1. Medications and Celiac Disease: A Gut Reaction
Steve Plogsted, PharmD, BCNSP, CNSC
March 12, 2018
Nationwide Children’s Hospital
(from that city in central Ohio we won’t mention)

2. Is there a cause for concern?
Gluten in Medications
Is there a cause for concern?

3. What makes up a medication formulation?
Active ingredient
Excipients
Capsule shell or
tablet coating
Keep in mind:
This applies to medications taken by mouth
**Excipients are pharmacologically inactive substances included in the final formulation of the drug product
Purposes:
Provide bulk to the product
Allow for the drug to be dissolved and absorbed at different rates in the body (as in extended release formulations)
Decrease stomach upset
Protect the product from moisture contamination
And simply make the final drug appearance more pleasing to eye

4. How can there be gluten in medications?
Potential sources of gluten contamination primarily from excipients in medications
Excipients have several functions:
1) Provide bulk
2) Act as a lubricant for the powder
3) Absorb water which enables tablet to swell and disintegrate
** Excipients added to active drug to make a particular dosage form
**Excipients facilitate dissolution of a tablet in the stomach

5. However, they have also been known to contain starch from wheat
These excipients can be obtained from any starch source, but are primarily derived from:
Corn
Potato
Tapioca
However, they have also been known to contain starch from wheat

6. Frequently Used Excipients
The following are the most commonly used
excipients in U.S.-manufactured drug products:
Magnesium Stearate >2500
Povidone
Lactose >2000
Pregelatinized Starch
Microcrystalline Cellulose >1500
Hydroxypropyl Methylcellulose
Starch (corn)
Coatings and Ink
Silicone Dioxide
Croscarmellose
Titanium Dioxide
Hydroxypropyl Cellulose >250
Stearic Acid
Ethycellulose
Sod Starch Glycolate
Calcium Phosphate
Gelatin
Crospovidine
Talc
Shellac (and Glaze)
Sucrose
Calcium Stearate

7. Typical Drug Formulation
Active Ingredient (s)
Silicon Dioxide
Crospovidone
Povidone
Stearic Acid
FD&C Red No. 3
Croscarmellose Sodium
Microcrystalline Cellulose
Pregelatinized Starch
Sugar

8. Sources of information
Pharmaceutical manufacturer’s drug information department
Package insert

9. Sources of information
Pharmaceutical manufacturer’s drug information department
Package insert
Drug company web site

10. Sources of information
Pharmaceutical manufacturer’s drug information department
Package insert
Drug company web site
Internet web sites

11. Internet Resources Glutenfree Drugs http://www.glutenfreedrugs.com
Celiac Sprue - A Guide Through the Medicine Cabinet, by Marcia Milazzo,
Wheaton Gluten Free Support Group
DailyMed - Provides high quality information about marketed drugs (US)
Pillbox – Provides a way to search by ingredient

13. NIH/NLM Pillbox Website
Starch records
Corn-8321 records
Sodium Starch Glycolate-3994 records
Potato-3570 records
Maltodextrin-1172 records
Lactose-9568 records
Soy-510 records
Lecithin-397 records
Wheat-13 records

16. Sources of Information
Pharmaceutical manufacturer’s drug information department
Package insert
Drug company web site
Internet web sites
Safety Data Sheet

17. Safety Data Sheet
Mandated by OSHA for all hazardous chemicals which is how prescription medications are classified
Requires that the chemical manufacturer, distributor, or importer provide Safety Data Sheets (SDSs) (formerly MSDSs or Material Safety Data Sheets) for each hazardous chemical to downstream users to communicate information on these hazards

18. Cytomel (liothyronine)
Thyroid replacement product
Company states that it CONTAINS gluten
MSDS May 16, 2016 lists sugar, corn starch, calcium sulfate, stearic acid and gelatin as the potential hazardous ingredients
Company is known for providing false information to the public

19. Sources of Information
Pharmaceutical manufacturer’s drug information department
Package insert
Drug company web site
Internet web sites
Safety Data Sheet
Chat rooms/Blogs

20. Sources of Information
Pharmaceutical manufacturer’s drug information department
Package insert
Drug company web site
Internet web sites
Chat rooms/Blogs
Your local pharmacist?
Besides asking the pharmacist about the gluten status don’t forget to ask if the drug itself will cause intestinal issues

