Mast Cell Activation Syndrome and Excipients

Mast cell activation syndrome (MCAS) is a complex disease that I’ve previously written about at length. It’s a multi-faceted condition that can often be frustrating and difficult to manage for both the patient and the provider.

Mast cells are immune cells that function to help your body get rid of what they deem to be harmful compounds. In the presence of a harmful substance, the mast cells release mediators such as histamine, leukotrienes and prostaglandins which help your body to expel the invader.

However, in certain individuals, mast cells can be oversensitive and release large amounts of mediators in response to certain triggers. These include heat, cold, sunlight, certain medications, and certain foods, among other things. These reactions can cause a cascade of symptoms of varying severity, up to and including anaphylactic shock.

Treatment for MCAS involves identification and strict avoidance of your triggers, along with medication therapy and lifestyle changes. Medications that may help with the management of MCAS include H1 and H2 histamine blockers.

However, sometimes these changes alone aren’t enough to help you completely manage your MCAS. You may also struggle to identify what triggers your MCAS reactions.

MCAS is considered ‘idiopathic’ when triggers can’t be identified. If you’re struggling with idiopathic MCAS, this article will be of interest to you.

Common drugs known to trigger MCAS

  • Vancomycin is an antibiotic often used in C. Difficile treatment, which is known to cause ‘Red Man Syndrome’.
  • Morphine and other opiates, with fentanyl and Dilaudid being the opiates that are the most easily tolerated.
  • Aspirin and non-steroidal anti-inflammatories (NSIADS), like Motrin and Advil, are only sometimes a problem as in certain people they can actually act as mast cell inhibitors.
  • Angiotensin converting enzyme inhibitors, known as ACE inhibitors, are drugs used to treat hypertension and can increase bradykinin levels, which in turn activates mast cells.
  • Beta-blockers are used to treat hypertension, anxiety and tachycardia and lower the threshold for mast cell activation, interfering with the efficacy of epinephrine if this is needed for anaphylaxis. A glucagon pen can be used as an alternative if beta-blockers are necessary to treat other conditions.
  • Some local anesthetics, such as benzocaine, procaine, tetracaine, and chloroprocaine, can trigger mast cell activation, although lidocaine is usually well tolerated.
  • Some muscle relaxants like atracurium and succinylcholine can act as triggers, but vecuronium and pancuronium are usually well tolerated.

One relatively recent development in the treatment and management of MCAS involves considering drug and supplement excipients or inactive ingredients, rather than the actual drug itself. Drug formulations vary significantly between brands and there’s mounting evidence to suggest that many people with MCAS may have reactions to certain excipients found in their medications and/or supplements. The same drug or supplement made by different manufactures with different dyes, excipients, or fillers may provoke very different reactions in patients with MCAS. The active drug itself may not be the issue, but the excipients, dyes, and fillers may be the culprit.

In this article, you’ll learn:

  • What excipients are
  • How they can trigger mast cell responses
  • Some of the most common harmful excipients
  • How to tell if you’re having a reaction to an excipient
  • How to identify and avoid excipients that may worsen your MCAS

What are excipients?

Excipients are inactive ingredients found in over-the-counter and prescription medications, as well as in vaccines. These ingredients play a number of different roles in the proper delivery of the active ingredient to the body and many of these roles are absolutely necessary to facilitate the efficacy of the drug. (1)

In fact, most drugs are made mostly of excipients and the active ingredients represent only a small percentage of the drug by weight.

According to Dr. Jill Schofield of the Center for Multisystem Disease, excipients “are supposed to be ‘inert’ and ‘safe,’ but they may cause problematic reactivity in MCAS patients, including anaphylaxis.” (2)

Unfortunately, many excipients pose a risk of reactivity in people with MCAS, so it’s important to fully consider the impact of not only the active ingredients of a drug, but also its inactive ingredients when starting a new medication.

