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.

This article originally appeared on MPR