Proton pump inhibitor leaflets: Is there information on deprescribing?Abstract
This study aims to analyze the existence of information about deprescription in the leaflets of proton pump inhibitor (PPI) medications. The leaflets available on the Brazilian Health Regulatory Agency (ANVISA) and Food and Drug Administration (FDA) websites for the following medications were analyzed: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole. The variables collected in each leaflet were the existence: a) about deprescribing; b) of guidance on the deprescription process; c) maximum recommended time for use; and d) risk of prolonged use. This information was analyzed in accordance with the PPI deprescription guideline, from Canada. Regarding the medication leaflets, 83.33 % from ANVISA and 100 % from the FDA did not present explicit and systematic guidance on deprescribing. Regarding the maximum time of use, 100 % of the leaflets from both agencies contained this information. Regarding the risks of prolonged use of the medication, 33.33 % of the ANVISA leaflets and 33.3 % of the FDA leaflets did not report the increased risks described in the guideline. The results highlight a large gap in information about deprescribing in PPI leaflets; this highlighting is necessary to contribute to the promotion of the rational use of medicines.
Keywords:
Leaflet; Deprescription; Rational Use of Medicines; Proton Pump Inhibitors; Brazilian Health Regulatory Agency (ANVISA); Food and Drug Administration (FDA)
INTRODUCTION
Since the end of the 1980s, proton pump inhibitors (PPIs) have become a therapeutic option in the treatment of acid-peptic disorders, and have made significant contributions to therapy, as they have enabled better regulation of acid secretion in the stomach (Costa, Damascena, 2020). This class of medications acts to inhibit the enzyme H+/K+ ATPase, altering the physiology of the oxyntic glands (secreting hydrochloric acid) (Morschel, Mafra, Eduardo, 2018). These anti-secretors inhibit H+/K+ ATPase, the gastric proton pump, by covalently binding to cysteine residues of the ATPase in the parietal cell. PPIs have a pKa of 4.0, causing the medication of this class to selectively accumulate in the acidic space of the secretory parietal cells (Mullin et al., 2009 apud Salgado, 2019).
Currently, PPIs are among the most prescribed and used medications worldwide (Costa, Damascena, 2020; Kondapalli et al., 2023). In Brazil, the following medications in the class are available for clinical use: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, and pantoprazole. All are recommended for gastroesophageal reflux disease (GERD), peptic ulcer disease (ulcers associated with Helicobacter pylori infections, the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the prevention of recurrence of bleeding from peptic ulcers), non-ulcer dyspepsia, prevention of stress-related mucosal bleeding, gastrinoma, and other hypersecretion disorders (Lima et al., 2017). Unlike the United States (USA), all PPIs in Brazil require a medical prescription to be dispensed by pharmacies, however it is common practice for them to be sold in pharmacies without requiring a medical prescription (Araújo et al., 2021). Furthermore, it is observed that these medications, when prescribed, do not have a delimited and defined treatment time, so the time of use becomes indeterminate and/or chronic (Martins, Menezes, 2019). As a result, the number of patients developing complications due to improper use is growing. The main complications include reduced absorption of essential nutients such as vitamin B12, iron, magnesium and calcium (Coelho et al., 2023). Another problem observed is the off-label use of these medications, for example, to treat digestive manifestations and to prevent the emergence of gastrointestinal symptoms, especially in the case of polypharmacy (Macfarlane, 2018). From this context, there is a scenario of irrational use of PPIs, therefore requiring studies that address concerns about irrational and prolonged use without medical indication (Schnoll-Sussman et al., 2020).
Although the class demonstrates good effectiveness and safety, there are studies that associate prolonged use of PPIs with dementia (Gomm et al., 2016), gastric cancer (Melo et al., 2021), pneumonia, kidney diseases (Aquino et al., 2022; Guedes et al., 2020; Proença et al., 2020), bone fragility, micronutrient deficiency, and lead to the rebound effect and the consequent development of dependence (Cunha, Machado, 2018; Araújo et al., 2021), in addition to increased mortality (Aquino et al., 2022).
