Exploring the Role of the Pharmacist in OTC PPI Use for Frequent Heartburn

Release Date: April 30, 2010

Expiration Date: April 30, 2012

FACULTY:

John W. Devlin, PharmD, BCPS, FCCM
Associate Professor
School of Pharmacy
Northeastern University
Boston, MA

David C. Metz, MD
Professor of Medicine
University of Pennsylvania School of Medicine
Philadelphia, PA

FACULTY DISCLOSURE STATEMENTS:

John W. Devlin, PharmD, BCPS, FCCM has disclosed the following: Non-CME Fees from Takeda Pharmaceuticals.
David C. Metz, MD has disclosed the following: Consulting Fees from Novartis Consumer Health, Takeda Pharmaceuticals, Xenaport, and Novartis Pharmaceutical/Oncology; Contracted Research from Xenaport; Ownership Interest with Johnson & Johnson.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 809-999-10-093-H01-P
Credits: 1.5 hours (0.15 ceus)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 90 minutes.

Exam processing and other inquiries to:
CE Customer Service: (800) 825-4696 or cecustomerservice@jobson.com

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

The goal of this program is to acquaint pharmacists and allied healthcare professionals with the appropriate use of proton pump inhibitors (PPIs) available “over the counter” (OTC) for frequent heartburn.

OBJECTIVES:

After completing this activity, participants should be able to:

  1. Define frequent heartburn
  2. Describe how to take a focused clinical history to exclude other possible causes of heartburn-like symptoms
  3. Identify appropriate individuals for self-treatment with an OTC PPI
  4. Discuss the dose selection, efficacy, and rationale for use of OTC PPIs in individuals with frequent heartburn
  5. Explain possible long-term consequences of PPI use and place these in appropriate perspective

Introduction

Proton pump inhibitors (PPIs) were originally available as prescription‐only medicines with carefully defined approved indications. However, as of April 2010, omeprazole (Prilosec OTC), immediate‐release omeprazole with sodium bicarbonate (Zegerid OTC), and lansoprazole (Prevacid 24hr) are available for over‐the‐counter (OTC) purchase. The fact that these powerful and effective medicines have been approved for OTC purchase is a testament to their safety and efficacy.

Since their introduction into clinical practice in the early 1980s, PPIs have become established as the most effective medical treatment for gastroesophageal reflux disease (GERD) and physicians and patients have developed a high level of confidence in them.1 Now that some PPIs are available for OTC purchase, and may cost less than the co‐payment that would be charged for a branded prescription medication, some potential consumers are likely to approach their pharmacists – rather than their physicians – for guidance about the appropriate use of these medicines. Pharmacists should have a clear understanding of the approved indications for these products and should also be able to recognize key elements in a patient’s history that would require more detailed evaluation by a physician. They should also be aware of adverse events that can occur with these medicines and the possibility of drug–drug interactions.

The Relationship Between Heartburn and GERD

GERD is a medical condition or diagnosis. It has been defined as "a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications".1,2 Heartburn, on the other hand, is a symptom. It is defined as a burning retrosternal discomfort radiating towards the neck that is often worse after eating or while recumbent.1 The terms "GERD" and "heartburn" are, therefore, not synonymous. Heartburn is the most typical symptom of GERD. However, some patients may experience heartburn unrelated to acid reflux.

Indication for OTC PPI use

OTC PPIs are approved for the management of frequent heartburn for up to 2 weeks of continuous use. It is important that the 3 major components of this indication are clearly understood. First, "frequent" implies at least 2 days per week. Second, it is crucial that the term "heartburn" be accurately defined. Although this term is frequently used by patients and healthcare professionals, it is often used incorrectly to indicate any of a variety of symptoms thought to originate from the upper gastrointestinal tract. Properly used, heartburn refers to "a burning retrosternal discomfort radiating upward from the abdomen into the chest toward the neck that is often worse after eating or while recumbent".1 Typically, heartburn is worse after eating or when the patient bends or lies down. In general, it is not associated with physical exertion and the discomfort should not radiate all the way into the neck, shoulders, or upper arms. It is generally alleviated by antacids.

Heartburn should not be confused with dyspepsia, which is upper abdominal discomfort that comes and goes at intervals but which is not always predictable and, although it can occur after meals, may not be relieved by antacids. The discomfort of dyspepsia is variably described as a pain, distension, or feeling of fullness, but is generally not burning in nature; a cardinal feature of true heartburn is that the discomfort is appreciated in the chest – not in the abdomen. Some patients with true reflux‐associated heartburn may also complain of discomfort in the upper abdomen. Those patients who only complain of upper abdominal discomfort and do not experience any burning sensation in the chest do not have heartburn and actually have dyspepsia. Patients with dyspepsia may have peptic ulcer disease or an alternative diagnosis – most typically, functional (or nonulcer) dyspepsia. Although dyspepsia may improve with PPIs, this is not an FDA‐approved indication for prescription or OTC PPI use.

Third, is the acceptable duration of treatment for OTC PPI use. GERD is typically a chronic condition that requires prolonged maintenance therapy, but OTC use is primarily intended for initial, milder reflux‐ symptoms allowing for a brief course of therapy that can be repeated once if symptoms recur. The aim of this limitation in therapy is to ensure that patients do not mask more severe underlying disease with continuous therapy without being appropriately evaluated by a physician before committing to longer‐ duration therapy.

