Steve Plogsted

Cross-Contamination in Gluten-Free Medications

I was receiving a prescription generic medication and was having no problems with it. With my last refill, I received another company’s brand. After taking the medication for a couple of doses, it felt as though I received some gluten. I checked with the drug manufacturer and was told that they do not use any gluten in the manufacturing of that medication. Both my previous brand and the current brand have similar fillers, including some cornstarch. Is it possible that there was some cross-contamination that occurred in the new drug?

There is no standard for gluten levels in medications like there are in food. If a drug company did test its products, the lowest level of detection is 3 parts per million (ppm), and it is known that people can adversely react to gluten with levels as low as 1 ppm. As you are aware, the standard for the food industry is <20 ppm. The Food and Drug Administration (FDA) has stated that wheat, barley or rye are rarely, if ever, used in drug products. It has further stated that if any cross-contamination did occur, it would likely be undetectable. Does this mean that there was no gluten in the new medication? The answer is no; there could be a miniscule amount, and there would be no way to detect that small amount. When you compare this information to what is available for food, you can see that even guaranteed gluten-free food could have levels of gluten high enough to cause an unwanted reaction. Since your medication contained cornstarch, there is a small chance of gluten contamination. Products that contain no grain derivatives lower that chance even further.

What kind of precautions do drug companies employ to minimize the chance of cross-contamination when manufacturing their medications?

There are several engineering controls that drug manufacturers employ, and these apply to drugs manufactured both in the United States and manufacturing facilities in foreign countries that sell their drugs in the U.S. market. They are required to employ systems that minimize the degree of cross-contamination, with building and facilities designed so that the operations performed within do not contribute to an actual or potential contamination. These pharmaceutical drug manufacturers have very defined cleaning procedures that remove any contaminants between batch runs to ensure quality.

Besides my celiac disease, I also have a lactose intolerance. Is there lactose in prescription medications?

Lactose is commonly used as a filler in many drug products. The amount depends on both the type of the drugs and the size of the tablet or capsule. Larger-sized drug products could easily have as much as 120 mg per tablet, the same amount of lactose as in approximately 2 ounces of cheddar cheese. If you don’t have issues with low levels of lactose-containing foods, you are unlikely to have any issues with certain lactose-containing medications.

Steve Plogsted, a pharmacist at Nationwide Children’s Hospital in Columbus, Ohio, is an expert on gluten in medications. His website, glutenfreedrugs.com, is widely recognized as the most reliable source of information on gluten-free prescription and over-the-counter drugs. Have a question about gluten and medications? Send it to [email protected].

Symptoms After Taking Gluten-Free Medications

While I was vacationing in Canada, I fell ill and required an antibiotic. I found that the drug they prescribed me was available in both the U.S. and Canada. I called the U.S. manufacturer and was told that it contained no gluten. Do U.S. and Canadian drugs use the same ingredients and would it be safe for me to take the drug that I had filled in Canada?

You ask a very good question. It just so happens that you cannot rely on the fact that two drugs with the same name or same manufacturer, when made in different countries, will have the same ingredients. I found this out on a drug called cefalexin. The one made in the U.S. used cornstarch, but the Canadian version from the exact same manufacturer contained wheat starch. Please note that this situation is not the same as when purchasing a drug in the U.S. that was manufactured in a foreign country. All drugs manufactured for sale in the U.S. that are made in a foreign manufacturing facility must comply with all U.S. regulations as though they were manufactured in the U.S.

I take a particular oral contraceptive, and it seems like every time I get to the last few days of the pill pack I feel sick. Is this just a reaction to an accumulation of gluten?

No. You are probably taking medication for a package that contains 28 tablets. The first 21 tablets are the active drug, and the last seven contain iron. My suspicion is that you are reacting to the iron, which has a tendency to upset the gut.

I have been taking an antibiotic for Lyme disease, and when I called the manufacturer, I was told that the product contains gluten, but I can’t find the source when I looked into the ingredients. Can you help me figure this out since I am experiencing gluten consumption-like symptoms?

