Friday, May 5, 2017

Excipient Recipient: Mast Cell Reactions To Excipients

Patients with Mast Cell Disease and its related conditions are obviously on the severe end of the spectrum if considering the addition of intravenous infusions to their treatment regimen. It becomes disheartening when the last resort options prove to be a failure. Treatments for the disease are not always effective. They are obscure and the risks are significant. What gives? Shouldn't the benefits be just as immense?

Severe forms of the disease present the perplexing phenomena of reacting to excipients in the medications and the ingredients that compose the infusion supplies. Excipients are "usually inert substances." They are added to medications, saline, or supplies to provide stability and substance.


Frequently, the therapies are not a total fail. There is great potential in receiving treatments, but reactions to the excipients prevent desired improvements.

Excipients are a topic of discussion in the Facebook group that I moderate, IV Therapies For Mast Cell Disease + Related Conditions. This post is meant to serve as clarification.

For medical references outside of patient experience, Pharmacological treatment options for mast cell activation disease has valuable information regarding excipients.

Medications

Oral / PO Form

Before resorting to, or in combination with IV therapies, miscellaneous medications by mouth or through feeding tube are attempted.

Histamine (H1 and H2) blockers are a must in the treatment of Mast Cell Disease. The non-drowsy, second generation antihistamines are preferred. These medications are commonly purchased over the counter at a local drug store because they are intended to use in the treatment of allergies, but many are prescription too.

Along with the active drug ingredient, medications in PO form contain a plethora of inactive excipient ingredients. They include dyes, fillers, and preservatives.

Reasons for excipients/inactive ingredients: 

  • Aesthetic 
Whether a bright red liquid suspicion or a florescent pink pill, medication manufactures like to believe that dyes make their products look visibly appealing. Excipients are added to change the appearance of the medication.

  • Preservation
Preservative ingredients increase the shelf life of medications. It is inconvenient to replace a medication every few days. Preservatives allow a medications to last months to over a year!

  • Substance 
Medications under a certain dose require filler ingredients that provide enough powder to physically scoop the medication into a capsule or to form it into a pill.

Medications frequently do not work like they should in sensitive patients because of varying reactions to excipients. Just as someone with a Mast Cell Disease would not ingest a reaction inducing packaged cookie that is laden with preservatives or consume a hot dog soaked in nitrates, one would want to avoid the "bad stuff" in medications also.

Cetirizine (Zyrtec) is an OTC (over the counter) example.
10 mg of pure Cetirizine (Zyrtec) is too minuscule to be a stand alone ingredient. Various forms of cellulose gives it bulk to form a pill. Yellow iron oxide colors the pill. Silicon dioxide prevents clumping. 
The above ingredients is approved safe for consumption in the normal population, but it is not conducive to chemically sensitive patients with Mast Cell Disease.  
There is a recourse to the toxic medications at the pharmacy or purchased in a store. Special compounding pharmacies have the ability to compound medications, omitting the unnecessary ingredient in medications and substituting them with safer options.

Compounding Ideas

Compounding medications is still trial and error, but it is superior to the alternative.

  • Sterile water
Compounding with sterile water in a liquid solution is preferable if the drug is available in a liquid form. Medications compounded in sterile water typically require refrigeration. Depending on the active ingredient, the solution does not remain stable longer than a couple of weeks.

  • Pure powder 
There is no need for additional ingredients, aside from the pure powder, if the medication is equal to or exceeding 50 milligrams. The pure powder must be placed in a vessel of some sort.

Capsule: The pure drug can be put into a safe, vegetable capsule. If the tolerance of a capsule is unknown, try dumping the powder out of the capsule and into a glass of water to drink.

Parchment: An unsafe capsule can contaminate the pure drug powder in extremely sensitive individuals. To avoid reactions, the pure drug powder can be put into parchment paper until the patient is ready to mix the powder into a glass of water to administer.

  • Sugars or Flours
For smaller milligram doses, the pharmacist can substitute excipients with safe food ingredients. Sugars or flour provides a powder substance to combine with the medication, ensuring there is enough substance to make a pill or to put into a capsule.

Examples of sugar/flour fillers are: cane sugar, palm sugar, all purpose flour, rice flour, oat flour, chickpea flour, spelt flour, buckwheat flour, coconut flour, almond flour, sorghum flour.

  • Avicel
The sole ingredient in Avicel is microcrystalline cellulose. For some patients, it is a safe compounding option.

  • Elemental Formula
Elemental formula is a nutritional, powdered formula designed for patients with severe food allergies. Recently, I was made aware that Neocate and/or Elecare can be used in compounding. 

