This report was reviewed for medical and scientific accuracy by Diana Vamos, PharmD, Clinical Oncology Pharmacist, The Cancer Institute of New Jersey,New Brunswick, New Jersey

Expert Commentary

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

According to the results of a recent study, subjects treated with the combination of famotidine 10 mg/calcium carbonate 800 mg/magnesium hydroxide 165 mg (Pepcid Complete) reached a gastric pH ≥3.0 and pH ≥4.0 significantly faster than subjects treated with omeprazole 20 mg (Prilosec OTC) or placebo.¹ These results suggest the combination of famotidine/calcium carbonate/magnesium hydroxide will provide significantly faster relief than omeprazole 20 mg for symptomatic and episodic heartburn associated with gastro-esophageal reflux disease (GERD). Moreover, the combined use of an antacid and famotidine provides the dual benefit of a rapid onset of heartburn relief with a prolonged duration of heartburn relief. The delayed onset of acid suppression and symptom relief noted with omeprazole makes it a less desirable choice for most patients. These results complement recent recommendations from an American Gastroenterological Association Consensus Development Panel on the use of famotidine/calcium carbonate/ magnesium hydroxide in the treatment of episodic heartburn.²

Heartburn is a predominant and frequent symptom of GERD. Heartburn is routinely encountered by pharmacists since GERD is one of the most common chronic disorders of the gastrointestinal tract,³ producing intermittent symptoms. In its milder manifestation, the heartburn associated with GERD is typically transient. However, in some individuals, the heartburn is severe and typically is accompanied by prolonged episodes of reflux, particularly at night. Symptoms concurrent with heartburn may include regurgitation of gastric contents, nocturnal wheezing, coughing, hoarseness, and with disease that is more advanced, dysphagia or bleeding. Thus, for most patients with heartburn, treatment should provide rapid symptom relief and protection from recurrence.

A systematic review of population studies of GERD symptoms (eg, heartburn) indicated a prevalence range between 10% and 48%.⁴ The socioeconomic impact of GERD is substantial given that 61 million adults in the United States experience heartburn at least once a month and 18 million individuals take some form of medication for indigestion at least twice weekly,⁵ resulting in estimated annual direct costs of $9.3 billion.⁶

Pharmacists are often 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. Furthermore, pharmacists can qualify the patient for possible referral to their primary care physician for treatment.

The purpose of this Gastroenterology Express Report^TM is to review the data recently presented on the combination of famotidine/calcium carbonate/magnesium hydroxide, as well as alternative treatment options for the treatment of symptomatic and episodic heartburn. By combining appropriate patient evaluation and counseling together with rational OTC product selection, pharmacists will be able to effectively manage many patients with symptomatic and episodic heartburn.

Treatment Options for Heartburn Associated with Gastroesophageal Reflux Disease

Lifestyle Modifications
Simple life-style modifications should be emphasized and incorporated into all stages of GERD treatment.⁷ Such modifications include sleeping with the head of the bed elevated approximately 6 inches, smoking cessation, weight reduction, decreased fat intake, minimal alcohol consumption, avoidance of coffee, chocolate and peppermint, and avoidance of recumbency for 3 hours postprandial. Avoidance of medications that reduce lower esophageal sphincter (LES) tone or decrease motility would require consultation with a pharmacist or the individual's primary care physician. Medications associated with lowering the LES tone include nitrates, ethanol and anticholinergic agents,⁸ theophylline,⁹ progesterone and tricyclic antidepressants,¹⁰ and calcium channel blockers.^11,12 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. If symptoms are not resolved with lifestyle modifications, pharmacologic therapy with OTC medications is warranted.

OTC Treatment Options for Heartburn
Pharmacologic therapy of heartburn is designed to decrease the amount of acid that refluxes from the stomach back into the esophagus or make the refluxed material less irritating to the esophageal lining by neutralizing the pH of the gastric acid.

To relieve episodic heartburn, pharmacists can recommend an empiric trial of OTC therapy. Available OTC medications have been proven to reduce the severity and frequency of episodic heartburn and are considered rapid, effective, and safe when used for periods not exceeding 4 weeks.² The availability of a multitude of OTC preparations including antacids, antacid/alginate combinations, H₂ receptor antagonists (H₂RAs), antacid/H₂RA combinations, and proton pump inhibitors provides a seemingly endless number of treatment options. However, most pharmacists will select a few products to recommend based on the patient's presentation.