I looked into the product and saw that in addition to the cornstarch and potato starch, it contains polyethylene glycol. Glycols are produced through a manufacturing process on a substance called ethylene glycol, which could have been derived from a wheat starch source. Just like in the case of sugar alcohols, the manufacturing process is so thorough that it removes all traces of the gluten protein, rendering it gluten free.

As far as the gluten-like symptoms you are experiencing, it is most likely due to the characteristic of the drug itself. Clarithromycin is very similar to azithromycin, and both can cause a direct stimulation of the gut, resulting in symptoms such as cramps and/or diarrhea. This will subside within a few days of stopping the medication. I know that when speaking with the drug companies, it can be very frustrating, especially if you are told that the medication you are interested in contains gluten. If this occurs, be very persistent in asking exactly which ingredient (or ingredients) are the source of gluten. This information is available to them, so if they can’t answer you immediately, have them call you back. Once you get their answer, do a little research on your own, and you will almost certainly discover that the so-called gluten is no more than a sugar alcohol or polyol, which are gluten free. Just like the polyethylene glycol, the polyols could have been derived from a wheat source but are so thoroughly processed that no gluten protein remains.

Do you know if triamcinolone cream 0.1% is gluten free?

All prescription topical medications are gluten free.

FDA Issues Guidance On Labeling Gluten-Free Medications

Q: I get very frustrated when I ask my pharmacist or physician if a medication I am prescribed contains gluten. Nobody seems to know the answer or where to find it. Can’t the federal government help this situation?

A: Our celiac community received some important help from the government. On Dec. 12, 2017, the FDA issued guidance to drug manufacturers on voluntarily labeling medications to state that no known gluten-containing ingredients were used in their product. This effort has been ongoing since 2015, when Rep. Tim Ryan (D-Ohio) introduced legislation to Congress. His persistent efforts, along with those of other experts and stakeholders in the celiac community, paid off.

Although this legislation asks for voluntary compliance for now, it could lead to more mandatory labeling in the future. I am particularly excited because Congressman Ryan’s office has contacted me to provide them with some background information on gluten in medications. This legislation also addresses the sugar alcohol issue. Sugar alcohols, or polyols, are substances used as sugar substitutes in food products. Some manufacturers categorically state that their drug product contains gluten simply due to the presence of one of these sugar alcohols. While sugar alcohols could be derived from a wheat source, the gluten protein is removed during the manufacturing process. The major celiac organizations do not recommend avoiding these sugar alcohols.

Since there is no official definition of gluten free in drug products, this is the best they can do at this time. You can read the legislation at http://bit.ly/2CzPCug.

For more of Steve Plogsted’s advice and information on gluten-free medications, read these past Q&As:

To read resident dietitian Amy Keller’s advice on following and thriving on the gluten-free diet, check out these Q&As:

Gluten in Immunoglobulin Therapy

Q: I have celiac and am also being treated for myasthenia gravis. My physician wants to start me on immunoglobulin therapy and told me that it was “mostly gluten free.” Of course, I am concerned, and I can’t seem to find any answers.

A: Rest assured, this treatment is fine for people with celiac. There are numerous brands of immunoglobulin therapy currently on the market, but they share many of the same characteristics. There are two important issues to remember when using these products: none of them contain any gluten material, and for you to experience a gluten reaction, the gluten must first be absorbed through the gut. As a side note, no intravenous products currently only the market contain any form of gluten.

To read more of Steve Plogsted’s advice and information on gluten-free medications, read these past Q&As:

To read resident dietitian Amy Keller’s advice on following and thriving on the gluten-free diet, check out these Q&As:

Preventing Gluten Cross-Contamination in Medications

Q: What steps are taken to minimize or prevent cross-contamination in a pharmaceutical manufacturing facility?

A: There are numerous requirements and precautions employed by any pharmaceutical manufacturer who plans to sell their product in the U.S. market. This includes plants in other countries that manufacture for a U.S. distributor. They must maintain the same standards and are required to undergo examination by a U.S. Food and Drug Administration (FDA) inspector. People who work with the drug products wear suits similar to what you might see in an operating room. All facilities and production procedures must be approved by the FDA. Here are excerpts from the FDA manual on manufacturing practices:

“All utilities that could affect product quality (e.g., steam, gas, compressed air, heating, ventilation and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available. Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimize risks of contamination and cross-contamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust humidity and temperature, as appropriate to the stage of manufacture.