Assuming that a consumer with an interest in purchasing an OTC PPI does have heartburn that is occurring at least 2 days per week, he or she may be a candidate for an OTC PPI. However, it is important that such potential users of these products do not have other symptoms aside from heartburn that might be indicative of more serious underlying pathology. It is therefore important to ask patients with upper gastrointestinal symptoms, including heartburn, about the presence or absence of a number of "alarm symptoms" in an attempt to rule out other more sinister conditions and to identify those patients who require further diagnostic evaluation. Table 1 lists potential alarm symptoms, and some other features from a patient’s presentation, that should alert pharmacists to the possibility of more serious disease. Potential purchasers of an OTC PPI who have any of these alarm features should be advised to seek a medical opinion immediately.

Table 1. Alarm features that should prompt advice to seek a medical opinion

Classic alarm features

Dysphagia: Subjective difficulty in swallowing

Gastrointestinal bleeding: Vomiting of blood or “coffee-ground” material, or the presence of fresh or altered blood in the stool

Unexplained/unintentional weight loss

Anemia

Jaundice

Other features

Odynophagia: Pain or discomfort with swallowing

Protracted or recurrent vomiting

Heartburn with light-headedness, sweating, or dizziness

Chest pain with shortness of breath, sweating, pain spreading to arms, neck, or shoulders: Although chest pain may occur in GERD, it may be indicative of another disease process, including coronary heart disease.

Frequent wheezing, particularly with heartburn

Persistent severe symptoms

While some patients may consider heartburn to be little more than a nuisance, others may have more significant disruption of their daily activities and substantial impairment of quality‐of‐life because of it. This may include avoiding favorite foods, missing social events, or being less productive at work.3 Recently, attention has focused on the impact of nocturnal heartburn and other symptoms of GERD on patients’ sleep habits. Heartburn, and other symptoms of GERD such as regurgitation (the effortless movement of bitter‐tasting gastric contents into the esophagus or pharynx), that occur at night can cause serious disruption to sleep patterns. Indeed, in a survey of 1000 people who had heartburn at night, 75% said this had interfered with their sleep and ability to work the next day.4 It is important for pharmacists to ask heartburn sufferers if they are experiencing nighttime symptoms of GERD. Aside from heartburn and regurgitation, individuals with nighttime GERD may also complain of waking because of choking, coughing, or throat discomfort. It is also worth noting that although odynophagia (pain with swallowing) is typically caused by esophagitis, it is more characteristic of infectious or pill‐ induced esophagitis and not classically associated with reflux esophagitis.

How Do PPIs Work?

PPIs are substituted benzimidazoles that are highly acid labile and thus generally administered as enteric‐coated tablets or capsules that allow them to pass through the stomach intact and subsequently be absorbed in the proximal small bowel. They are metabolized in the liver via the cytochrome P450 enzyme system. They are all prodrugs with no intrinsic antisecretory activity until they become activated in the parietal cell secretory canaliculus. They are absorbed relatively quickly, with peak plasma concentrations occurring about 1 hour after dose and a half‐life (t½) of 1 to 2 hours. They are weak bases that rapidly concentrate in the secretory canaliculus of the parietal cell – the most acidic compartment of the body where they become protonated.

PPIs act to inhibit gastric acid secretion by covalently binding to the proton pump (H+/K+ ATPase), the final common pathway for acid secretion. PPIs diffuse into the canalicular lumen of the parietal cell, where they are concentrated and activated by conversion to sulfenamides in the highly acidic microenvironment. This change in morphology allows the PPI to bind to cysteine residues ion the alpha a subunit of the proton pump and inhibit acid secretion into the canalicular lumen. PPIs bind irreversibly to the gastric proton pump, requiring synthesis of new pumps or activation of resting pumps for acid production to resume.

Not all proton pumps are active at any given time. Proton pumps become active at various times throughout the day, usually in response to food. Following maximal stimulation by a meal, only up to about 75% of available pumps are activated by insertion into the secretory canalicular membrane. The body also continuously synthesizes new pumps throughout the 24‐hour day, thus providing a continuing ability for acid production. Because PPIs inhibit only actively secreting proton pumps, gastric acid suppression is optimal when the PPI is taken about 30 minutes before a meal.

Who Is Suitable – and Who Is Not Suitable – for OTC PPI Use?

Consumers for whom OTC PPI use is appropriate include:

  • Those adults who are experiencing heartburn on at least 2 days per week
  • Those who do not have additional alarm or other concerning features (Table 1)
  • Those who do not have predominant dyspepsia.

Those who only experience heartburn infrequently – in which case, it will likely be associated with over‐eating or some other dietary indiscretion – should, in the first instance, make the appropriate changes to their eating habits and other aspects of their lifestyle; they may not require any form of medicine on a regular basis for the management of heartburn (Table 2).

