This report was reviewed for medical and scientific accuracy by Evelyn R. Hermes De Santis, PharmD, Clinical Associate Professor, Department of Pharmacy Practice and Administration, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, New Jersey

Editorial

John R. Horn, PharmD, FCCP, Professor of Pharmacy, University of Washington School of Pharmacy and Associate Director of the University of Washington Medical Center Pharmacy Services, Seattle, Washington

Heartburn, the predominant symptom of gastroesophageal reflux disease (GERD), is one of the most common conditions encountered by pharmacists. GERD is a chronic disease that produces intermittent symptoms. Pharmacists are likely to be the first healthcare providers consulted by patients who are experiencing heartburn. Upon appropriate and thorough questioning of the patient to ascertain duration and severity of symptoms, pharmacists can be instrumental in helping patients with heartburn successfully self-manage their condition with a variety of safe and effective over-the-counter (OTC) medications. Moreover, pharmacists can qualify the patient for possible referral to their primary care physician for treatment. The availability of these medications enhances consumers' access to efficacious treatment options, empowers patients to improve self-care, and in the era of managed care and fiscal constraint, may possibly reduce health care expenditures. However, the multitude of available OTC products, combined with differing mechanisms of action, can create confusion among consumers and healthcare providers alike. What is the most effective treatment for heartburn? How long should the product be used before determining whether alternative treatment is needed? At what dose is this product most effective? Should the dose be increased? When should you take the product? How do you treat breakthrough episodes? At what point should the patient see their physician? In this context, the pharmacist is challenged to individualize appropriate patient therapy through understanding of the advantages and disadvantages of each of the multiple treatment options.

The availability of OTC therapies including antacids, H₂ receptor antagonists (H₂RAs), and the combined use of these agents, provides a seemingly endless number of treatment options. However, most pharmacists will select a few products to recommend based on the patient's presentation. Since antacids have the most rapid onset of action, they are most appropriate for the treatment of active heartburn. A chewed antacid tablet would seem to provide an optimal drug delivery method to neutralize esophageal acid and terminate the heartburn resulting from acid refluxing into the esophagus. H₂RAs have the advantages of suppressing gastric acid production, producing a longer duration of action than an antacid, and are preferred for heartburn prophylaxis and the control of nocturnal heartburn. I believe all patients should be provided with both an antacid and a H₂RA, either in combination or as separate products, and given instructions on how to use the product to treat their symptoms. The combined use of an antacid and H₂RA provides the dual benefit of a rapid onset of heartburn relief with a prolonged duration of heartburn prevention. By combining appropriate patient evaluation and counseling together with rational OTC product selection, pharmacists will be able to effectively manage many patients with uncomplicated heartburn.

At the recent 2003 American Pharmaceutical Association Annual (APhA) Meeting & Exposition, data was presented on currently available and future OTC treatment options for heartburn associated with GERD. The purpose of this Express Report is to review and summarize this data from the pharmacist's perspective in order to prepare and assist the pharmacist in recommending effective pharmacologic therapies for his/her patients with heartburn.

Heartburn Perspective

In a presentation titled "Prevention and Treatment of Heartburn: Sorting out the Options",¹ A. Mark Fendrick, MD, Associate Professor of Internal Medicine and Associate Professor of Health Management and Policy, University of Michigan Health System, Ann Arbor, Michigan called attention to the considerable impact of this condition, noting that persons with GERD have demonstrated a poorer quality of life, for example, than persons with angina or mild heart failure.² Fortunately, OTC interventions are largely effective in reducing GERD symptoms, and this significantly improves patients' quality of life,³ advised Dr. Fendrick.

"Heartburn must be given due respect," Dr. Fendrick commented. "Heartburn must be evaluated and appropriate treatment must be initiated, aimed at improving symptoms."

This offers opportunities for education and therapeutic guidance. "Given the availability of effective treatment options, and excluding patients with frequent or severe symptoms, I do believe that individuals with intermittent, uncomplicated heartburn can be managed with OTC agents almost entirely by pharmacists," Dr. Fendrick noted.

Indications for Self-Treatment: What Should the Pharmacist Advise?