“Particular attention should be given to areas where APIs [active pharmaceutical ingredients] are exposed to the environment. If air is recirculated to production areas, appropriate measures should be taken to control risks of contamination and cross-contamination. Permanently installed pipework should be appropriately identified. This can be accomplished by identifying individual lines, documentation, computer control systems or alternative means.

“Pipework should be located to avoid risks of contamination of the intermediate or API. Drains should be of adequate size and should be provided with an air break or a suitable device to prevent back-siphonage, when appropriate. Equipment should be constructed so that surfaces that contact raw materials do not alter quality of the intermediates and APIs beyond the official or other established specifications. Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination.”

The manufacturers predominantly use materials that are easy to clean and sterilize, such as stainless steel, and employ specific cleaning processes. I spoke with a generic drug manufacturer and learned that a precise cleaning and sterilization procedure is used in a production room where a single drug product is manufactured. If more than one type of drug product is produced in that room, additional cleaning steps are employed, and the room is quarantined until the results are thoroughly evaluated. The cleanliness and sterility of these facilities is a crucial point of emphasis.

Confusion About Gluten in Medications

Q: Is a drug that is considered gluten free in the United States also considered gluten free in Canada?

A: The simple answer is that you should not apply information obtained from U.S. manufacturers to any foreign-manufactured drug product if that product was intended for the foreign market. For example, I called a drug company about the antibiotic cephalexin. The U.S. version used cornstarch whereas the Canadian product used wheat. This does not mean that a drug product produced in a foreign country and sold in the U.S. is unsafe. All prescription drug products for the U.S. market must meet all of the stringent standards applied to U.S.-manufactured drugs. The foreign facility is routinely monitored and inspected by employees of the U.S. Food and Drug Administration (FDA). Paperwork, production lines and all other quality assurance requirements are monitored and enforced by the FDA.

Q: Some companies have told me that their product contains gluten not from a starch but, rather, from a sugar alcohol. What exactly is a sugar alcohol?

A: As you know, gluten is obtained from certain starches or starch derivatives. Sugar alcohols are also known as polyols because they are not true sugars or alcohols; they are carbohydrates. Because they are not sugars, products that rely on these polyols are labeled sugar free. Some examples of polyols are xylitol, maltitol, sorbitol, mannitol, lactitol, isomalt, erythritol and polydextrose. The body metabolizes them in a slightly different manner compared to a traditional sugar, and therefore they are safer for people with diabetes. These polyols can be obtained from many starches. There are a number of steps involved in purifying these polyols from their starch source, which results in the removal of the protein responsible for the gluten reaction (when wheat, barley or rye is used as the starch source). Certain drug manufacturers do not care that the polyol is purified; they only look at the original source and therefore label their product as containing gluten. This same principle applies to wheat-derived glucose, which MAY be used in producing gummy vitamins, or wheat-derived dextrin, which can be found in medications and other products, such as Benefiber. A 2004 study demonstrated that celiac patients who consumed products from wheat glucose experienced no adverse reactions. In 2011, Tricia Thompson, MS, RD, nutrition consultant and founder of Gluten Free Watchdog, LLC, addressed wheat dextrin in one of her newsletters, writing that wheat-derived dextrin products should be safe. This is not to say that any person with celiac should totally disregard these concerns but, rather, consider all of these facts when deciding whether to take a product that contains a wheat-based polyol or glucose.

Generic vs. brand-name: How do they differ?

Steve Plogsted, a pharmacist at Columbus Children’s Hospital, is an expert on gluten in medications. His website, glutenfreedrugs.com, is widely recognized as the most reliable source of information on prescription and over-the-counter drugs. Have a question about gluten and medications? Send it to [email protected].