In order to avoid or reduce the risk of adverse effects of these medications, deprescribing is a strategy, which is a process that consists of an analysis of the prescription, with the objective of suspending or reducing the dose of medications when the potential risk of harm exceeds the benefits to the patient (Sgnaolin, Engroff, 2019). This practice is not random decision making, but an evidence-based decision.
Currently, there is a lack of studies, protocols, and information in leaflets and guidelines to assist in the PPI deprescription process. And, in this context, it is considered that the medication leaflet is a source of technical-scientific information that must be easily accessible for health professionals and patients and that must contain reliable information that contributes to the safe and rational use of medications, including information on indication, withdrawal, and treatment time (Fujita, Machado, Teixeira, 2014 apud Proença et al., 2020).
Considering the importance of the existence of information on deprescribing in PPI leaflets and the lack of studies on the subject, investigations that contribute to reducing this existing gap in scientific knowledge become essential. Therefore, this study aims to analyze the existence of information about deprescribing in the leaflets of PPI medications.
MATERIAL AND METHODS
This is a documentary-type study that analyzed the content of PPI leaflets contained on the Brazilian Health Regulatory Agency (ANVISA) website, https://consultas.anvisa.gov.br/#/medicamentos/, and on the Food and Drug Administration (FDA) website, https://labels.fda.gov/, intended for prescribers. Considering that in the USA and Brazil, leaflets are standardized documents, the focus of the investigation was on the existence of content on deprescribing. In Brazil, the standardization of leaflets is regulated by Collegiate Board Resolution (RDC) No. 47, of September 8, 2009, from ANVISA (Brasil, 2009). The analysis was carried out using leaflets available in June 2023 for the following medicines: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole. The most recent package leaflets for generic medications (when available) and reference medications (when there was no generic) were chosen, thus covering the entire class of PPIs available and guaranteeing the analysis of more complete and up-to-date information.
After selecting the leaflets, each one was read in full. Furthermore, the following keywords were used to identify the content: “deprescription”, “withdrawal”, and “reduction” (in Portuguese for ANVISA leaflets and in English for FDA leaflets). The variables collected in each leaflet were the explicit existence of the following information: a) about deprescribing; b) guidance on the deprescription process; c) maximum recommended time for use; and d) risk of prolonged use. For comparison purposes, the same procedure was carried out for the FDA leaflets.
Finally, analysis was carried out to determine whether or not the information on deprescription corroborated the information in the PPI deprescription guideline prepared by Farrell and colleagues (2017) which recommends that deprescription be described in the following situations: a) unknown indication; b) use after the maximum recommended treatment time; and c) in cases of Barrett’s esophagus, chronic users of NSAIDs with risk of bleeding, severe esophagitis, and for a documented history of bleeding from a gastrointestinal ulcer, it is recommended that a gastroenterologist be sought. For purposes of comparing information, explicit and systematic deprescription guidelines were considered when the leaflet presented a logical scheme for gradual withdrawal with a description of the dose and/or percentage to be reduced throughout the process.
RESULTS
Of the six leaflets analyzed available on the ANVISA website, five (83.33 %) did not present explicit and systematic guidance on deprescribing. And only one leaflet (16.66 %) addresses the topic of deprescription by suggesting a gradual dose reduction. Regarding the maximum time of use, the information varied from medication to medication, however all leaflets (100 %) reported this information. Regarding the risks of prolonged use of the medication (increased risk of fracture, vitamin B12 deficiency, hypomagnesemia) two leaflets (33.3 %) did not report about these risks (Table I). The leaflet insert for Esomeprazole states that the risk of hypomagnesemia is very rare and addresses a precaution in the use of omeprazole by patients with osteoporosis (risk of bone fracture). On the other hand, the leaflet insert for Lansoprazole indicates that hypomagnesemia is a possible reaction. These two leaflets do not mention interference with vitamin B12 absorption and it is noteworthy that they do not associate such reactions with prolonged use.