Table 2. Dietary/lifestyle factors that may cause or worsen heartburn

Possible factors that may aggravate heartburn

Dietary factors1,2,5

Lifestyle factors1,5

Spicy foods

Lying down 1–3 hours after a meal

Acidic foods

Obesity

Fatty foods

Overeating at meals

Alcohol3

Smoking

Caffeinated drinks

Exercising too soon after eating

Carbonated drinks

Certain types of exercise

Chocolate

Stress4

Mint

 

References: 1. Oliveria SA, Christos PJ, Talley NJ, Dannenberg AJ. Heartburn risk factors, knowledge, and prevention strategies: A population-based survey of individuals with heartburn. Arch Intern Med 1999; 159: 1592–8; 2. WebMD Top 10 heartburn foods. www.webmd.com/heartburn-gerd/features/top-10-heartburnfoods (Accessed July 30, 2009); National Heartburn Alliance. 3. Alcohol consumption and heartburn. www.heartburnalliance.org/print.php?id=11 (Accessed March 23, 2010); 4. National Heartburn Alliance. Sufferers point to stress as an aggravator of heartburn. www.heartburnalliance.org/stress_and_heartburn.php (Accessed March 23, 2010); 5. National Heartburn Alliance. Selfcare strategies. www.heartburnalliance.org/print.php?id=66 (Accessed March 23, 2010).



Patients who report some – but incomplete – symptom relief from an OTC antacid or H2‐receptor antagonist (H2RA) may be appropriate candidates for an OTC PPI, assuming they do not have any of the alarm features listed in Table 1. OTC H2RAs, including cimetidine, ranitidine, famotidine, and nizatidine, are frequently used for the management of heartburn. They work differently from the PPIs to suppress gastric acid secretion (acting on the basolateral surface of the parietal cell where they competitively antagonize the secretagogue histamine). They are also potent inhibitors of gastric acid output and produce rapid relief from heartburn, but tend to have much shorter durations of action. They are appropriate for patients with mild, infrequent heartburn.

In addition to the symptoms listed in Table 1, consumers who should be advised to see their doctor before using an OTC PPI include:

  • Consumers <18 years of age (unless advised by a physician)
  • Those with atypical and/or nonspecific symptoms
    • predominant epigastric pain
    • belching
    • hoarseness
    • sore throat
    • cough
  • Those with significant comorbidities, including any requiring multiple other therapies that can interact with PPIs, such as:
    • medications that require a low gastric pH for absorption: prescription antifungal or anti‐ yeast medicines (e.g. ketoconozole), digoxin, tacrolimus, and atazanavir
    • CYP450 interaction: clopidrogel, warfarin, and theophylline
  • Chronic NSAID takers
  • Those with heartburn lasting >3 months
  • Consumers needing >1 course of treatment every 4 months
  • Those with a family history of gastric and/or esophageal cancer

Pharmacists should be aware that the elderly may have less severe symptoms than non‐elderly patients for the same severity of GERD disease.

Pathophysiology of GERD and Frequent Heartburn

GERD tends to be a chronic illness. The American Gastroenterological Association (AGA) Institute published a technical review on GERD in 2008.1 This expert overview accepted a definition of GERD as, "a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications." This document also defined heartburn, the principal symptom of GERD, as, "a burning retrosternal discomfort radiating toward the neck that is often worse after eating or while recumbent."

Although it is usually treated with medicines that reduce gastric acid secretion, GERD is not a condition of excessive gastric acid secretion. Hypersecretory states such as Zollinger‐Ellison syndrome can present with reflux symptoms, but more commonly they are associated with peptic ulcer symptoms (dyspepsia) and diarrhea. In fact, GERD is actually a motility disorder in which there is more than a usual amount of gastric refluxate (containing acid) that comes into contact with the esophageal mucosa, leading to symptoms because of dysfunction of the gastroesophageal (GE) barrier and/or poor clearance of refluxate from the esophagus. The most common pathophysiological abnormality in GERD patients is transient, inappropriate relaxations of the lower esophageal sphincter (TLESRs) that allow for the retrograde movement of acidic gastric contents from the stomach into the esophagus (this can be thought of simply as an exaggerated burp reflex). Although this also happens, to some extent, in individuals who do not have GERD (we all tend to burp after large meals), patients experiencing heartburn have excessive numbers of TLESRs. Actual disruption of the GE barrier by disease processes such as scleroderma, leading to free reflux of gastric contents especially when individuals lie down, are rarer but more severe causes of GERD, and patients with these conditions usually have significant symptoms such that they require evaluation by a physician and more aggressive management.

In addition, many frequent heartburn sufferers also have impairment of their normal esophageal clearance mechanisms. Therefore, refluxed acidic gastric contents remain in contact with the esophageal mucosa for longer in these GERD patients than in healthy subjects with intermittent physiological gastroesophageal reflux. Acid – along with the digestive gastric enzyme pepsin – is caustic to the esophageal mucosa. Recall that the esophagus is normally lined by a stratified squamous epithelium, whereas the stomach has a simple columnar epithelium. The esophageal mucosa is highly permeable to acid, which can permeate into deeper layers of the mucosa and activate chemosensitive pain receptors causing the typical symptom of heartburn or, in some individuals, a sensation that is perceived as pain.

Some patients with GERD develop erosions of the esophageal mucosa. These can only be recognized at endoscopy; such patients have erosive esophagitis (EE), but they only comprise a minority of all GERD patients. In general, EE should be managed long‐term with daily prescription PPI therapy, since relapse of EE is almost inevitable if PPI maintenance treatment is stopped. One of the reasons to limit OTC PPI use to a 2‐week trial of therapy is to try and prevent EE patients from undertreating themselves with intermittent low dose therapy and ultimately developing complications that could otherwise have been prevented. In contrast, GERD patients without EE may be considered as having nonerosive reflux disease (sometimes abbreviated as "NERD"). Patients with NERD may have symptoms of reflux that are as bad as – if not worse than – those with EE, although their risks for long‐term complications are less. Although the PPIs were initially restricted to prescription use in EE patients, there is now considerable evidence that they are also the most effective agents available for the management of heartburn and other symptoms of reflux in NERD patients.

