Gluten in pharmaceutical products: a scoping review

Celiac disease (CD) is a chronic immune-mediated enteropathy of the small intestine precipitated by exposure to dietary gluten in genetically predisposed individuals [1]. It is one of the most common lifelong disorders worldwide, with a mean prevalence of 1.4% when individuals diagnosed by serologic test are included and an overall prevalence of 0.7% based on biopsy results [2]. Despite the advances in CD diagnosis, in developed countries, for every case diagnosed, an average of five to ten cases remain undiagnosed, usually due to the presentation of atypical, minimal, or even an absence of symptoms. Undiagnosed cases remain untreated, so they are exposed to the risk of presenting other types of complications associated with CD in the long term [3].

Gluten refers to a broad group of prolamins found in wheat, rye and barley [1]. Immune activation of the small bowel due to intolerance to the peptide antigen derived from prolamins produces villous atrophy, crypt hyperplasia and increased intra-epithelial lymphocytes of the lamina propria. At the local level, these changes generate gastrointestinal symptoms and malabsorption [4].

In addition to CD, there are other types of gluten-related disorders, the most important of which is non-celiac gluten sensitivity (NCGS), with intestinal and extra-intestinal symptoms similar to CD [5]. Complete avoidance of gluten intake as well as maintaining a strict and lifetime gluten-free diet (GFD) is the key to reducing symptoms and improving the quality of life of these patients [5].

CD also represents a significant economic burden in terms of healthcare-related expenditures and productivity loss. According to a recent systematic review, healthcare resource utilisation by celiac patients is higher than that of patients without CD, usually because much of the cost of the management derives from outpatient care. These costs drop after diagnosis and adherence to a GFD [6].

Although sensitive patients tend to strictly adhere to a GFD, there is a possibility of unintentional intake via medicines since these may contain gluten in the formulation itself (excipients) or as a result of the manufacturing process (traces) [7]. This amount, which should not be ignored by physicians, pharmacists and patients, could reactivate the small bowel immune response of a sensitive patient.

While patients with gluten intolerance are usually aware of their condition and intake restrictions, there is still doubt about whether healthcare professionals involved in patient treatment share this awareness and are sufficiently informed about the presence of gluten in medicines. Hence, we hypothesise that if current information regarding the awareness and dissemination in clinical practice about the gluten content of medicines is scarce, it must be studied, promoted and developed to ensure patient safety. This scoping review aimed to find out the current evidence for initiatives that either describe the gluten content of medicines or intend to raise awareness about the risk of prescribing and dispensing gluten-containing medicines in patients with CD and other gluten-related disorders. Specifically:

A scoping review was conducted following the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews (PRISMA-ScR) checklist” (Additional file 1) [8].

We identified a total of 3146 records, 2505 through database search strategies (PubMed/MEDLINE n = 798; TripDatabase n = 146; Web of Science n = 1561) and 641 through references in other studies. After the elimination of duplicates, 3062 articles remained and then 2456 were excluded after the title and abstract screening process. Eligibility assessment was carried out on 282 full texts. At this stage, 269 articles were excluded (reasons are given in Fig. 1), and ultimately 13 full texts were included in the narrative synthesis.

This review included full-text articles published from 1985 to 2021, mostly targeted to CD patients (n = 11). They were all written in English. While the first studies about the presence of gluten in medications were published in the 1980s and were from Canada and Australia, the subsequent studies, conducted up through 2021, were all from the United States (US) (n = 11).

In total, 5623 patients with gluten-related disorders and 418 pharmacists were surveyed in the included studies. A total of 1239 medications and 700 manufacturers of pharmaceutical products were analysed.

Table 2 shows an overview of the characteristics of the included studies, and Fig. 2 describes the mapping of literature.

Most of the initiatives associated with gluten in medicines were targeted to the prescription [10‐17], based on practical and user-friendly tools for physicians, such as databases with the gluten content of medicines from manufacturers that could guarantee manufacturing policies of gluten-free products. In the case of dispensation of medicines [7, 18, 19], concerns regarding pharmacists’ knowledge of CD were observed. Consequently, initiatives were aimed at raising awareness and identifying topics that needed further training to guide and support patients. Initiatives that did not make a particular distinction between prescription and dispensation of medicines [20, 21] analysed the presence of unlabeled gluten in medicines through quantitative testing, in order to prevent potential adverse events. It should be noted that studies reporting initiatives addressed to or carried out by other healthcare professionals different from general practitioners or pharmacists were not identified.