21. Are Certain Meds Hurting You?
Mayo Clin Proc. 2012;87(8):

22. Olmesartan Angiotensin II Receptor Antagonist (ARB)
Primarily used to treat HTN
Dr Joe Murray and colleagues from Mayo Clinic identified 22 patients (2012)
Villus atrophy and variable degrees of mucosal inflammation in 15 patients
tTG antibodies were NOT detected
Histologic recovery once medications stopped

23. Olmesartan
October 2012
American College of Gastroenterology meeting noted that this drug had been linked to 40 such cases of sprue-like enteropathy

24. 2013
Safety Announcement
[ ] The U.S. Food and Drug Administration (FDA) is warning that the blood pressure drug olmesartan medoxomil (marketed as Benicar, Benicar HCT, Azor, Tribenzor, and generics) can cause intestinal problems known as sprue-like enteropathy. FDA has approved changes to the labels of these drugs to include this concern

25. Olmesartan Mayo Clinic 2014
Conclusion: Our findings suggest that neither olmesartan nor other ARBs were associated with diarrhea among patients undergoing endoscopy. The spruelike enteropathy recently associated with olmesartan is likely a rare adverse effect and milder presentations are unlikely
Mayo Clin Proc. 2014;89(9):

26. Are There Other Meds Hurting You?
Aliment Pharmacol Ther 2017; 45: 1084–1093

27. The Study 1351 symptomatic CD patients
511 had active CD with persistent villus atrophy
The median duration on a GF diet was 4 yrs
81% were females
98% were white
Median age 48 yrs

28. The Results Males were more likely to have persistent villus atrophy
Older age was associated with a higher risk
The longer the patient was adhering to a GF diet decreased the likelihood of damage
79% were DQ2 positive, 11% were DQ8 positive and 8% were positive for both

29. Medications and Persistent Villus Atrophy
Users
Non-Users
NSAID
168/362 (46.4)
339/962 (35.2)
PPI
167/349 (47.9)
340/975 (34.9)
SSRI
98/209 (46.9)
409/1115 (36.8)
Statins
67/127 (52.8)
440/1197 (37.8)
H2 Receptor Antagonists
29/60 (48.3)
478/1264 (37.8)
ARBs
8/18 (44.4)
499/1306 (38.2)

31. Recent Publication
TITLE: Gluten in Medication: Qualifying the extent of exposure to people with celiac disease and identifying a hidden and preventable cause of an adverse drug event

32. Results
Tested 24 prescription drugs and 15 OTC drugs for the presence of gluten
Sandwich ELISA (higher specificity)
3 drugs tested above 20 ppm or mg gluten (limit set by FDA Office of Food Safety)
Likely source-excipient manufactures
Limitations of the study:
Is this the best test of medications
Sampling error
Possible inaccurate data and assumption

33. Gluten in Drug Products and Associated Labeling Recommendations Guidance for Industry
On December 12, 2017 the FDA issued guidance to the drug manufacturers to voluntarily label medications stating that no known gluten containing ingredients were used in the manufacturing of their product
Asks for voluntary compliance for now it could lead to more mandatory labeling in the future

34. Gluten in Drug Products and Associated Labeling Recommendations Guidance for Industry
Legislation also addresses the sugar alcohol issue
Sugar alcohols, or polyols, are substances found in foods as a sugar substitute
Sugar alcohols could have been derived from a wheat source but during the manufacturing process the gluten protein has been removed
celiac organizations do not recommend avoiding these sugar alcohols

35. Gluten in Drug Products and Associated Labeling Recommendations Guidance for Industry
If a drug included an ingredient derived from wheat, barley, or rye, the ingredient would most likely be wheat-derived
The amount of gluten potentially contributed by a wheat-derived ingredient to a unit dose of an oral drug product (unless that ingredient is wheat gluten itself or wheat flour) is expected to be less than 0.5 mg, as a high estimate

36. Gluten in Drug Products and Associated Labeling Recommendations Guidance for Industry
This leads FDA to conclude that individuals who respond well to a gluten-free diet are at low risk of experiencing problems as a result of the possible presence of gluten in a drug product
FDA expects that you might choose to avoid using oral drug products labeled as containing wheat gluten or wheat flour as an ingredient in the absence of more information about the product’s actual gluten content

37. Drugs Containing Wheat Starch
Tekturna HCT
Grifulvin V 500 mg
Sanctura
Doryx Capsule

38. Conclusion Drug products can contain gluten
Patients need to be aware and investigate and ask questions
Drug companies are not always right!

39. Contact info
Steve Plogsted
Nationwide Children’s Hospital