August 5, 2020
Inactive Drug Additives May Have Unwarranted Effects
Vector illustrations of pharmacists at workSource: Envato Elements
Inactive ingredients are a common staple of prescription medications. Often, they’re pretty harmless additives, like water, salt, or table sugar.
But some inactive ingredients may not be so inactive after all. A press release published by the National Institutes of Health yesterday says some inactive ingredients display biological activity, including “inflammation-related properties.”
“Inactive ingredients are approved by the FDA and considered to be safe,” the NIH says. “Some have been used for decades in medicines based on these tests. However, technologies for studying the biological activity of drugs have greatly advanced over the years.”
An inactive ingredient may be safe in relation to the medication’s dose, but not as safe when taken in larger quantities, the NIH explains.
This is a concern for those who take multiple daily medications. And according to a 2013 MayoClinic Journal study, about 70 percent of Americans are on at least one prescription drug. Half of the country is on two prescriptions.
To explore the safety of inactive prescription ingredients, researchers screened 639 of them for potential biological activity at over 3,000 human targets.
The team was led by Dr. Brian K. Shoicet at the University of California and Dr. Laszlo Urban at the Novartis Institutes for Biomedical Research. Together, they found 38 inactive ingredients with potential for biological activity.
“They chose those that are most frequently used in medicines and would cover a wide variety of purposes as drug additives,” the NIH explains. “Seven compounds showed some biological activity, such as inflammation-related properties.”
Five out of seven of the compounds were concentrated at blood volumes too low to become active at their predicted targets.
“However, two compounds could reach high enough concentrations to potentially activate their predicted biological targets,” the NIH says. “Excipients that are injected directly into the body also showed biological activity.”
Their results justify further research on whether the potentially active “inactive ingredients” have any unanticipated side effects in people. Research is also needed to determine how much of the inactive ingredients need to be taken in order to produce side effects.
“These data illustrate that while many excipient molecules are in fact inert, a good number may have previously unappreciated effects on human proteins known to play an important role in health and disease,” Shoichet says. “We demonstrate an approach by which drug makers could in the future evaluate the excipients used in their formulations, and replace biologically active compounds with equivalent molecules that are truly inactive.”
Adverse Reactions to Inactive Ingredients
According to a 2020 PLOS One Journal review, there are only 17 case reports of adverse events related to inactive ingredients documented in literature.
These adverse events include injection site reactions, anaphylaxis, high blood sugar, and acute kidney failure.
For their review, the researchers focused on the three largest classes of inactive ingredients: surfactants, sugars and polyols, and preservatives.
Then, they honed in on specific reactions to ingredients in these three categories.
“Of the 17 case reports found, six were due to an adverse effect to a surfactant,” the review says. Polysorbate 80 and polysorbate 20 — common scientific, cosmetic, and food ingredients — caused injection site reactions and anaphylaxis in multiple people.
There were 10 case reports of adverse reactions to inactive ingredients in the sugar and polyols category. Four of them were due to sucrose, four were due to mannitol, one was due to alpha-gal, and the other was due to lactose.
Three of the cases resulted in acute kidney failure due to significant amounts of sucrose in the IV immunoglobulin formula.
Two cases involved patients with type 2 diabetes who developed high blood sugar after exposure to high concentrations to the inactive sucrose-based ingredient.
Mannitol also caused a tolerable rash or anaphylaxis in a few patients.
The final case found was due to zinc, which is in the preservatives category of inactive ingredients. It had cause a “generalized allergy” in an 11-year-old boy with type 1 diabetes who was treated with an insulin pump.
“Considering the chemical instability of these ingredients, the high prevalence of use, and their varying concentrations, clinicians should be informed about the potential adverse events in some patients for biologics containing these excipients,” the review says. “Although data on the clinical effects of these compounds is limited, we have enough examples to support the importance of increasing clinical awareness on the potential of some excipients to have serious consequences in certain patients.”
What Does All of This Mean
Both studies demonstrate the importance of diving deeper into the seemingly harmless inactive ingredients abundant in prescriptions and other products.
While these inactive ingredients have been tested in animals and some have withstood the test of time among the general population, there are exceptional cases.
At the very least, doctors should be informed of the potential risks associated with some inactive ingredients.
They also need to be made aware of what might put someone at higher risk of having an adverse reaction. For example, someone with type 2 diabetes is understandably at an increased risk when taking a prescription that has sugars or polyols in it.
“With the rapidly expanding biopharmaceutical market, adverse drug reactions to biological products will continue to be a growing concern,” the PLOS One review concludes. “These adverse event occurrences are often not described in literature and further analysis to include adverse effects beyond case reports is warranted.”
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