Databases with gluten content are intended to help prescribers make informed decisions. However, it is recommended that they be continuously updated by directly contacting the manufacturer, since raw materials or some formulation procedures could be different from those used when the data was originally collected [11‐14, 16] and because, although many manufacturers believed that their products were devoid of gluten, they did not certify or test the gluten-free status in the final products [15, 17].

Pharmacists must support patients with CD and other gluten-related disorders, and they should be prepared to inform them about GFD and resolve all kinds of concerns about the disease [7, 18]. A targeted case finding service for CD showed that patients commented on the professionalism exhibited by the pharmacists and on the usefulness of the information provided in a service for CD [22], adding value to the relationship between patients and their local pharmacists and confirming that the upskilling of the healthcare professional can be a valuable tool [19, 23].

A lack of clarity in the labelling of medicines could be a risk for susceptible patients, possibly leading to an adherence problem, as a patient may not adhere to a prescribed regimen or the patient’s therapy may be changed because of unknown or suspected information, even if the medicine showed no presence of gluten after a quantitative analysis [20, 21]. As shown by other authors, some patients experienced anxiety and they did not adhere to prescribed medication regimens, ending a treatment against medical advice due to suspicion of unintentional gluten intake from excipients [24].

There is wide variability between countries on provided information and labelling of gluten-containing medicines. Definitely, the most cost-effective and easiest way to provide information on whether a medicine contains gluten or not would be including a clear statement in the packaging (i.e. quantity, source). In this regard, the European Medicines Agency (EMA) and other national agencies such as The Spanish Agency of Medicines and Medical Devices (AEMPS) have been developing and updating medicine labels, as well as publishing gluten status databases and public access guidelines with information for health professionals and patients [25, 26]. The declaration of gluten content is mandatory for those member states and drug manufacturers which are under the umbrella of the EMA. For instance, the statement “Gluten-free” applies only if the gluten content in the medicinal product is less than 20 parts per million (ppm). However, the US Food and Drug Administration (FDA) only recommends that drug manufacturers use the following statement about gluten, “Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye)”, when it is truthful and substantiated, according to a draft guidance that contains nonbinding recommendations [27].

Table 3 summarises the findings identified in the scoping review, as well as the future challenges of the different stakeholders involved in the management of patients with gluten-related disorders, from healthcare professionals to patients, including manufacturers and medicines agencies. Therefore, it is clear that different initiatives to raise awareness among healthcare professionals have been developed, although the usefulness of these initiatives has not yet been evaluated. There is room for improvement and further studies should be developed with more robust study designs, such as prospective observational studies, since it is necessary to confirm the effectiveness of the initiatives and the impact on the outcomes and quality of life of susceptible patients.

This scoping review is subject to certain limitations since there are very few publications on this subject, many of which were written more than 30 years ago. The true extent of the initiatives could be underestimated, since grey literature was not explored. In addition, the results incorporated in this scoping review derive from a heterogeneous set of studies with different methodologies used. In this regard, the methodology of the analysis was not clearly described in some publications, or the results were presented as aggregated, and thus could not be analysed in detail. Furthermore, some studies could not be directly compared because of the diversity of countries and periods analysed.

Initiatives that raise awareness of prescription and dispensation of gluten-containing medicines have been designed for more than 35 years and most of the efforts have focused on the prescription process, through practical tools that should be continuously updated. However, in the last decades, the dispensation process has been considered as critical as prescribing and research was aimed at improving pharmacists’ knowledge of CD, highlighting the problem of unintentional gluten intake from medicines and their potential adverse effects.

These initiatives establish that collaborative objectives are necessary to address safe therapy for patients with gluten-related disorders and are the first step towards the development of further studies whose objectives should be focused on updating initiatives that take into account the gluten content of medicines, as well as measuring the effectiveness in daily healthcare professionals’ practice.

Future studies such as randomised controlled trials and observational studies are needed, including specific interventions related to inadvertent prescription and/or dispensation and/or use of gluten-containing medicines that will help by adding more evidence and raising awareness about adverse drug events at the level of healthcare professionals as well as health consumers. The inclusion of other relevant patient-reported outcomes like quality of life and satisfaction would be also recommended.

In addition, it is important to establish a collaborative model between community pharmacy and primary healthcare to complete the patient’s journey. For instance, integrated alerts in the electronic prescription system could be established to support the prescription and dispensation processes, and thus avoid the consumption of medications that may contain gluten by susceptible patients.