Types of excipients

There are over a thousand known drug excipients and the list grows almost daily, as researchers continue to develop new drugs and drug delivery systems.

Here are some of the main categories of excipients and their role in medications, according to Dr. Schofield:

  • Lubricants: These prevent pills from sticking together in storage, examples being silica and magnesium stearate
  • Binders and fillers: These provide volume to pills and bind ingredients together. Binders and fillers include cellulose and polyethylene glycol.
  • Coatings: These protect pills from damage, make them easier to swallow, and may provide ‘time-release’ or ‘extended-release’ function, examples being shellac and gelatin.
  • Dyes: As you’d expect, these alter the color of medications. Dyes used include FD&C red #5 and FD&C blue #2.
  • Flavourings: These alter the taste of the drug to mask bad-tasting ingredients and improve acceptance of the medication, especially in the case of children. Flavouring examples include sucralose and xylitol.
  • Preservatives:Substances such ascitric acid and retinol palmitate improve the shelf life of medications.

This is just a small sampling of some commonly used excipients. Not only are there hundreds more individual excipients, there are also many more categories of excipients that play different roles in medications.

How can excipients affect MCAS?

Dr. Schofield describes people with MCAS as “canaries in the coal mine.” If you’re unfamiliar with this turn of phrase, it refers to the canaries that were carried by miners deep into mines when they worked. If there were toxic levels of gases present in the mine, the canary would die well before the miners, serving as warning that they needed to get out of the mine.

People with MCAS, like the canaries in the coal mine, are profoundly more sensitive to the chemicals they’re exposed to than other people. Unfortunately, this means that many people with MCAS experience reactivity to one or more drug excipients. These reactions can manifest in the following ways:

  • Fatigue
  • Malaise
  • Gastrointestinal upset, such as abdominal pain, nausea, vomiting, or diarrhea
  • Skin rashes
  • Itchy skin
  • Hives
  • Headache
  • Anxiety
  • Flushing
  • Anaphylaxis
  • Headaches
  • Insomnia

However, this isn’t a complete list of symptoms of excipient reactivity. MCAS is such a complex and individualized disease and symptoms can differ vastly from person to person.

If you’ve been diagnosed with MCAS and have removed your known triggers but are still experiencing symptoms, it may be time to investigate drug and supplement excipients and how they may be affecting you.

What are some of the common harmful excipients?

Some of the most common excipients that people with MCAS are reactive to include alcohol, dyes, and povidone. In fact, according to Dr. Schofield, dyes and alcohol are a great starting point for determining excipient reactivity in MCAS patients, primarily because so many people are reactive to them.

Povidone

Povidone is an extremely common excipient, used as an ingredient in hundreds of drugs. (3) It’s a polymer that’s added to drugs to help disperse the active ingredient evenly throughout a liquid or powder solution. It’s also used as a binder and to help drugs in pill form disintegrate properly. It’s water-soluble, so it’s commonly used in liquid drug solutions as well as in tablets or capsules.

It’s an ingredient in betadine, an antiseptic iodine solution that’s used to prep the skin before medical procedures. According to Lawrence B. Afrin, M.D., if you’ve previously been diagnosed with a betadine allergy, it’s highly likely that you’re actually sensitive to povidone. (4) You see, iodine is absolutely vital for proper body functioning so it’s illogical, and emerging research suggests it’s impossible, to be allergic to iodine (5). Because the only ingredients in iodine solutions like betadine are often water, iodine, and povidone, and it’s highly unlikely that you are allergic to water or iodine, this leaves povidone as the likely culprit.

Dyes

Dyes are ubiquitous in medications, a very common MCAS trigger, and unfortunately serve no purpose beyond an aesthetic one.

Although you may find that you’re only sensitive to one or two dyes, it’s often best to avoid all FD&C dyes when possible. Ferric oxide red and yellow may be better tolerated by people with MCAS, according to Dr. Schofield.

