The Safety of Appropriate Use of Over-the-Counter Proton Pump Inhibitors: An Evidence-Based Review and Delphi Consensus
The availability of over-the-counter (OTC) proton pump inhibitors (PPIs) for the short-term (2 weeks) management of frequent heartburn (≥2 days/week) has increased markedly, yet evidence-based recommendations have not been developed. A panel of nine international experts in gastroesophageal reflux disease developed consensus statements regarding the risks and benefits of OTC PPIs using a modified Delphi process. Consensus (based on ≥80% approval) was reached through multiple rounds of remote voting and a final round of live voting. To identify relevant data, the available literature was searched and summarized. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system terminology was used to rate the quality of evidence and strength of recommendations; consensus was based on ≥2/3 agreement. After 4 rounds of review, consensus was achieved for 18 statements. Notably, the available data did not directly reflect OTC use, but instead, prescription use; therefore, extrapolations to the OTC setting were often necessary. This limitation is regrettable, but it justifies performing this exercise to provide evidence-based expert opinion on a widely used class of drugs. The panel determined that using OTC PPIs according to label instructions is unlikely to mask the symptoms of esophageal or gastric cancer or adversely impact the natural history of related precursor conditions. OTC PPIs are not expected to substantially affect micronutrient absorption or bone mineral density or cause community-acquired pneumonia, Clostridium difficile infection, or cardiovascular adverse events. However, OTC PPI use may be associated with slightly increased risks for infectious diarrhea, certain idiosyncratic reactions, and cirrhosis-related spontaneous bacterial peritonitis. The available evidence does not suggest that OTC PPI use consistent with label instructions is associated with substantial health risks. To minimize potential risks, healthcare professionals and consumers must actively participate in decision making when managing reflux-related symptoms in the self-care setting.
Based on the available data, the consensus panel determined that OTC PPIs are unlikely to mask the symptoms of esophageal or gastric cancer if used as directed.
OTC PPIs are not likely to affect micronutrient absorption or bone mineral density or cause community-acquired pneumonia, Clostridium difficile infection, or cardiovascular adverse events.
However, using an OTC PPI may increase the risks for infectious diarrhea, certain idiosyncratic reactions, and cirrhosis-related spontaneous bacterial peritonitis.
Due to the high prevalence of acid reflux-related symptoms in the general population, the increasing availability of over-the-counter (OTC) proton pump inhibitors (PPIs), and the limited direct data that are available in this area, evidence-based treatment recommendations are needed to discuss the potential risks and benefits of treating gastroesophageal reflux symptoms in the OTC setting . A recently published position paper describes the benefits and potential harms of using PPIs; however, it does not specifically discuss issues related to OTC PPI use. It focuses instead on use of PPIs that is more consistent with prescription indications . The authors suggest that PPIs are essential for treating acid-related conditions, but that, as with any drug therapy, there are potential risks. These potential risks should not, however, outweigh the established benefits of PPIs when they are used as indicated, which means they should only be used when appropriate and for the shortest duration of time to achieve symptom response . Many of the safety concerns related to the use of PPIs have been observed in studies conducted under conditions that are consistent with prescription use, which differs from OTC use in several key ways that are relevant for assessing safety . Prescription PPIs are generally administered at higher doses, the durations of treatment are longer, and users of prescription PPIs often differ from OTC users in terms of their underlying conditions, which are frequently more severe [4, 5]. In contrast, OTC PPIs are used for shorter durations and generally represent the lower end of the dose range. Omeprazole was the first PPI to be approved for OTC use and is widely available in multiple international markets . Omeprazole 20 mg is available OTC for treating frequent heartburn (defined as having symptoms ≥2 days/week) and is administered as a single daily dose for 2 weeks . In contrast, omeprazole 20 mg once daily is used for 4–8 weeks for treating gastroesophageal reflux disease (GERD), and omeprazole 40 mg is used for 4–8 weeks for treating gastric ulcers . By their nature, users of prescription PPIs are directly under a physician’s care for their perceived acid-related disease, while users of OTC PPIs are not necessarily under a physician’s care. As a result of these issues, interpreting the evidence to address concerns related to OTC PPI use requires reviewing the literature to identify relevant data and systematically extrapolating these findings to the OTC setting from studies that likely only indirectly address these issues. Therefore, specifically exploring these issues in the context of OTC use necessitates using evidence available from studies conducted with prescription PPIs, for which the safety profiles have been widely discussed. To achieve this end, an international group of experts was convened to develop evidence-based recommendations and provide accompanying literature reviews to inform global best practices among healthcare providers for the safe and appropriate use of OTC PPIs in the self-care setting.