OTC Antacids and Antacid/Alginate Combinations
OTC antacids (eg, Maalox, Mylanta, Tums, Rolaids) are effective for heartburn because they neutralize gastric acidity with a rapid onset of action and are an inexpensive treatment option. Due to their short duration of action and lack of effect on acid secretion, antacids must be dosed frequently throughout the day for symptom control. Since antacids have the most rapid onset of action, they are most appropriate for the treatment of active heartburn. A liquid antacid or a chewed 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.

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

H₂ Receptor Antagonists
The H₂RAs are a widely-accepted and effective treatment for the symptoms of heartburn. There are four commercially available products: famotidine 10 mg or 20 mg (Pepcid AC), cimetidine 200 mg (Tagamet HB), ranitidine 75 mg (Zantac 75), and nizatidine 75 mg (Axid AR). The H₂ RAs act through competitive binding to parietal cell H₂ receptors thereby inhibiting basal and stimulated-acid secretion and diminishing acid-dependent peptic activity. Numerous clinical trials have shown H₂RAs to be superior to placebo for efficacy of heartburn relief.²

H₂RAs have a slower onset of action compared to antacids. 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. H₂RAs have the potential to cause drug interactions; particularly with those medications whose absorption is gastric pH-dependent (eg, ketoconazole, itraconazole).^13,14 Metabolic inhibition with cimetidine is dose-related, especially at doses above 400 mg daily.¹⁵ Cimetidine interactions with propranolol, warfarin, theophylline, phenytoin, nifedipine, and diazepam are the most noteworthy.¹⁵ Increased or decreased prothrombin times have been reported during concurrent use of ranitidine and warfarin.¹⁶ No metabolic drug interactions have been identified with famotidine.¹⁷

Proton Pump Inhibitors
Omeprazole 20 mg (multi-unit pellet system (MUPS) formulation) was recently approved by the FDA for the OTC treatment of frequent heartburn.¹⁸ Proton pump inhibitors suppress gastric acid production by blocking parietal cell hydrogen/potassium ion adenosine triphosphatase. Although proton pump inhibitors offer longer-lasting acid suppression than H₂RAs, they also have a slower onset of maximal acid suppression. According to the product labeling, omeprazole 20 mg must be taken once daily for a total of 14 days and may take up to 1 to 4 days for full effect.¹⁸ Therefore, omeprazole 20 mg is not optimal for the treatment of acute episodes of heartburn and impractical for patients with infrequent heartburn (≤1 episode weekly).

While proton pump inhibitors are considered safe, there is never-theless the potential for interaction with drugs that are CYP2C19 substrates. Omeprazole inhibits CYP2C19 enzyme activity; therefore, medications that are metabolized through this system may be adversely affected. The concomitant administration of omeprazole with warfarin or phenytoin, which are both narrow therapeutic range drugs, would result in altered distribution of these agents.¹⁹ The pharmacokinetics of medications that have pH-dependent absorption may also be altered. For example, the absorption of ketoconazole, itraconazole, indinavir and delavirdine may be decreased while that of digoxin and nifedipine may be increased by the concomitant administration of omeprazole.¹⁹

H2 Receptor Antagonist/Antacid Combination
Given their differing mechanisms of action, a fixed combination of famotidine/calcium carbonate/magnesium hydroxide provides the benefits of more rapid relief of symptoms than famotidine alone and a longer duration than antacid alone. The FDA approval of omeprazole 20 mg has generated considerable discussion and investigation to compare the properties of these agents in the treatment of symptomatic and episodic heartburn.