You should note that even white tablets may contain dyes, so you’ll need to check the ingredient list for confirmation.Many drugs have dye-free formulations or, in the case of drugs in capsule form, you can discard the capsule. This is often the only portion of the drug containing the dye and you can then simply take the powder inside.

Alcohol

According to Dr. Schofield, alcohols are an extremely common trigger. They’re commonly added to liquid medications, IV medications, or topical medications, which are applied directly to the skin.

Alcohol has some antiseptic qualities, which is why it’s used to disinfect the skin prior to medical procedures, along with being used as the active ingredient in most hand sanitizers. It’s also used as a solvent, to help suspend the active ingredient evenly throughout a drug, and as a preservative, to extend the shelf life of a drug.

Luckily, tablet or capsule forms of alcohol-containing liquid or IV medications are often alcohol-free. This makes them a potential alternative that wouldn’t cause reactivity.

Although these are some of the most common excipients that MCAS sufferers may react to, theoretically you could have a reaction to any of the hundreds of excipients that are used in medications today. This is why an understanding of how to identify an excipient reaction is of the utmost importance for people with MCAS that suspect they have excipient triggers.

Adhesives

Many adhesives are based in glycerin, which is corn-derived. If people react to corn, they may have problems with standard adhesives. Standard tegaderm adhesive wound dressings may be replaced with Opsite 3000 and the IV 3000 line of adhesive products.

Another product is DuoDerm Extra Thin CGF Dressing. If adhesives can’t be used and a patient needs an IV line, this can be wrapped with guaze, on top of which tape is then fastened. All IV bags should be DEHO free to reduce the risks of mast cells reactions

How to tell if you’re reacting to an excipient

There are several ways to tell if you’re reacting to an excipient in a drug, according to Dr. Schofield.


First and foremost, you should suspect excipient reactivity if you have an unexpected reaction to a drug that you previously tolerated well. In this case, some questions you can ask are:

  • Did you get this from a different pharmacy than usual?
  • Is this drug from a different manufacturer than the one that was well tolerated?
  • Was there a risk for environmental contamination when this drug was compounded?

Next, you should suspect an excipient reaction if you have different reactions to two different medications that are in the same class of drug. For example, loratadine and fexofenadine are two over-the-counter antihistamines that function in similar ways to help manage allergies. If you react differently to these drugs, it may be because one contains an excipient that you’re reacting to.

Additionally, if you experience side effects that aren’t typical for a drug, these side effects may actually be a result of reactivity to one of the excipients in that particular formulation of the drug.

You should also consider an excipient reaction if you react to a drug or supplement within the first few doses of taking a new pill. 

Finally, if you’ve been diagnosed with multiple drug allergies or intolerances, you should strongly suspect excipient reactivity. Particularly if you’ve been diagnosed with an iodine or betadine allergy, this is a strong indicator that you may actually be sensitive to povidone. This is an excipient that’s commonly added to iodine solutions along with a variety of other medications, including those as seemingly harmless as over-the-counter pain medications.

Identifying and avoiding harmful excipients

Identification of excipients to which you’re sensitive will require collaboration between you, your physician, and your pharmacist.

According to Dr. Schofield, once you’re able to identify an excipient that you react to, it should be added to your allergy list. However, you shouldn’t add the medication in which it was found to that list, as it’s likely you’re only sensitive to the specific excipient and not the medication itself.

Luckily, due to the availability of different brands and formulations of drugs, it’s often easier than you expect to find a formulation of your needed medication that doesn’t contain any of your excipient triggers.

However, you’ll need to thoroughly review the ingredient list of all medications you’re prescribed, or purchased over-the-counter, to see if they include any excipients that you’re sensitive to. Dr. Schofield recommends using DailyMed, a service of the U.S. National Library of Medicine that provides detailed information about medication ingredients, including excipients.