When Is Endoscopy Required?

The distinction between EE and NERD can only be made by endoscopy. The timing of endoscopy in patients with GERD symptoms is a matter of controversy and disagreement. Endoscopy is of little diagnostic value; since most GERD patients will actually have NERD and EE, patients on PPI therapy will have healed. Endoscopy should be considered:

  • To exclude other diseases or, rarely, to identify inadequately treated EE, especially in patients not responding to PPI treatment
  • For patients who have experienced GERD symptoms for ≥5 years
  • To evaluate for the presence of Barrett’s esophagus (BE) which persists despite PPI therapy

Barrett’s esophagus is a condition in which there is an abnormal alteration of the mucosal lining of the esophagus, which is thought to be caused by damage from chronic acid exposure or reflux esophagitis. In BE the normal stratified squamous epithelium of the lower esophagus is replaced by columnar lined epithelium with intestinal differentiation. It is considered to be a premalignant condition because it is associated with an increased risk of esophageal cancer. The epidemiologic factors that contribute to susceptibility to BE and associated esophageal cancer include genetic predisposition, age, male gender, smoking, Caucasian race, central obesity, an absence of H. pylori infection, and the presence of GERD. Although people without GERD can have BE, the condition is found about 3 to 5 times more often in people who also have GERD. Current best available evidence from population‐based analysis suggests that the prevalence of BE is 1.6%, but this is probably an underestimate as many individuals with BE are asymptomatic. The precise rate of progression from BE to esophageal adenocarcinoma varies from ~0.5 to 1.0% per year.

The Role of the Pharmacist

Pharmacists should be prepared to take a brief, focused history from potential purchasers of OTC PPIs with a particular emphasis on excluding – as far as possible – the alarm and other concerning features listed in Table 1. They should also attempt to identify patients with nuisance heartburn who may not need medication therapy at all and should help patients understand the need for an evaluation by a physician if their symptoms respond to therapy but recur after completion of a second course of therapy. Questions that pharmacists should consider asking potential purchasers of OTC PPIs are listed in Table 3.

Table 3. Questions for a pharmacist to consider when interviewing a potential purchaser of an OTC PPI

Tell me about your problem
The principal – or only – complaint of the potential consumer should be heartburn – a burning discomfort felt in the central chest region just behind the breastbone.

Where do you experience the discomfort?
Heartburn is an unpleasant sensation that is experienced in the chest – not in the abdomen. If the consumer’s discomfort is only experienced in the upper abdomen, he/she is not experiencing heartburn and OTC PPI treatment is not an appropriate choice.

How would you describe the discomfort?
People with heartburn may use terms such as “burning” to describe their symptom. While this is by no means diagnostic, it is supportive of the diagnosis of heartburn. People who describe their chest discomfort using terms such as “crushing” or “squeezing” are less likely to have heartburn and could have a cardiac explanation for their symptom. They should be advised to seek medical attention. Similarly, people who use terms like “stabbing” to describe their chest discomfort are unlikely to have heartburn. They too should be advised to seek medical attention.

What tends to bring on the discomfort?
People with heartburn may report that their discomfort is worse after eating, when they bend over, or when they lie flat – as in bed. Discomfort should not be closely related to physical exertion. If the person reports that his/her discomfort is typically brought on by exertion, the cause is less likely to be heartburn and may be heart disease. Medical consultation should be recommended.

How often does this bother you?
OTC PPIs are FDA-approved for the management of “frequent heartburn”, which is defined as heartburn that occurs on 2 or more days per week. Heartburn that is less frequent than this does not require PPI treatment and may respond to dietary modifications and/or the use of simpler medicines such as antacids, alginates, or H2‑receptor antagonists (H2RAs).

Does this problem disturb your sleep or wake you at night?
Many people with gastroesophageal reflux disease (GERD) report nighttime problems that may include typical heartburn (as defined above) and/or regurgitation (the effortless return of gastric contents into the pharyngeal region or mouth). Individuals with nighttime GERD may also complain of waking with coughing or choking spells, as well as poor quality of sleep or excessive daytime drowsiness because of disturbed sleep. People with prominent nighttime GERD symptoms may have more severe disease and should probably be evaluated by a physician.

Have you tried any other medicines before for this problem?
Many people with heartburn may already have tried other medicines – either OTC or by prescription. OTC medicines may include antacids, alginates, H2RAs, or another OTC PPI. Prescription medicines may include H2RAs and PPIs. At least a partial response to one of these other medicines is supportive of a diagnosis of true heartburn. More importantly, complete failure of other medicines to improve the person’s symptom suggests something other than heartburn as the cause of their problem.

Do you have any difficulty or pain with swallowing?
The answer should be “No”. People who answer “Yes” require medical evaluation; they may have more severe GERD or an alternative diagnosis that would not be expected to improve with OTC PPI treatment.

Are you taking any other medicines?
The FDA has required alerts on OTC PPI product labels for individuals taking some other medicines – including warfarin, digoxin, theophylline, atazanavir, and antifungal agents. People taking one or more of these medicines should probably consult a physician before starting PPI treatment – even though the absolute risk of a clinically meaningful drug–drug interaction is low.