A panel of nine international experts comprising eight gastroenterologists and one general practitioner convened to develop consensus, evidence-based recommendations for using OTC PPIs utilizing a modified, evidence-based Delphi process [7, 8]. The concept for this panel was conceived by the co-chairs (DAJ/POK) and discussed with the sponsor, who provided full latitude to select the international working group to represent the perspectives of general practitioners and gastroenterologists. Selection of the consensus panel was led by the panel co-chairs in August 2015. The members were primarily selected based on their expertise in the areas of gastroenterology and/or treating acid-related conditions. Additionally, their regional location was considered in order to provide international representation and to gain a global perspective on these topics. Because OTC PPIs may be more frequently recommended in a general practice versus a specialty care setting, a primary care physician was also included in the group. The panel co-chairs also developed a preliminary set of statements based on clinically important topics and assigned statement leads to review the available literature related to each topic based on their level of expertise in these areas.
To identify relevant evidence for each statement, the statement leads conducted literature reviews based upon their preferred search methodologies. These literature reviews included searches of the PubMed and Cochrane databases and were conducted beginning in September 2015 in preparation for a live meeting in November 2015. Searches were conducted utilizing terms that were based on relevant keywords for each statement (e.g. proton pump inhibitor <AND> esophageal cancer; Limits: humans). No limits were set on publication date, and the focus was on English-language publications. After literature searches were completed, the results were reviewed to identify the appropriate sources to be summarized. Because the topics that were analyzed were often based on indirect evidence, the criteria for determining the relevance of the available data differed for each statement. Additional relevant publications were identified by reviewing the bibliographies of the relevant articles. During the same time period that the literature searches were being conducted, consensus for each statement was reached through a series of three remote rounds of anonymous voting and feedback followed by a fourth round at the live meeting.
The level of agreement was rated using a 5-point scale: agree strongly (A+), agree with reservation (A), undecided (U), disagree (D), or disagree strongly (D+). Consensus was defined a priori as ≥80% of panelists strongly agreeing or agreeing with reservation (A+ or A). The quality of the evidence (high: ★★★★; moderate: ★★★; low: ★★; very low: ★) supporting each statement and strength of recommendation were categorized using GRADE (Grading of Recommendations Assessment, Development and Evaluation) terminology  and were developed by the statement leads and voted on by the panel using a consensus definition of at least two-thirds agreeing (yes/no) with the rating. A full summary of the voting through each round is provided in Figure 1 (Online Resource 1) and Table 1 (Online Resource 2), and questions about the integrity of the process and a description of withdrawn statements are provided in Online Resource 3.
3 Delphi Statements
When taken in accordance with label instructions, PPIs have not been shown to mask the symptoms of early esophageal cancer or meaningfully delay presentation. Available OTC PPIs would not be expected to differ.
A+: 78%; A: 22%
When taken in accordance with label instructions, it is unlikely that OTC PPIs produce achlorhydria.
A+: 89%; A: 11%
When taken in accordance with label instructions, PPIs have not been shown to meaningfully delay the presentation of early gastric cancer. Available OTC PPIs would not be expected to differ.
A+: 78%; A: 22%
When taken in accordance with label instructions, OTC PPIs may improve symptoms of peptic ulcer or GERD but are extremely unlikely to adversely affect the natural history of the conditions. Individuals with persistent (>1 month) or recurrent symptoms after use of an OTC PPI should consult a physician.
A+: 56%; A: 33%; D: 11%
Patients with upper gastrointestinal alarm features should be referred for endoscopy.
Baseline or routine monitoring of iron, calcium, magnesium, and vitamin B12 levels in those taking OTC PPIs is not necessary.
Patients requiring repeated courses of OTC PPIs do not need baseline bone density measurement or bone density monitoring unless other clinical risk factors are present.
There are rare idiosyncratic drug reactions that may be associated with PPIs.
A+: 78%; A: 22%
Patients who have ascites secondary to cirrhosis should be advised to consult a physician about the slightly increased risk for spontaneous bacterial peritonitis. Although this association has been reported for only prescribed PPIs, the relative risk with OTC PPI use has not been studied. A risk/benefit assessment for any PPI use in these patients, with close monitoring, is warranted.
A+: 56%; A: 44%
It is very unlikely that OTC PPI therapy leads to an increased risk of community-acquired pneumonia.
A+: 78%; A: 22%
Use of OTC PPIs may increase risk of infectious diarrhea.