Investigators recently compared the onset of the acid-reducing effect of famotidine/calcium carbonate/magnesium hydroxide to that of omeprazole 20 mg (MUPS formulation) and placebo in a randomized, open-label, 3-way crossover study conducted in 24 healthy volunteers aged 18 to 43 years.¹ Each patient received single doses of famotidine/calcium carbonate/magnesium hydroxide, omeprazole 20 mg, and placebo at separate treatment sessions preceded by an overnight fast and separated by approximately 1 week. Intragastric pH was monitored for 3 hours, beginning 1 hour prior to treatment administration and extending to 2 hours post-treatment. The primary endpoints of the study were time to gastric pH ≥3.0 and pH ≥4.0. Following administration of famotidine/calcium carbonate/magnesium hydroxide, all 24 subjects reached a gastric pH ≥3.0 during the 2-hour evaluation period. Following treatment with omeprazole 20 mg, 23 of 24 subjects failed to reach a gastric pH ≥3.0. Following treatment with placebo, all 24 subjects failed to reach a gastric pH ≥3.0 within the 2-hour timeframe. The median time to gastric pH ≥3.0 was 2.5 minutes for famotidine/calcium carbonate/ magnesium hydroxide and >2 hours for omeprazole 20 mg and placebo (P≤.001 for both comparisons) (Figure 1).

Following administration of famotidine/calcium carbonate/magnesium hydroxide, 22 of 24 subjects reached a gastric pH ≥4.0 during the 2-hour evaluation period. Following treatment with omeprazole 20 mg and placebo, all 24 subjects failed to reach a gastric pH ≥4.0 in the 2-hour evaluation period. The median time to achieve gastric pH ≥4.0 was significantly shorter with famotidine/calcium carbonate/ magnesium hydroxide administration (3.5 minutes) than omeprazole 20 mg or placebo (both >2 hours; P<.001 for both comparisons) (Figure 2).

The safety profiles of famotidine/calcium carbonate/magnesium hydroxide and omeprazole 20 mg were comparable to each other and placebo and no subject withdrew from the study due to an adverse event.

These results add to larger previous studies supporting the effectiveness of famotidine/calcium carbonate/magnesium hydroxide therapy for symptomatic and episodic heartburn. The FACT (famotidine/ antacid combination tablet) Study (N = 1,640 patients with GERD) was a randomized, placebo-controlled clinical trial that compared the efficacy of famotidine/calcium carbonate/magnesium hydroxide (n = 410), an H₂RA alone (famotidine 20 mg; n = 411), an antacid alone (calcium carbonate 800 mg and magnesium hydroxide 165 mg; n = 411), and placebo (n = 115) for postcibal heartburn.² Analyses of efficacy were based on 6,281 episodes of heartburn, 90% of which occurred during waking hours, between 7:01 AM and 11:00 PM.

Results were reported on three areas of efficacy-time to onset of relief, duration of symptom relief, and a global assessment. Famotidine/calcium carbonate/magnesium hydroxide was found to be superior to placebo on all measures. While the onset of relief in the patients treated with famotidine/calcium carbonate/magnesium hydroxide was essentially equal to patients treated with antacid, it was significantly faster than that in the patients receiving placebo (odds ratio 1.59; 95% Confidence Interval (CI), 1.31-1.94; P<.001) or famotidine alone (odds ratio 1.42; 95% CI, 1.17-1.73; P = .001).

Furthermore, patients treated with famotidine/calcium carbonate/ magnesium hydroxide maintained relief from heartburn symptoms significantly longer than famotidine alone, antacid alone or placebo (P<.05 for comparison to famotidine alone and P<.001 for comparisons to antacid alone and placebo). Odds ratios indicated that patients treated with famotidine/calcium carbonate/magnesium hydroxide were more than twice as likely to sustain relief compared to famotidine alone (95% CI, 1.26-1.92), antacid alone (95% CI, 1.31-1.95), or placebo (95% CI, 1.77-2.62). The finding that famotidine/calcium carbonate/magnesium hydroxide has a longer duration than famotidine alone is notable and suggests an incremental improvement in efficacy for the combination of famotidine/calcium carbonate/magnesium hydroxide.

Overall symptom response was "excellent" or "good" in more patients treated with famotidine/calcium carbonate/magnesium hydroxide compared to famotidine alone, antacid alone, and placebo. Eighty-one percent of patients taking famotidine/calcium carbonate/ magnesium hydroxide reported an "excellent/good" response compared with 72% of patients taking antacid alone (P≤.004) or 65% taking famotidine alone (P<.001).