Consumers should be specifically asked about their use of clopidogrel. The FDA has recommended avoidance of omeprazole – both prescription and OTC – for people taking clopidogrel. This recommendation also extends to avoidance of prescription esomeprazole, but not – as of April 2010 – to other OTC or prescription PPIs.


Based on this information, pharmacists should also be able to identify those individuals who are not candidates for PPI therapy or who should consult their doctor before starting treatment.

The pharmacist, therefore, will occupy an important position as a potential "gatekeeper" as well as point of first call for some individuals with distressing symptoms of heartburn. Given the media attention that has been placed on heartburn, it is virtually certain that pharmacists will be approached for advice. If there is any doubt as to the nature of a person’s symptoms or if there is any uncertainty as to that person’s suitability for self‐management with an OTC PPI, the pharmacist should err on the side of caution and recommend that the consumer discusses his/her symptoms with their physician.

If the pharmacist is comfortable that a consumer satisfies the criteria for OTC PPI use, it might be useful to inquire as to previous use of antacids, alginates, or H2RAs. Numerous preparations are available for OTC purchase and it is likely that some consumers will have tried one or more of these before considering an OTC PPI. Those consumers who report a partial response to an antacid or an OTC H2RA are likely to do well with OTC PPI use and should be advised accordingly. However, complete failure of OTC H2RAs to alleviate a consumer’s symptom(s) might suggest that the diagnosis of frequent heartburn is incorrect, that intragastric acid is not the primary cause and, therefore, OTC PPI use might not be the most appropriate next course of action.

PPIs as Treatment for GERD

It is unequivocal that the PPIs are the most effective agents available for the management of GERD. The AGA technical review on GERD1 firmly endorsed this view. Furthermore, a Cochrane Collaboration systematic review and meta‐analysis found that PPI treatment was the most effective strategy for EE – both for initial healing and for subsequent maintenance.5 Numerous randomized controlled trials have demonstrated that PPIs are superior to H2RAs for the healing of EE, for the maintenance of healing of EE, and for the control of GERD symptoms – both in patients with EE and in those with NERD.1,5 Some GERD patients – particularly those with EE – are likely to require long‐term, daily maintenance treatment with a PPI. However, many others do not appear to require continuous daily PPI treatment in order to obtain satisfactory control of their GERD symptoms. Although PPIs are not FDA‐approved to be taken on an "as-needed" or "on-demand" basis, many patients opt to use them in that manner.6 Numerous randomized control trials have demonstrated that, among GERD patients with PPI‐responsive heartburn, on‐demand use of a PPI is more acceptable than on‐demand use of a placebo.7 Furthermore, many patients report satisfaction with this approach and find that their symptoms are controlled adequately.

The currently available OTC PPIs are approved to be taken once daily before breakfast for a 14‐day course. They are approved for the management of frequent heartburn, defined as heartburn occurring on 2 or more days in a week. They are not intended to be used for the immediate relief of heartburn. Some users do experience complete relief on the first day of PPI treatment, but it may take up to 4 days to obtain the full effect.8 Consumers are advised not to take an OTC PPI for longer than 14 days, and not to take a 14‐day course more often than every 4 months, unless directed by a doctor.

Currently Available OTC PPIs

As of April 2010, three PPIs – namely omeprazole, lansoprazole, and immediate‐release omeprazole with sodium bicarbonate – had been made available for OTC purchase. Initially, the only OTC form of omeprazole that was available was Prilosec OTC. However, now other generic forms of the 20‐mg dose of omeprazole are also available for OTC purchase. In its initial prescription formulation, omeprazole was dispensed as encapsulated enteric‐coated granules. However, the OTC form has a different formulation; it is described as an "omeprazole magnesium delayed‐release 20.6 mg" tablet. This was formulated as a multi‐unit pellet suspension (MUPS) rather than as the initial prescription form.

Lansoprazole was approved by the FDA for OTC purchase in late 2009. It is available in a 15‐mg dose and is marketed as Prevacid 24hr. OTC lansoprazole has the same formulation as the original prescription form, namely as a delayed‐release capsule. This may be reassuring and less potentially confusing for some consumers who may switch from prescription to OTC lansoprazole.

Immediate‐release omeprazole with sodium bicarbonate (Zegerid OTC) has been approved by the FDA for OTC use in a dose of 20 mg once‐daily.

Dose Justification for OTC PPIs

When omeprazole was only FDA‐approved for prescription use, the approved doses included both 20 and 40 mg once‐daily. Omeprazole 20 mg was the FDA‐approved prescription dose for symptoms of heartburn and GERD. The 40 mg dose was FDA‐approved for gastric ulcers. Many patients took more than 20 mg daily for adequate control of symptoms of GERD. The FDA‐approved OTC dose of omeprazole is 20 mg once‐daily for 14 days.

Lansoprazole was FDA‐approved as a prescription drug for the healing of EE in a dose of 30 mg once daily for up to 8 weeks. The prescription dose of 15 mg once daily was FDA‐approved for the management of heartburn in patients with symptomatic GERD and for the maintenance of healing of EE.9–11 Thus, the FDA‐approved OTC dose is in line with the original prescription label.