A+: 67%; A: 33%
The use of OTC PPIs is not strongly associated with increased risk of Clostridium difficile infection. There is insufficient evidence to determine an associated causal risk of relapsing C. difficile infection.
A+: 33%; A: 67%
Patients taking medication, the absorption, metabolism, or effect of which may be affected significantly by PPI therapy, should be advised to consult with a healthcare professional before starting OTC PPI therapy.
PPIs may interact with other medications by decreasing gastric acidity (leading to subsequent changes in solubility and absorption), by modifying metabolism [most commonly through the cytochrome P450 (CYP) enzyme system], or by inhibiting extragastric renal proton pumps (leading to altered drug excretion) [118, 119].
The solubility of atazanavir decreases at high pH in vitro, leading to an 87% reduction in exposure when administered in a buffered solution [120, 121]. Pharmacokinetic studies conducted in healthy volunteers have reported widely varying degrees of decreased exposure (10–94%) of atazanavir with concurrent use of an H2RA or PPI based on the timing of administration . The clinical relevance of this interaction is unclear because the effect of acid suppression is mitigated if atazanavir is taken approximately 16 hours after the PPI and because atazanavir treatment outcomes are affected by other factors, in particular, adherence to antiviral therapy . The potential effect of increased pH on ledipasvir solubility may also be mitigated by using acid suppressive therapies at different times of the day .
Citalopram and its S-enantiomer, escitalopram, are selective serotonin reuptake inhibitors that are metabolized primarily by CYP3A4 and CYP2C19, and at higher doses citalopram and escitalopram are associated with QT interval prolongation . The FDA has recommended that the maximum dose of citalopram should be 20 mg daily in older adults . Based on the analysis of a therapeutic drug monitoring database reporting markedly increased serum escitalopram concentrations in patients taking omeprazole and esomeprazole, the authors proposed a dose reduction of 50% for escitalopram if coprescribed with omeprazole or esomeprazole .
Renal proton pump inhibition is thought to be the mechanism whereby PPIs decrease methotrexate clearance; however, the clinical significance of this interaction is likely to be small . PPI coadministration, therefore, is very unlikely to have any adverse impacts on patients taking low, immunomodulatory doses of methotrexate for inflammatory bowel disease, rheumatoid arthritis, or psoriasis.
The pharmacodynamic interaction of clopidogrel with omeprazole and esomeprazole has not been shown to have clinically meaningful adverse cardiovascular effects. Individuals being treated with clopidogrel may continue using OTC PPIs.
A+: 33%; A: 56%; U: 11%
It is extremely unlikely that PPIs increase risk for myocardial infarction. OTC PPIs would not be expected to differ.
A+: 89%; A: 11%
There is no contraindication for the use of category B OTC PPIs for heartburn during pregnancy.
A+: 56%; A: 44%
There is a rapid treatment response for heartburn with OTC PPIs, which begins on day 1 for many patients.
A+: 78%; A: 22%
As there is a rapid treatment response for heartburn-related sleep impairment with PPIs, which begins on day 1 in many patients, OTC PPIs are likely to have the same effect.
A+: 67%; A: 33%
Nocturnal reflux symptoms and related sleep impairments are common and can have a significant negative effect on quality of life, general well-being, and functionality [173, 174, 175]. PPIs, including pantoprazole 20 mg, lansoprazole 15 and 30 mg, and rabeprazole 10 and 20 mg, have been shown to have a significant impact on nighttime heartburn beginning on the first day of treatment [168, 169, 170]. In two studies conducted with individuals not specifically experiencing nocturnal heartburn, 43–46% of those treated with esomeprazole 20 mg were heartburn free on the first night of treatment . A more detailed description of these study results is provided in Data Summaries (Online Resource 4) [176, 177].
Many of the recommendations of this consensus panel are based on indirect evidence, as potentially relevant studies were not generally conducted in the OTC setting. In the absence of direct evidence, results from studies in other clinical scenarios were reviewed and extrapolated to OTC use. The studies that were reviewed differed from the OTC setting in terms of using higher doses, longer durations of therapy, and enrollment of more severely ill patients, yet any effect would not be expected to differ meaningfully from what would be observed with OTC PPIs. Notably, where there was an established or expected relationship between the outcome and cumulative drug exposure, the effect may be even less pronounced with OTC PPIs. In such cases, consideration was made for the applicability to the OTC setting. If there was an absence of risk in this scenario, an assumption was made that lower doses taken for shorter durations in a generally healthier population would pose no greater risk than prescription PPIs. From a practical standpoint, the process of extrapolating findings from these studies may have been further complicated by the lack of consistency in labelling for different products in different regions. For example, in the USA, the labelling for OTC PPIs indicates that they should be taken for 14 days and that a physician should be consulted if more than one course of treatment every four months is necessary . In the EU, the duration of treatment for nonprescription PPIs is up to 2 weeks, but the labelling specifically states that when complete symptom relief is experienced, treatment should be discontinued . In addition, there is no limitation on the number of treatment courses that can be taken annually. Because these differences are relatively minor, the material impact of these variations is not known. For many statements, a qualifier was used (i.e. “when taken in accordance with label instructions”) to account for variations in approved indications and usage instructions. Although these limitations are regrettable, they reflect the data that are available in the scientific literature, and in our opinion this lack of data provides additional support for our decision to convene this consensus panel. The Delphi process is utilized for areas of research where the data are limited and incomplete to allow for experts in the area to provide their opinion of available data. This is particularly pertinent for a class of drugs that is becoming more widely available without the need to consult a physician.