Pharmaceutical care for people with heartburn begins with a careful medical and medication history. This can help pinpoint triggers for heartburn and minimize the risk of OTC-related drug interactions or adverse effects, according to John R. Horn, PharmD, Professor of Pharmacy, University of Washington School of Pharmacy and Associate Director of the University of Washington Medical Center Pharmacy Services, Seattle, Washington.⁴

Common medications, whose use might induce heartburn through effects on upper gastrointestinal motility, include anticholinergic agents, calcium channel blockers, levodopa, nicotine, opiates, progestins, and theophylline. The pharmacist is in an optimal position to rule out medication-induced heartburn and also to identify and encourage patients to eliminate foods that trigger episodes of heartburn.

It is important for pharmacists to identify individuals who should seek counsel from a physician; primarily those patients who have symptoms of angina pectoris and those with disordered motility, as indicated by the presence of dysphagia and gas-related symptoms. Atypical symptoms such as hoarseness, laryngitis, and respiratory symptoms, need further evaluation as well, as do patients with any of the following "alarm symptoms": weight loss, severe pain or chest pain, blood in the stool or vomitus, current vomiting, dysphagia or odynophagia, and history of cancer or immunosuppression, especially in male patients over age 50, a high-index group, advised Dr. Horn.

But most patients are appropriate candidates for self-treatment under a pharmacist's guidance. Most clinicians recommend self-treatment for people with heartburn that occurs no more than twice weekly (episodic). Patients with more frequent symptoms or who require continued use of OTC products without relief (more than 4 weeks) should be referred to a physician, Dr. Horn stated.

An empiric trial of antisecretory therapy is an accurate diagnostic test for heartburn and GERD, both speakers agreed. "If the patient gets better with treatments that reduce acid in the stomach, you can be confident he or she has reflux disease," Dr. Fendrick said.

Endoscopy is best utilized on select patients for whom it is important to rule out more serious conditions. The frequency, severity, and duration of GERD symptoms are related to the risk of esophageal adenocarcinoma. In particular, symptoms occurring more than three times a week, symptoms lasting over 20 years, and high symptom severity scores are related to a 16-fold to 20-fold increased risk of esophageal adenocarcinoma,⁵ therefore these patients should be carefully evaluated, Dr. Fendrick noted.

Current OTC Therapeutic Options

To relieve episodic heartburn, pharmacists can recommend an empiric trial of OTC therapy with antacids, antacid-alginate combinations, H₂RAs, or H₂RA/antacid combinations, suggested Dr. Horn. It is anticipated that a fifth treatment option—proton pump inhibitors—will be available OTC in the near future.

Each treatment option has distinct advantages and disadvantages. OTC antacids (eg, Maalox, Mylanta, Titralac, Tums, Rolaids) are effective for heartburn because they neutralize gastric acidity with a rapid onset of action and are an inexpensive treatment option. However, because most antacids contain magnesium, aluminum or calcium, drug interactions are common and include, but are not limited to phenytoin, valproic acid, flouroquinolones, tetracycline, ferrous sulfate, and ketoconazole and itraconazole. Additionally, due to their short duration of action, antacids must be dosed frequently throughout the day for symptom control.

Antacid/alginate combinations (Gaviscon) have a rapid onset of action but are hampered by short duration and a lack of effect on acid secretion. These products provide more of a protective barrier to prevent refluxed contents from irritating the esophagus versus neutralizing acidity or reducing gastric acidity.

H₂RAs [famotidine 10 mg (Pepcid AC), ranitidine 75 mg (Zantac 75), nizatidine 75 mg (Axid 75), cimetidine 200 mg (Tagamet HB)] on the other hand, have a slower onset of action compared to antacids and thus are less useful for treating acute episodes of heartburn. However, H₂RAs have a significantly longer duration of effect and are able to provide excellent nocturnal acid control. The OTC H₂RAs are easy to use prophylactically, as they can be taken before a meal. Some H₂RAs have the potential to cause drug interactions; particularly with those medications whose absorption is gastric pH-dependent. Metabolic inhibition with cimetidine is dose-related, especially at doses above 400 mg daily. Interactions with propranolol, warfarin, theophylline, phenytoin, carbamazepine, and verapamil are the most noteworthy. Increased or decreased prothrombin times have been reported during concurrent use of ranitidine and warfarin.⁶ No drug interactions have been identified with famotidine.⁷

The combination of H₂RA (famotidine 10 mg) and calcium carbonate 800 mg/magnesium hydroxide 165 mg (Pepcid Complete) offers the dual benefits of rapid acid neutralization and long-term protection, that is, control of acid for up to 12 hours. In Dr. Horn's opinion, "It makes perfect sense from a pharmacologic basis to put these modalities together."