Lansoprazole 15 mg has a similar antisecretory effect compared with omeprazole 20 mg, but a more rapid onset of action and higher absolute bioavailability (detectable serum concentrations) after a single dose has been demonstrated.12,13 Tolman and colleagues initially compared the pharmacodynamic effects of lansoprazole 15 or 30 mg with omeprazole 20 mg in a randomized, crossover study in 14 healthy male volunteers.12 Each regimen was given once daily for 5 days, and 24‐hour intragastric pH was measured on the last day. Mean 24‐hour intragastric pH was 4.91 on lansoprazole 30 mg, 4.03 on lansoprazole 15 mg, and 4.16 on omeprazole 20 mg. The pharmacodynamic effects of lansoprazole 15 mg were not significantly different to those of omeprazole 20 mg. Moreover, after the first and fifth single daily doses of the drugs, there was no significant difference in pharmacodynamic effect between lansoprazole 15 mg and omeprazole 20 mg. Fifteen days after stopping lansoprazole or omeprazole, intragastric pH values had returned to baseline.13 In a study by Muller and colleagues, two doses of omeprazole MUPS (10 mg and 20 mg) and three doses of lansoprazole (7.5 mg, 15 mg, and 30 mg) were compared against placebo for inhibition of pentagastrin‐stimulated gastric acid secretion.14 Again, lansoprazole 15 mg and omeprazole 20 mg were very similar with respect to inhibition of acid output. Therefore, two separate, peer‐reviewed pharmacodynamic studies found no difference between lansoprazole 15 mg and omeprazole 20 mg. The studies used different methodologies and reached similar conclusions.

Effectiveness of OTC PPIs for the Management of Frequent Heartburn

Two randomized, controlled clinical trials compared omeprazole 10 mg and 20 mg with placebo once daily for the management of frequent heartburn.15,16 Following a 1‐week run‐in phase, 3124 participants took study medication in a blinded fashion for 14 consecutive days. The age range of the patients who completed the studies was 18 to 86 years. The primary efficacy endpoint was the proportion of participants who were heartburn‐free in the preceding 24‐hour period. In the first study, 49.7% of patients taking omeprazole 20 mg and 32.6% of patients taking placebo met the primary endpoint (difference 17.1%, p<0.001). Corresponding figures for the second study were 46.8% and 32.1%, respectively (difference 14.7%, p<0.001) (see Figure 1). On day 14 of each of the studies, over 70% of patients taking omeprazole 20 mg once daily reported being completely heartburn-free. A predetermined secondary endpoint in both studies was the proportion of patients who had no more than mild heartburn following the first dose of study drug. In study 1, the proportions were 81.0% of those taking omeprazole 20 mg once daily and 71.6% in the placebo arm (difference 9.4%, p<0.001); corresponding figures for the second study were 81.8% and 70.8%, respectively (difference 11.0%, p<0.001).


Figure 1. Results of a randomized, controlled trial comparing omeprazole 20 mg and placebo once daily for 14 days in patients with frequent heartburn.16


Lansoprazole 15 mg and placebo once daily for 14 days were compared in a self‐treating population for the management of heartburn occurring on 2 or more days per week over 1 month.17 The demographics of the study population were broadly representative of those consumers for whom OTC PPI would be considered appropriate; mean age was 47.9 years (range 18 to 90 years), and 64% were female. Almost all (95.8%) of participants completed the studies. The mean percentages of 24‐hour heartburn‐free periods during the 14‐day study were 58% for lansoprazole 15 mg (n = 861) and 40% for placebo (difference 18%, p<0.0001). In the lansoprazole‐treated group, 45.4% of patients were heartburn‐free on day 1 compared with 31.2% of the placebo group (difference 14.2%, p<0.0001). Additionally, 64.1% of patients taking lansoprazole 15 mg reported at least one heartburn‐free day during the first 2 days of double‐blinded treatment, compared with 49.5% of those taking placebo (difference 14.6%, p<0.0001).

In another recently reported study, lansoprazole 15 and 30 mg once daily were compared with placebo in 864 adults with heartburn occurring at least 2 nights per week within 1 month.18 The mean age of participants was 48.1 years; 63% were female. The proportions of nights without heartburn were 61.7% with lansoprazole 15 mg, 61.3% with lansoprazole 30 mg, and 47.8% with placebo (differences 3.9% and 3.5%, respectively; p<0.0001 for each lansoprazole dose versus placebo) (see Figure 2). The proportions of 24‐hour days that were heartburn‐free were 49.7% with lansoprazole 15 mg, 50.9% with lansoprazole 30 mg and 29.5% with placebo (differences 0.2% and 21.4%, respectively; p<0.0001 for each lansoprazole dose versus placebo) (see Figure 2). The proportions of subjects who were heartburn‐free on day 1 were 35.4% with lansoprazole 15 mg, 36.5% with lansoprazole 30 mg, and 22.5% with placebo (differences 12.9% and 14%, respectively; p = 0.0005 versus lansoprazole 15 mg; p=0.0004 versus lansoprazole 30 mg). Thus, lansoprazole performed similarly – and significantly better than placebo – whether it was dosed at 15 or 30 mg once daily in this patient population.


