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.

After reviewing the literature, the study authors found that 38 inactive ingredients have been described as a trigger of allergic symptoms following oral exposure, either “through direct allergenic potential or through contamination introduced through these ingredients.”1 Table 2 lists the most common of these inactive ingredients. The study authors also discussed several inactive ingredients in greater detail in their review, which are summarized in Table 3.

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Additionally, the study revealed that 92.8% of all oral agents possess at least 1 potential allergen.1 “Viewed through the lens of the APIs, only 28% of active ingredients have at least 1 available formulation that avoids all of these potential allergens, and only 12% of APIs are free of inactive ingredients that have been reported to cause allergic reactions,” the study authors added. Although certain classes of medications have a higher likelihood of containing specific ARAIIs, it was found that there are often agents within a class that avoid those specific inactive ingredients.

In their review, the study authors also emphasized the importance of recognizing that patients’ tolerance levels for specific allergens may differ.1 For example, the lactose content of a medication may be too low to elicit a reaction in one patient, however, it could greatly impact an individual with severe lactose intolerance. Furthermore, it is important to note that severe reactions may be caused by very low concentrations of specific allergens (i.e., submilligram range).

During their study, the investigators not only reviewed inactive ingredients and their characteristics but also discussed allergies and intolerances associated with them.1 They emphasized that the selection of a medication should include a review of the formulation in addition to the API in order to prevent any adverse reactions. The study authors concluded, “Recognizing that the inactive portion of a medication, which corresponds on average to two-thirds of the administered material, may be more ‘active’ than previously anticipated, we foresee potential implications for medical protocols, regulatory sciences, and pharmaceutical development of oral medications.”

Table 1Allergy versus intolerance1

AllergyIntolerance
Symptoms• Urticaria
• Angioedema
• Bronchospasm
• Anaphylaxis
• Characterized by gastrointestinal symptoms
• Symptoms tend to be more benign compared to those of an allergy
Notes• Majority are type I hypersensitivity reactions mediated by immunoglobulin E
• Can cause severe reactions even at low doses
• Typical affect a larger population
• May lead to decreased adherence to drug regimens

Table 2Inactive ingredients that act as allergens or contaminated with allergens1

Inactive ingredientPercentage occurrence in medications
Lactose
44.82%
Corn Starch
36.54%
PEG 36.03%
Povidone35.80%
Carboxymethylcellulose21.38%
Gelatin16.93%
Brilliant blue14.47%
Sunset yellow FCF12.27%
Allura red11.20%
Propylene glycol11.14%

Table 3Common excipients1

Inactive ingredientNotes
Lactose• 75% of the world population is lactose intolerant
• Present in 45% of all oral drugs
• Content can be close to 600mg/pill
• Content may be too low to cause symptoms in most patients
 o Severe cases – may be affected by <200mg
• Not recognizing lactose content could lead to drug non-compliance or discontinuation
Peanut Oil• Up to 4% of the US population has a peanut allergy
• APIs with peanut oil must be avoided in patients with peanut allergies → decreased therapeutic opportunities
• Present in 100% of progesterone and 62.5% of valproic acid capsules
 o Valproic acid – some formulated with corn oil → safer for patients with peanut allergies
Gluten• Causes severe reactions in celiac disease patients, even at low doses (1.5mg/day)
• 18% of manufacturers state their drugs contain gluten
• 69% of manufacturers claim they have gluten-free products
 o Only 17% examined their products and could provide testing documentation
• FDA has suggested adding gluten content to labels
Chemical dyes (i.e., tartrazine)• 33% of medications possess ≥1 chemical dye
• Associated with severe atopic reactions, especially in patients with allergic or asthmatic conditions

References

  1. 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.
  2. 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.