A patient recently asked me the difference between a branded drug product and a generic one. First, a generic drug must have the same active ingredient(s) as the branded drug. According to the U.S. Food and Drug Administration (FDA), the generic drug must also meet certain other requirements in areas such as drug dissolution time, absorption, distribution and elimination from the body. In other words, the generic drug must meet the same standards of quality as the branded drug. The production facilities that manufacture generic products are subject to the same inspections as the brand-name companies and must demonstrate all of the quality control steps required by the FDA. Of course, lower cost is a major benefit that generic drugs have over their brand-name counterparts. The Congressional Budget Office estimates that generic drugs save consumer $8 billion to $10 billion dollars a year at the retail pharmacy level and billions more at the hospital level.

Figuring out fillers
Generic and branded drugs differ in the use of excipients, or fillers. Generic equivalents do not have to contain the same excipients as their branded counterparts, which can result in issues for a patient who has some form of gluten intolerance.

The FDA defines an excipient as any inactive ingredient that is intentionally added to therapeutic products and not intended to exert any therapeutic effects on the intended dosage, although they may improve product delivery. Examples of excipients used as diluents include all types of starches, lactose, maltodextrin, dextrins, dextrates, sugars and sugar alcohols such as mannitol, sorbitol, maltitol and cellulose derivatives. Many of these also serve as tablet and capsule binders.

Other ingredients, called lubricants, allow the powders to flow smoothly by decreasing the friction between ingredients. Examples include the various stearates, mineral oil, some starches, talc and even vegetable oil. The colorings seen in the drug products are the food dyes FD&C reds and yellows, iron oxides (rust), titanium dioxide and fruit extracts. Some drug products require that the active ingredient be suspended in a liquid or the liquid have differing viscosities, which may entail the use of pectin, guar gum, xanthan gum, cellulose, gelatin or even differing starches. Coatings used in both capsules and tablets can be in the form of wax, shellac, gelatin, starch, titanium dioxide or other polymers.

Although several other types of excipients have not been mentioned here, all excipients have been deemed safe for human use by the FDA, meaning they are not likely to result in harm to the general public. However, this does not mean that certain excipients don’t pose a danger to individuals with conditions such as celiac disease or gluten intolerance. The FDA has never mandated that drug manufacturers test for the presence of gluten or even disclose in their literature the potential for gluten contamination.

Generic drugs from other countries

Another question I often receive is in regards to generic drugs manufactured in a foreign country. Here again the FDA mandates that any drug produced in a foreign country intended for legal sale in the U.S. must follow the exact same procedures as the U.S.-based companies and be inspected regularly by agents of the FDA. Such plants must maintain the same level of quality control that they would if they were based in the U.S.

Ever-changing products

Consumers face a major challenge when it comes to knowing which manufacturer’s product they will receive with each prescription fill and whether that product is safe for a person with gluten intolerance. Consumers who fill their prescriptions by a local pharmacy have a little easier time because they can inspect the product prior to taking it home. This gives them the opportunity to check a product’s status to make sure it is safe for people on the gluten-free diet. Most states’ boards of health do not allow the pharmacy to accept a returned medication once it leaves the pharmacy. Consumers who use a mail-order pharmacy service have limited options to ensure that they receive a gluten-free product.

Generic products are considered as safe and effective as the brand-name product and will likely save the consumer a significant amount of money in the long run. However, the consumer needs to be aware that their product could change from month to month depending on what is stocked at the pharmacy’s wholesaler. Don’t be afraid to ask you pharmacy to order the generic product that has worked for you in the past.

Gluten in Supplements, Probiotics and Medications

Q: I was interested in a gummy vitamin supplement, and during my search I came across a product that listed wheat as one of the ingredients. I was under the impression that gummy vitamins are generally gluten free. Can you explain this issue?

A: Vitamin E is a potential source of gluten in any gummy vitamin because it can be made from wheat germ, a potential source of gluten contamination. Unfortunately, some manufacturers label their product as containing wheat because the glucose used to give the product that gummy texture could have been derived from a wheat source and because of The Food Allergen Labeling and Consumer Protection Act. Glucose produced from a wheat source is considered safe for people with celiac disease, but manufacturers are trying to protect themselves. A simple call to the manufacturer should provide you with the answer. If the manufacturer says that the wheat is derived from vitamin E, it is best to avoid that product unless they can explain to you how the vitamin E was produced.