Figure 2. Results of a randomized, controlled trial comparing lansoprazole 15 mg, lansoprazole 30 mg, and placebo once daily for 14 days in self‐treating patients with frequent nighttime heartburn18

Kushner and colleagues have reported the combined results of two identical trials comparing lansoprazole 15 mg and placebo taken once daily in the morning for the management of frequent heartburn.19 In both trials, there was an initial 1‐week period for screening and washout of any heartburn medicines followed by 1 week of placebo treatment in order to confirm the frequency of heartburn. Participants were then randomized to a 2‐week period of once‐daily, double‐blinded treatment with lansoprazole 15 mg (n = 570) or placebo (n = 564). There was then a 1‐week period of placebo treatment as follow‐up. During the 2 weeks of double‐blinded treatment, subjects taking lansoprazole 15 mg once daily had significantly better control of heartburn than those taking placebo; the main results from these trials are illustrated in Figure 3.


Figure 3. Results of two randomized, controlled trials comparing lansoprazole 15 mg and placebo once daily for 14 days in patients with frequent heartburn19


As of April 2010, there were no data available concerning the OTC use of immediate‐release omeprazole with sodium bicarbonate by self‐treating individuals with frequent heartburn.

Possible Concerns Regarding OTC PPI Use

The PPIs are among the safest of drugs currently in use. Were this not the case, the FDA would not have approved them for OTC use. While they were still prescription‐only products, enormous cumulative clinical experience of the efficacy and safety of PPIs accumulated. The main concerns about the use of these drugs as OTC products relates to the possibility that they would be taken for clinically inappropriate reasons and that even if successful in controlling symptoms, they might mask underlying serious disease. However, if pharmacists follow the guidelines listed above, the potential for these outcomes can be minimized. Experience with the initial availability of omeprazole as an OTC agent was that consumers purchased it for appropriate indications and generally used it according to package instructions.20

The most common adverse events with omeprazole OTC are headache and diarrhea, consistent with those seen in clinical trials and postmarketing surveillance for prescription Prilosec. In all 3 clinical trials with lansoprazole 15 mg, the most frequently reported adverse events versus placebo over 14 days of treatment were diarrhea (1.7% versus 0.4%), headache (1.2% versus 1.4%), nasopharyngitis (1.0% versus 0.7%), nausea (0.7% versus 0.7%), abdominal pain (0.5% versus 0.2%), and vomiting (0.5% versus 0.4%). Pharmacists should communicate to consumers that they may have mild alterations in their bowel habits – if they experience any events which are severe and prolonged, they should be directed to their physician for follow‐up.

Drug–Drug Interactions (DDIs)

Some DDIs have been reported with PPIs but these are generally of pharmacokinetic interest only and few, if any, are of clinical relevance. A review of the data on DDIs with PPIs registered with the FDA found low reported rates and no apparent differences between the rates among omeprazole, lansoprazole, and pantoprazole.21

Clopidogrel: There have been recent concerns that omeprazole might impair the anti‐platelet activity of clopidogrel. Clopidogrel is a prodrug that requires hepatic conversion to an active metabolite, which in turn exerts an anti‐platelet effect by binding to the adenosine diphosphate (ADP) receptor on platelets. This binding impairs ADP‐mediated activation of platelet glycoprotein GPIIb/IIIa complex. Omeprazole might slow the conversion of clopidogrel to its active metabolite by competition for binding sites at cytochrome P450 2C19. Clopidogrel, often accompanied by aspirin, is recommended for patients who have had coronary artery stenting. Two retrospective studies reported higher rates of adverse cardiovascular outcomes in patients receiving clopidogrel, aspirin, and omeprazole, than in patients receiving clopidogrel and aspirin without the PPI. 22,23 However, both of these studies were conducted retrospectively and the control patients in each study (i.e., those not receiving a PPI) were significantly younger, had less comorbidity and less severe cardiac disease than the patients who were taking a PPI. Data from prospectively conducted trials in patients undergoing percutaneous coronary intervention have not found any deleterious effect of PPI co‐therapy.24,25 Furthermore, PPI co‐therapy was associated with reduced all‐cause mortality in one report,23 and with a significant reduction in gastrointestinal adverse events in the other.24

Nonetheless, this is an area of great concern and interest to physicians and pharmacists. Patients – especially the elderly – who have had coronary artery stenting and are being appropriately treated with clopidogrel and aspirin, are at increased risk of upper GI tract bleeding. Such patients are often prescribed a PPI to reduce this risk. Pharmacists should understand the potential consequences of such an interaction and may be asked about the risks and benefits of PPI co‐therapy (including with OTC PPIs) by some patients.

In November 2009, the FDA issued an alert advising that the combination of clopidogrel and omeprazole (prescription or OTC) or esomeprazole should be avoided.26 This advice was issued on the basis of an in vitro study demonstrating reduced levels of clopidogrel’s active metabolite during omeprazole co‐therapy. The FDA also stated that separating the dose of clopidogrel and omeprazole/esomeprazole in time (i.e., giving them 12 hours apart) will not reduce this drug interaction.

Other drugs interacting with the cytochrome P450 system: Studies have shown that lansoprazole does not have clinically significant interactions with other drugs metabolized by the cytochrome P450 system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. Omeprazole can prolong the elimination of diazepam, warfarin, and phenytoin. There have been case reports of increased INR/prothrombin time in patients receiving omeprazole and warfarin concomitantly. Increases in the INR/PT may lead to abnormal bleeding and even death. Patients treated with omeprazole and warfarin should be monitored for increases in the INR/PT.  