Dr. Fendrick agreed. "The double effect of the combination of famotidine/calcium carbonate/magnesium hydroxide is quick action with a longer lasting effect than antacids alone. Since the combination is only pennies more than famotidine alone, you might as well recommend the combination," said Dr. Fendrick.

A four-way crossover study of 20 healthy adults compared famotidine/calcium carbonate/magnesium hydroxide, ranitidine 75 mg (Zantac 75), calcium carbonate 1000 mg (Tums), and placebo.⁸ The combination of famotidine/calcium carbonate/magnesium hydroxide demonstrated an effect on gastric acid secretion that was as rapid as for calcium carbonate and whose duration of effect on gastric acid secretion that was similar to ranitidine, reported Dr. Horn.

A much larger trial of approximately 1600 patients experiencing heartburn showed the symptomatic response was excellent with the combination of famotidine/calcium carbonate/magnesium hydroxide. Patients took famotidine/calcium carbonate/magnesium hydroxide, single-agent famotidine, single-agent antacid, or placebo and rated their symptoms hourly for 8 hours. In terms of onset of symptom relief, the combination of famotidine/calcium carbonate/magnesium hydroxide and the single-agent antacid were equivalent, both were faster than single-agent famotidine, and all three treatment options were faster than placebo. For duration of relief, the combination of famotidine/calcium carbonate/magnesium hydroxide was better than single-agent famotidine, the single-agent famotidine lasted longer than the single-agent antacid, and all three were superior to placebo. For overall symptom response, the combination of famotidine/calcium carbonate/magnesium hydroxide was better than single-agent famotidine or single-agent antacid which were equivalent to each other, and all three were better than placebo, Dr. Horn said.

Although not currently available OTC, proton pump inhibitors offer longer-lasting acid suppression than H₂RAs but also have a slower onset of maximal acid suppression. They are, therefore, less optimal for treatment of acute episodes of heartburn but are very useful in controlling recurrent symptoms of GERD. They offer sustained meal-induced acid suppression, significant gastric pH elevation, and healing of gastric and duodenal ulcers when taken in prescription doses. However, Dr. Horn noted that acid control is somewhat inconsistent and nocturnal acid control is inadequate with proton pump inhibitors.

Omeprazole is expected to be the first proton pump inhibitor available as an OTC product. Patients will be instructed to take 20 mg daily for 14 days. Even at this full therapeutic dosage, however, some patients have indicated the need to treat breakthrough symptoms. In the May 2000 Gallup Study of Consumer's Use of Stomach Relief Products,⁹ 45% of individuals taking proton pump inhibitors also took OTC products, predominantly antacids, and half of those individuals took antacids daily.

"There is a fairly widespread use of OTC products in conjunction with the daily use of some proton pump inhibitor therapy," Dr. Horn remarked. "These are not agents with a rapid onset of action. You will need to explain to the patient that a single dose of proton pump inhibitor is not going to make them feel better."

While proton pump inhibitors are considered safe, there is nevertheless the potential for interaction with drugs that are also CYP2C19 substrates. For example, since omeprazole inhibits CYP2C19 enzyme activity, medications that are metabolized through this system will be adversely affected. The medication of most concern, in this regard, is the benzodiazepine diazepam, the blood levels of which may be doubled or even tripled by concomitant use of omeprazole. Additionally, the concomitant administration of omeprazole with warfarin or phenytoin, which are both narrow therapeutic range drugs, would result in altered distribution of these agents. Medications, whose absorption is pH-dependent, when given with omeprazole would result in decreased absorption include ketoconazole and itraconazole, indinavir and delavirdine; increased absorption of digoxin, nifedipine, could be seen with omeprazole, cautioned Dr. Horn.