The options are endless with a willing, understanding compounding pharmacist. Tolerating a medication may be the difference of altering one ingredient. For example:
"patients who react to wood-based microcrystalline cellulose might tolerate cotton-based microcrystalline cellulose without any difficulty at all, or vice versa." [ x ]
Intravenous / IV 

Intravenous medications do not necessarily contain the same fillers as their PO counterparts. They do have excipients deriving from preservatives and other contaminates though.

As previously expressed, very rarely is the patient reacting to the active ingredient in their medications. The reactions are likely from excipients. Do not rule a medication as ineffective until it is obtained in a completely preservative free form.

Benadryl (Diphenhydramine)

Mast Cell Disease patients frequently experience this predicament when seeking intravenous Benadryl (Diphenhydramine). The severely afflicted might notice that the Benadryl (Diphenhydramine) is not relieving symptoms. In all actuality, they become significantly worse after administering the medication until the active ingredient partially quells the reaction.

The described situation is distressing. Trialling various brands of intravenous Benadryl (Diphenhydramine) can help determine the cause of reactions. Not every IV Benadryl (Diphenhydramine) is the same, preservative free or not,  as they each undergo various processes in manufacturing. [ x ]

  • Westward
Benadryl (Diphenhydramine) produced by Westward is not preservative free. 

From personal experience, Westward Benadryl causes adverse reactions. My neurological symptoms increase with minuscule amounts of the medication, with strange head sensations accompanied by flashing lights in vision, tachycardia, and flushing. 

  • APP / Fresinus 
APP, which has now been bought out by Fresinus, manufactures preservative free intravenous Benadryl (Diphenhydramine). This is the brand I do best with.  


Intravenous medications undergo a rigorous analysis to ensure the product meets specifications for impurities.
Analysis for APP/Fresenius Diphenhydramine (Benadryl)
  • Hospira
Hospira is the "cleanest" brand of Benadryl (Diphenhydramine) in terms of excipients. 

The majority of patients do use this brand. However, there are always exceptions to the rule. I am one of them. Upon administering Hospira, I immediately began flushing, tachycardia, "locked-in syndrome" where I lost the ability to speak, and respiratory symptoms. A dose of APP Benadryl (Diphenhydramine) eventually settled the reaction. 

Reactions to excipients do not have to entail a life threatening reaction. They can consist of minor symptoms. Take the Continuous diphenhydramine infusion and imatinib for KIT-D816V-negative mast cell activation syndrome: a case report for example:
"She also had nausea and vomiting, probably due to the excipients (preservatives) in the CDI preparation. The diphenhydramine most likely helped control the dysfunctional mast cells, whereas some excipient simultaneously aggravated the dysfunctional mast cells." 
While impurities are minimal and deemed safe for humans, these subtle differences between the brands of intravenous Diphenhydramine (Benadryl) can cause reactions in a patient with a Mast Cell Disease. Just like no two brands of Diphenhydramine (Benadryl) are the same, no two patients are the same either.

Supplies

Various medical supplies are used in care: IV bags, syringes, IV tubings, oxygen tubings, enteral feeding bags, and more. As if excipients in medications are not difficult enough to manage, reactions are also caused by specific infusion and enteral (tube feeding) supplies because of how they are made,  thus contaminating the infusion.

Plastics

Pinpointing the exact trigger in the medical supplies is an arduous task. It could be ANYTHING. However, in my case the culprit is usually a plastic that leeches into the infusion.

  • DEHP
DEHP is a type of plastic. It is not supposed to be found in products in amounts harmful to humans, but mast cells are finicky. They do not care about that. Eliminating DEHP was a huge game changer. I no longer felt like I was reacting to my IV therapies, like the continuous Benadryl infusion, once I switched to products that did not contained DEHP.

Read Scientific Facts on Diethylhexyl phthalate by GreenFacts.

B. Braun makes products free of DEHP. They have (2) IV bags that are DEHP and latex free: L8000 and E8000. The latter is what I use. The post, Contaminates Be Gone, Thank You B.Braun discusses their products.

  • Latex 
Latex is a common allergen, so it is not as prevalent in medical supplies as it once was. There is the rare occasion it is in intravenous bags, syringes, and tubings. It is advisable to avoid if possible, as it does have allergenic properties. 

Lubricants

Another probable excipient is the lubrication in syringes. The black, rubber stoppers in syringes are lubricated for easier gliding when drawing up water or medications.

The lubrication is especially a problem in enteral supplies, like feeding tubes. Coviden syringes are better tolerated than when I flush my feeding tube with BD syringes. Thoroughly rinsing with hot water helps lessen the amount of lubricant on the syringe.

Mast Cell Disease is tricky. There is no concise answer as to what treatment is optimal. Eliminating triggering excipients is a good starting point though.