which includes information on 42,052 oral medications with 354,597 inactive ingredients, the investigators determined that the average oral drug product contains 8.8 excipients.1 Data analysis also found that there is an average of 82.5 formulations per API available for the top 18 most prescribed oral drug products in the United States. “Varying numbers of included inactive ingredients in such formulations indicate that different commercially available versions of medications can contain different excipient mixtures,” the study authors stated.
Although inactive ingredients enhance a drug product’s physical properties and have been deemed safe, clinical reports documenting adverse reactions caused by excipients have been increasing.1 In fact, during their study, the team of investigators found that >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.1,2 Table 1 summarizes the symptoms and characteristics of allergies and intolerances associated with inactive ingredients.