Pharmacist Treatment Algorithm for Heartburn Associated with GERD

In conclusion, Dr. Horn gave the following suggestions for counseling patients on self-medication of heartburn with currently available treatment options:

• Set appropriate expectations
• Explain how drugs work and when to take them
• Reinforce lifestyle changes
• Ask the patient to keep a symptom and treatment diary
• Discuss potential side effects and drug interactions
• Know when to refer the patient to a physician

New Era for OTC Medications

"For millions of Americans with heartburn, the stage is set for greater use of OTC medications," said Dr. Fendrick. "There has never been a better time to advocate for greater selection and availability of OTC products to manage heartburn and a number of other common conditions, for that matter."

"Access is the issue. There is currently a great amount of tension to simultaneously permit access to therapy while constraining cost growth," Dr. Fendrick said. "Millions of Americans do not have a regular physician, and patients who do have physicians may not have prescription drug coverage. Many individuals, even with a good insurance or medical plan, spend a lot money [out-of-pocket] for medications."

Dr. Fendrick observed that the higher the cost of the medication, the lower the compliance with pharmacologic therapy. "Evidence^[10,11] is accruing that increased patient cost leads to lower compliance for both essential and non-essential drugs," noted Dr. Fendrick. Patients support the trend toward prescription-to-OTC switches based on their perception of the efficacy and safety of these products, added Dr. Fendrick.

References

1. Fendrick AM. Heartburn: mild and persistent. Presented at a Symposium titled "Prevention and treatment of heartburn: sorting out the options" held during the American Pharmaceutical Association Annual Meeting & Exposition, March 29, 2003, New Orleans, Louisiana.
2. Dimenas E. Methodological aspects of evaluation of quality of life in upper gastrointestinal diseases. Scand J Gastroenterol Suppl. 1993;199:18-21.
3. Revicki DA, Crawley JA, Zodet MW, Levine DS, Joelsson BO. Complete resolution of heartburn symptoms and health-related quality of life in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 1999;13:1621-1630.
4. Horn JR. The pharmacist's role in heartburn: current management options. Presented at a Symposium titled "Prevention and treatment of heartburn: sorting out the options" held during the American Pharmaceutical Association Annual Meeting & Exposition, March 29, 2003, New Orleans, Louisiana.
5. Lagergren J, Bergstrцm, Lindgren A, Nyrйn O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340:825-831.
6. Zantac prescribing information [package insert]. GlaxoSmithKline. Available at http://corp.gsk.com. Accessed April 2, 2003.
7. Pepcid prescribing information [package insert]. Merck & Co. Inc. Available at http://www.merck.com. Accessed April 2, 2003.
8. Ohning G, Walsh JH, Thomas D, et al. Famotidine/antacid combination is superior in overall control of gastric acid output compared to ranitidine 75 mg or calcium carbonate 1000 mg. Pract Gastroenterol. 2000;24:37-42.
9. The Gallup Organization. 2000 Gallup Study of Consumers' Use of Stomach Relief Products, May 2000.
10. Tamblyn R, Laprise R, Hanley JA, et al. Adverse events associated with prescription drug cost-sharing among poor and elderly persons. JAMA. 2001;285:421-429.
11. Federman AD, Adams AS, Ross-Degnan D, Soumerai SB, Ayanian JZ. Supplemental insurance and use of effective cardiovascular drugs among elderly medicare beneficiaries with coronary heart disease. JAMA. 2001;286:1732-1739.

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Disclosure

A. Mark Fendrick, MD
Consultant-AstraZeneca, Merck, Procter & Gamble, TAP; Speakers Bureau-AstraZeneca, McNeil, TAP

John Horn, PharmD, FCCP
Speakers Bureau-Bristol-Myers Squibb, Janssen Pharmaceuticals, Novartis, Pfizer, TAP

Evelyn R. Hermes De Santis, PharmD
Speakers Bureau-Janssen Pharmaceuticals

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Merck Consumer Pharmaceuticals Co.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; Rutgers University Ernest Mario School of Pharmacy; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Digestive Health Express Report(tm) does not include discussion of treatment and indications outside of current approved labeling. This Digestive Health Express Report(tm) was made possible through an educational grant from Merck Consumer Pharmaceuticals Co.

(c) 2003 Millennium Medical Communications, Inc., UMDNJ-Center for Continuing and Outreach Education and Rutgers University Ernest Mario School of Pharmacy