A potential issue associated with use of OTC PPIs involves allowing consumers direct access to these products without the need to consult a physician, which could lead to inappropriate use by some individuals. Although this is a potential concern, real-world-use data suggest that individuals using OTC PPIs self-select appropriately based on symptom presentation and are more likely to take the appropriate number of doses or fewer rather than take more than is recommended . In addition, these data show that those who required more than the recommended doses frequently consulted a physician. Other studies also suggest that individuals with frequent symptoms of gastroesophageal reflux will consult a physician when their symptoms become more severe or frequent, significantly impact their daily lives, or if alarm features appear [180, 181].
Consistent with the tenets of evidence-based medicine, results of RCTs were considered paramount. However, definitive data from these studies were not widely available and may never be conducted in many instances, particularly in relation to safety. As such, available epidemiological data from large administrative databases and observational studies were interpreted cautiously, due to the inherent limitation in their ability to inform clinical practice as they are not designed to determine causality, are subject to biases from potential confounding variables, and often evaluate multiple endpoints . As a result, the risk for observing spurious effects is increased. It has, therefore, been suggested that outcomes with ORs <3–4 may be the result of these extrinsic factors rather than the treatment or other variable that is being evaluated [182, 183]. Thus, findings from observational studies that do not reach this threshold—even if statistically significant—may not have any actual clinical significance, particularly if the underlying mechanisms have not been established. Notably, subsequent to conducting the literature reviews used for this consensus panel, additional studies have been published that reported an increased risk for chronic kidney disease  and dementia  associated with PPI use. However, as is noted above and by the authors of these reports, there are significant limitations with these studies that preclude establishing a causal relationship between these events and PPI use. As a result, we did not feel the need to reconvene this panel to address these reports.
Consensus statements and accompanying evidence-based reviews were developed to provide guidance on the safe and appropriate use of OTC PPIs for treating frequent heartburn. Although direct evidence for many areas was limited, based on the available empirical evidence and clinical experience accumulated over nearly 30 years with prescription and OTC PPIs, the panel considers that OTC PPIs are generally safe and effective when used according to the label instructions. To minimize the risk of adverse outcomes associated with OTC PPIs, healthcare professionals should provide guidance to individuals taking them to help them make appropriate treatment decisions and to help identify specific risk factors.
The authors thank Tore Lind, MD, PhD, for his thoughtful input, guidance, and expertise in support of this manuscript.
Compliance with Ethical Standards
Pfizer Consumer Healthcare provided funding for the live consensus panel meeting and provided recommendations and background information on prospective members of the panel (with final decisions determined by the co-chairs). Literature search assistance and writing/editorial assistance for the publication were provided by Dennis Stancavish, MA, and Diane Sloan, PharmD, of Peloton Advantage and were funded by Pfizer.
Potential conflict of interest
David A. Johnson, MD, is a paid consultant to Pfizer Consumer Healthcare and serves as an advisor for Pfizer. Philip O. Katz, MD, is a paid consultant to Pfizer Consumer Healthcare. David Armstrong, MA, MB BChir, has received an honorarium from Pfizer Consumer Healthcare and serves as an advisor for Pfizer. Henry Cohen, MD, has received an honorarium from Pfizer Consumer Healthcare. Brendan C. Delaney, MD, is a paid consultant to Pfizer Consumer Healthcare. Colin W. Howden, MD, has received an honorarium from Pfizer Consumer Healthcare. Peter Katelaris, MD, is a paid consultant to Pfizer Consumer Healthcare. Radu I. Tutuian, MD, PhD, has received an honorarium from Pfizer Consumer Healthcare. Donald O. Castell, MD, has no conflicts to disclose.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
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