Conclusion

Heartburn is routinely encountered by pharmacists. 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 OTC medications. To relieve episodic heartburn, pharmacists can recommend an empiric trial of OTC therapy. Available OTC medications have been proven to reduce the severity and frequency of heartburn and are considered rapid, effective, and safe when used for periods not exceeding 4 weeks. The availability of a multitude of OTC preparations including antacids, antacid/alginate combinations, H₂RAs, antacid/H₂RA combinations, and proton pump inhibitors provides a seemingly endless number of treatment options. Recent studies suggest the combination of famotidine/calcium carbonate/magnesium hydroxide will provide significantly faster relief than omeprazole 20 mg as well as single- agent famotidine and longer duration of relief than antacid or famotidine alone, for symptomatic and episodic heartburn.

References

1. Lanza FL, Replogle A, Stauffer L, Furtek C, Levine JG. Comparison of the onset of the acid-reducing effect of famotidine/antacid combination tablets, omeprazole 20 mg, and placebo on gastric pH profiles in healthy volunteers. Am J Gastroenterol. 2003;98(9 Suppl):S51. Abstract 147.
2. American Gastroenterological Association Consensus Development Panel. Improving the management of GERD: evidence-based therapeutic strategies [monograph]. American Gastroenterological Association; 2002:1-28. Available at http://www.gastro.org/edu/GERDmonograph.pdf. Accessed May 10, 2004.
3. Lee JM, O'Morain CA. Trends in the management of gastroesophageal reflux disease. Postgrad Med J. 1998;74:145-150.
4. Heading RC. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol. 1999;231:3-8.
5. The Gallup Organization. A Gallup Organization National Survey: HB Across America. Princeton, 1998 and 2000.
6. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500-1511.
7. DeVault KR, Castell DO, and The Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 1999;94:1434-1442.
8. Ross H. GERD in the elderly patient. US Pharmacist. 1994;19:80,82-85,88.
9. Ruzkowski CJ, Sanowski RA, Austin J, et al. The effects of inhaled albuterol and oral theophylline on gastroesophageal reflux in patients with gastroesophageal reflux disease and obstructive lung disease. Arch Int Med. 1992;152:783-785.
10. Richter JE. Gastroesophageal reflux: diagnosis and management. Hosp Pract. 1992;27:59-66.
11. Bortolotti M, Labriola E, Bacchelli S. "Esophageal angina" in patients with angina pectoris: a possible side effect of chronic therapy with nitroderivatives and Ca-antagonists. Ital J Gastroenterol. 1992;24:405-408.
12. Kahan A, Bour B, Couturier D, et al. Nifedipine and esophageal dysfunction in progressive systemic sclerosis: a controlled manometric study. Arthrit Rheumat. 1985;28:490-495.
13. Nizoral prescribing information [package insert]. Janssen Pharmaceutica. Available at http://www.janssen.com/files/nizoral.pdf. Accessed May 10, 2004.
14. Sporanox prescribing information [package insert]. Janssen Pharmaceutica. Available at http://www.sporanox.com/files/sporanox.pdf. Accessed May 10, 2004.
15. Tagamet prescribing information [package insert]. GlaxoSmithKline. Available at http://corp.gsk.com. Accessed May 10, 2004.
16. Zantac prescribing information [package insert]. GlaxoSmithKline. Available at http://corp.gsk.com. Accessed May 10, 2004.
17. Pepcid prescribing information [package insert]. Merck & Co. Inc. Available at http://www.merck.com. Accessed May 10, 2004.
18. U.S. Food and Drug Administration, Department of Health and Human Services. FDA News - FDA Approves Prilosec OTC to Treat Frequent Heartburn, P03-48, June 20, 2003. Available at http://www.fda.gov/bbs/topics/news/2003/NEW00916.html. Accessed May 10, 2004.
19. Prilosec prescribing information [package insert]. AstraZeneca. Available at http://www.astrazeneca-us.com. Accessed May 10, 2004.

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Disclosure

John R. Horn, PharmD, FCCP
Consultant-Janssen Pharmaceutica; Speakers Bureau-Bristol-Myers Squibb, Janssen Pharmaceutica, Pfizer, Inc.

Diana Vamos, PharmD
No significant relationships to disclose.

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

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; 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 Gastroenterology Express Report(tm) does not include discussion of treatment and indications outside of current approved labeling. This Gastroenterology Express Report(tm) was made possible through an educational grant from Johnson & Johnson/Merck Consumer Pharmaceuticals Co.

© 2004 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education

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