Information about proton pump inhibitors (PPIs) available in the leaflets on the National Health Surveillance Agency (ANVISA) website
In relation to the six leaflets analyzed with valid registration on the FDA website, none (0 %) presented explicit and systematic guidance for dose reduction. Regarding the maximum time of use and the risks of prolonged use of the medication, the information varied from medication to medication, however all leaflets (100 %) reported this information. When analyzing the risks of prolonged use of PPIs, two leaflets (33.33 %) did not address the increased risk of prolonged use and influence on the absorption of vitamin B12 (Table II).
Information about proton pump inhibitors (PPIs) available in the leaflets on the Food and Drug Administration (FDA) website
DISCUSSION
The package leaflets for PPI medications, in general, do not provide sufficient, explicit, and systematic information about the process of deprescribing these medications. The existing information is non-specific to support the professional’s conduct to withdraw the medication and/or reduce the dose. In the literature there are dozens of studies that explain the types of interventions and highlight the feasibility of deprescribing in different contexts (Imparato, Toma, 2022). In this sense and considering the need to promote the rational use of these medicines, it is imperative to review the content of these leaflets, in order to include information about the deprescription process.
Regarding deprescription guidelines, only the Brazilian leaflet for the medication lansoprazole provided information on how the deprescription process should be, but the proposed reduction is not in accordance with what is established in the literature. Farrell et al. (2017) recommended that lansoprazole be deprescribed gradually, however they did not explain how this reduction occurs.
Regarding the maximum time of use, information varies, indicating four to eight weeks with regard to GERD. Therefore, all leaflets analyzed are in accordance with this indication. With regard to other signs and symptoms of prolonged use of PPIs, such risks were mentioned, such as bone fragility and micronutrient deficiency, among others (Cunha, Machado, 2018; Araújo et al., 2021; Gomm et al., 2016). The Brazilian leaflets for the medications esomeprazole and lansoprazole do not provide information regarding the increased risk of bone fracture, influence on the absorption of Vitamin B12, and also hypomagnesemia (associated with prolonged use). While in the American leaflets, regarding the influence on the absorption of vitamin B12, the leaflets for omeprazole and lansoprazole do not provide such information.
Finally, it is noted that over the decades, Brazil, through ANVISA, modified the regulations on leaflets, through laws and resolutions, in order to have standardization, especially in terms of language, form, and content of leaflets, considering different audiences, medication users, and health professionals (Fujita, Machado, Teixeira, 2014). While in the USA, the FDA has been working since 2015 to change and modernize its regulations, however, there are political challenges in the National Congress (Nielsen, Mardov-Egvang, Dave, 2023).
Regarding the limitations of the study, it should be noted that the study only used a clinical deprescription protocol to compare with the content of the leaflets, but in contrast it is important to note that this is a validated protocol and that it has been used in several countries in the world (Lee et al., 2017; Nguyen-Soenen et al., 2022). Furthermore, this is an innovative study that fills an important gap in knowledge, explaining the weaknesses in the contents of PPI leaflets.
Finally, it is noted that the content of the leaflets is fragile and, at times, silent in relation to deprescribing which could support the prescriber with relevant information. In this sense, it is important to note that although there are, in Brazil and the USA, rules and standards for the production of medication leaflets, these sources of information are prepared by the pharmaceutical industries responsible for producing the medication. This shows that changes are necessary, in the sense of: i) expanding the participation of regulatory agencies in the process of preparing and updating leaflets; ii) having minimum qualitative parameters in the content of the leaflets, not restricted only to the formatting of the leaflets; and iii) monitoring and demanding from the pharmaceutical industry the inclusion of up-to-date quality information of interest to public health. These actions are necessary to promote the rational use of medicines and prevent the risks of using PPIs in the long term, especially in a context of medicalization of life.
ACKNOWLEDGEMENTS
Federal University of São João del-Rei (UFSJ).
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