Q: I was reading all of the controversy surrounding gluten in probiotics, and I just don’t know what to do or who to believe. Do you know of any probiotic that I can really trust?

A: I recently attended a professional meeting and had the opportunity to speak with the manufacturer of the probiotic Florajen3. The product contains rice maltodextrin and is free of all allergens and dairy. The company does extensive testing for the presence of gluten and other contaminants. I am not recommending the product but providing you a gluten-free option to consider if you choose to take a probiotic.

Q: I have been taking Cytomel for my thyroid condition. I recently called the company that manufacturers it and was told that it could contain gluten. I can’t do without this medication. Can you help me?

A: Several manufacturers make a generic substitute for Cytomel. Ask your physician if switching to one of the generics is a viable option for you. Interestingly, although the manufacturer of Cytomel is telling people that it won’t disclose the source of the starch in Cytomel, it publishes a Material Safety Data Sheet, a document mandated by the Federal Occupational Safety and Health Administration that lists the ingredients of its product. This document, last revised on May 16, 2016, includes sugar, cornstarch, calcium sulfate, stearic acid and gelatin in the list of ingredients, with no mention of wheat.

Q: Can you tell me what the ingredient sodium starch glycolate is and whether it is safe for people with celiac disease?

A: Sodium starch glycolate (SSG) helps medications dissolve upon exposure to water by swelling, which helps break the tablet or capsule apart. There are basically three types of SSG: Type A, Type B and Type C, with Type A the one most commonly used in medications. SSG Type A is primarily manufactured using potato starch, with a small percentage coming from a corn source. Theoretically SSG can be made from any starchy source, however, I have not found a manufacturer who uses a starch other than potato or corn to make SSG. Several manufacturers produce SSG. Three of the most popular brands, Vivastar®, Explotab® and Primojel®, use potato starch. Sodium starch glycolate is considered generally safe for people with celiac disease although it may cause an issue in those who experience symptoms when exposed to corn-derived products. Still, it is wise to call the drug manufacturer to find out what type of SSG they use.

Drug Treatments for Celiac in the Pipeline

While the gluten-free diet effectively reduces and even eliminates symptoms of celiac disease, many people still experience distress. To that end, a number of drugs aimed at treating celiac disease are in various stages of development. But it is not known when the U.S. Food and Drug Administration (FDA) will approve them for market. Three products are furthest along in the process.

Larazotide acetate

Taken orally, larazotide acetate drug works in the gut to decrease the permeability of the intestine, one manner in which gluten causes symptoms. The medicine is not meant to allow those with celiac disease to eat gluten-containing foods. Instead, it works with the gluten-free diet to prevent “leaky gut” syndrome in cases of incidental cross-contamination.

The compound has consistently reduced symptoms in multiple clinical trials in more than 800 patients with celiac disease. It will begin testing in a large Phase 3 clinical trial in late 2016. This is the first celiac disease drug to get this far in the approval process.

IMGX-003

Formerly ALV003, this oral drug combines two protein enzymes that degrade gluten. Patients who were given this medication and then a gluten challenge showed no significant signs of intestinal mucosal injury.

Already through Phase I and Phase 2, it is the only treatment that has shown both histologic success and improvement of symptoms in clinical trials. Biopharmaceutical company ImmunogenX, which acquired IMGX-003 in March 2016, plans to take it through late-phase clinical trials.

Nexvax2

This injectable vaccine-like product changes the body’s immune response to gluten. According to ImmunosanT, the company behind Nexvax2, it is the only celiac disease treatment in clinical development today that has the potential to empower patients to return to “a normal diet, good health and improved quality of life.” After positive results in Phase I clinical trials, the next step will be Phase 2 testing, in which it will be given to larger group of people and further evaluated for safety and effectiveness.

Some experts feel taking a combination of products may be the best protection against symptoms and damage caused by exposure to gluten, but that will be evaluated once the products enter the market.

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