You may need to get creative in your avoidance of your excipient triggers. For example, if the tablet form of a medication contains an excipient you’re sensitive to, check to see if there’s a capsule, liquid, or IV form that would be okay for you.

As I already mentioned, if you’re sensitive to dyes, you can often just discard the capsule that contains the dye and still use the powder inside the capsule. You can sprinkle it on top of yogurt or mix it into a drink.

If you find that you’re profoundly sensitive to a certain excipient, you may need to have your medications especially compounded in a ‘clean room’ that poses minimal risk for cross-contamination with your triggers. Your local compounding pharmacist should be intimately involved with the challenges of MCAS and the potential risks of excipient reactivity. Sourcing of the pure powder ingredient in a medication may be necessary. Compounding pharmacies should be accredited with their parent organization, the Pharmacy Compounding Accreditation Board (PCAB).Established in 2007 by eight of the nation’s leading pharmacy organizations, PCAB offers the most comprehensive compliance solution in the industry. This includes the combining, mixing, or altering of drug ingredients to create a medication pursuant to a prescription order for an individually identified patient.

In Canada, most of the compounding pharmacies will use microcrystalline cellulose, known as Avicel, as a filler. This compound is derived from wood pulp and contains strings of glucose molecules strung together. It’s commonly used a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production.The most common form is used in vitamin supplements or tablets or as an alternative binder in compounding medications. Some people may also not tolerate gelatin capsules and are given vegicaps as a substitute. These are composed of hypromellose, short for hydroxypropyl mMethylcellulose (HPMC), a substance that’s prepared from cellulose, which is the main polysaccharide and constituent of wood and all plant structures.

Additionally, excipients aren’t only found in medications. If you’re sensitive to an excipient, you’ll also need to check foods, supplements, cleaning products, cosmetics, and body care products to see if they contain any of your excipient triggers.

Please reach out to me or my team if you need help managing your MCAS or identifying potential triggers or excipient reactivity. My team is extremely experienced with the management of MCAS, and we can help you formulate a plan to identify your potential triggers and remove them so that you can have some relief.

References:

  1. Abrantes CG, Duarte D, Reis CP. An Overview of Pharmaceutical Excipients: Safe or Not Safe? J Pharm Sci. 2016;105(7):2019‐2026. doi:10.1016/j.xphs.2016.03.019 Abstract: https://pubmed.ncbi.nlm.nih.gov/27262205/
  2. Schofield J. The Problem of Excipient Reactivity in MCAS Patients. Lecture from The Center for Multisystem Disease, n.d.
  3. National Center for Biotechnology Information. PubChem Database. Povidone, CID=131751496, https://pubchem.ncbi.nlm.nih.gov/compound/povidone (accessed on May 31, 2020)
  4. Afrin LB. Re: [MASTerMinds] Precautions for Oral Surgeons doing Wisdom tooth extractions in CCI patients? #cci #mcas #dental. Email communication from MASTerMinds listserv. 2020 May 8.
  5. Dewachter P, Mouton-Faivre C. Allergie aux médicaments et aliments iodés : la séquence allergénique n’est pas l’iode [Allergy to iodinated drugs and to foods rich in iodine: Iodine is not the allergenic determinant]. Presse Med. 2015;44(11):1136‐1145. doi:10.1016/j.lpm.2014.12.008

5 thoughts on “Mast Cell Activation Syndrome and Excipients”

  1. Thank you for this very helpful information. It explains why I have to stick to certain brands of Generic prescription medications. I would love to find a doctor near Charlotte, NC that understands and treats Mastocytosis as my PCP told me: “It is a rare disease and there is no treatment for it, so what do you want me to do?” She is unwilling/uninterested (maybe has no scientific curiosity) despite my providing her with research and data) . I found a wonderful Walmart Pharmacist who is very willing to work with me and orders the specific meds I need. I will share this with her. If you know of any physicians who are in my area please let me know,
    Susan S. Jay PhD., RN (Retired/76 years old)

    Reply

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