Drugs requiring low gastric pH for absorption: All PPIs may reduce the absorption of the antiretroviral agent atazanavir; co‐prescription of a PPI with atazanavir may lead to treatment failure or the emergence of drug‐resistant strains of HIV. All PPIs may increase the absorption of digoxin by around 10%; this is generally not of clinical consequence. The packaging of all currently available OTC PPIs advises consumers to consult a physician or pharmacist if they are taking medicines including digoxin, theophylline, tacrolimus, atazanavir, and prescription anti‐fungals.

Potential complications of long‐term PPI use

As has already been alluded to, OTC PPI use should not extend beyond two 2‐week trials of therapy without physician involvement. However, because of the vagaries of insurance medication coverage and the costs of OTC therapy versus prescription therapy, individuals may well switch prescription PPIs for maintenance OTC therapy instead (even though this is off‐label use). Consequently, pharmacists may encounter patients using OTC PPIs for prolonged periods. Therefore they need to be aware of potential long‐term effects of prolonged PPI use.

Some potential long‐term safety concerns with the PPIs have been discussed recently.27,28 In general, these concerns, summarized in Table 4, focus on potential consequences of PPI treatment that are of small absolute risk. Furthermore, most of the data have been acquired retrospectively rather than prospectively. Some of the most important concerns are discussed below.

Table 4. Some potential adverse effects of long-term PPI use

Adverse effect

Comment

References

Enteric infections

Mostly retrospective studies; suppression of acidity by PPIs might predispose to bacterial enteric infection by raising intragastric pH; absolute risk is low

27, 28, 33, 37, 38

Community-acquired pneumonia (CAP)

Reduction of gastric acid secretion might predispose to gastric colonization with bacteria that may trans-migrate to the lungs. Note that GERD per se is a risk factor for pneumonia. PPI taking may be a surrogate for GERD. No increased risk of CAP seen with long-term PPI use in one study.35

27, 28, 34, 35

B12 malabsorption

Suppression of gastric acidity might impair the ability to extract dietary vitamin B12 from food proteins. No true B12 deficiency has been described as attributable solely to PPI taking.

27, 28

Hip fracture

Suppression of gastric acidity might reduce the ability to absorb dietary calcium, ultimately leading to an increased tendency to fracture. Quantitative risk is low. No evidence that PPIs increase rate of osteoporosis or accelerate bone demineralization.

27, 28, 29, 30, 31, 32, 33

Hip fracture: Studies have reported an association between PPI taking and hip fracture.29–31 The exact mechanism of this is unclear. It has been hypothesized that decreased gastric acid production from PPI use might partially impair the intestinal absorption of dietary calcium, ultimately leading to a decrease in bone mineralization and an increased tendency to fracture. However, recent studies did not find any association between PPI taking and osteoporosis or accelerated loss of bone mineral density.32,33 The AGA Institute technical review on GERD did not recommend any additional screening for osteoporosis or any additional calcium supplementation for patients on PPI treatment.1

Community‐acquired pneumonia: PPI use has been proposed as a risk factor for the acquisition of community‐acquired pneumonia (CAP).34 However, the risk of CAP with PPI use was not materially different from that attributed to H2RA use and it may be that either taking a PPI or H2RA was simply a surrogate marker for GERD. Furthermore, a more recent study found no association between long‐term PPI use and CAP.35

Enteric infections: Risks of PPI therapy may include an increased rate of Clostridium difficile infection and other bacterial enteric infections.36,37 However, the quantitative risk is small and the in‐hospital spread of C. difficile could largely be avoided by simple measures such as proper hand washing rather than inappropriate restriction of PPI use.38

Vitamin B12 deficiency: Some studies have shown that short‐term use of PPIs decreases the absorption of vitamin B12, but the results of studies into long‐term PPI use and vitamin B12 deficiency are inconsistent. Reduced serum vitamin B12 (cobalamin) levels have been documented occasionally during long‐term treatment with a PPI in selected groups of patients, especially the elderly. Results from a recent study show that vitamin B12 deficiency is common in the elderly and suggests periodic monitoring of vitamin B12 status while taking PPI long-term is advisable to enable correction before complications ensue.

Summary: Best Practice for Pharmacists

When asked for advice from a consumer regarding OTC PPI therapy, pharmacists should take a brief, focused history to determine if the person is a suitable candidate. The information summarized earlier should be helpful in this setting. If there is any doubt as to the individual’s suitability for OTC PPI use, the pharmacist should err on the side of caution and the potential consumer should be advised to seek a medical opinion. However, for most potential consumers, OTC PPI use is a safe and effective means of dealing with frequent heartburn.

Pharmacists should advise consumers to follow the recommendations on the PPI package insert. Adults with heartburn on 2 or more days per week over the preceding month should take a single dose of their OTC PPI each day before breakfast for 14 days. If frequent heartburn persists, medical attention should be sought. If symptoms respond completely, the OTC PPI should be discontinued after the 14‐day course. Relapse of symptoms within 3 months, or the development of any alarm features at any time, should prompt referral to a physician. Relapse of frequent heartburn 3 months or longer after completing the first 14‐day course of an OTC PPI can appropriately be managed by another 14‐day course. An algorithm summarizing this approach can be found in the publication by Haag and colleagues,39 however, it should be noted that while Haag and colleagues recommend OTC PPI use for 2 to 4 weeks, the FDA has specifically approved OTC PPI treatment as a 14‐day course.


Figure 4: Algorithm for pharmacy‐based management of typical reflux symptoms (heartburn and/or acid regurgitation) 39

 

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