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Picking a PPI: It comes down to cost
Treatment strategy
- Choose the least expensive product available to the patient.
- Differences in drug interactions, efficacy, and adverse events are not significant. (A)
Dose and duration
- Use PPIs at the lowest effective dose for the minimum duration. (C)
- Since many indications for PPI therapy are for a finite duration, attempt to “step down” therapy to a lower dose or try switching to an H2 receptor antagonist periodically, to achieve the goal of minimum effective dose. (C)
- If stress ulcer prophylaxis was started in the hospital, re-evaluate the need for continued use of PPIs after hospital discharge. (C)
Safety
- PPIs have been on the market for more than 15 years and have a good adverse-event profile, which is comparable to placebo. (A)
- Limited data which attempt to link PPIs to several rare adverse events do not establish a cause-effect relationship. (B)
Strength of recommendation (SOR)
- Good quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
A 33-year-old man returns to see you about his bothersome heartburn, which tends to occur after lunch and dinner. He says the trouble began about 2 weeks ago. Chewing Tums tablets after meals relieves his symptoms, but he does not like the chalky taste or frequent dosing. He tried OTC Pepcid, but it relieved his symptoms only occasionally. He says he has not lost weight or had nausea, vomiting, bleeding, or dysphagia. Since you saw him the previous month, he has been trying to exercise and watch his diet, to help manage his hypertension, as you advised. His blood pressure has improved, but his heartburn has not.
THE DILEMMA
You decide to start a PPI, but wonder whether there are significant differences in PPIs, and whether there are long-term health consequences.
The last time you wrote a prescription for a proton pump inhibitor, what came to mind? Did you write a prescription for the PPI you always use? Did you prescribe Prilosec because it is available in generic form? Did you decide on Prevacid because the patient had responded well to it before? Did you consider cost, even if the patient was insured? Was your main concern side effects?
Nexium, Prevacid, and Protonix were among the 25 most commonly dispensed medications in 2006.1 With multiple indications, high clinical efficacy, low incidence of adverse events, convenient dosing, and few drug interactions, it is understandable why PPIs are popular with physicians and patients. Use of prescription PPIs has continued to increase even after Prilosec OTC became available.
TABLES 1–3 give recommended dosing for PPI indications, formulations, drug interactions, cost, and adverse event profiles.
Drug action and efficacy. PPIs have a pharmacokinetic elimination half-life of 30 minutes to 2 hours, but once-daily dosing is possible due to long-lasting inactivation of the proton pump.2
Genetic polymorphism. Up to 6% of Caucasian and 23% of Asian patients are CYP P450 2C19 poor metabolizers.2,3 This is the common hepatic clearance pathway for currently available PPIs. However, due to PPI efficacy, low potential for drug interactions, and infrequent adverse events, this genetic polymorphism is not likely to affect the vast majority of patients on PPI therapy.
Are differences clinically significant? Many trials have compared PPIs using a variety of surrogate endpoints. A new PPI, S-tenatoprazole [not available in the US] has shown greater acid suppression than esomeprazole.4 However, no single agent has proven more efficacious than other PPIs at equipotent doses.5,6 Even though lansoprazole and omeprazole have the most FDA-approved indications, this should not discourage you from using any PPI for a variety of gastrointestinal indications. For example, lansoprazole and esomeprazole are the only PPIs approved for healing or risk reduction of NSAID-related gastric ulcers. Yet other PPIs have been used for this indication without any reason to suspect lack of effectiveness. A meta-analysis of 41 randomized, double-blind studies evaluated head-to-head clinical trials for many conditions, including Helicobacter pylori, gastroesophageal reflux disease (GERD) and peptic ulcer disease.5 No clinically important differences were noted when equipotent doses were used.5-7
Only 1 difference in the treatment of GERD was noted between esomeprazole 40 mg and omeprazole 20 mg in the pooled results (relative risk 1.18; 95% confidence interval 1.14-1.23). This is not surprising because the 2 medications were not given at equipotent doses.
All PPIs are well tolerated. The most common adverse effects are headache, diarrhea, and abdominal pain.8-12 The side-effect profile is consistent among PPIs. An exception is dose-related increases in the frequency of diarrhea reported with lansoprazole (ranging from 1.4% to 7.4%) and higher dose omeprazole therapy.2,8
Although considered relatively safe, several considerations have arisen from clinical trials. Some (occurrence of rebound acid hypersecretion after PPI discontinuation) are better documented than others.13 Additional data are needed to determine whether there is any significant association with PPI-induced elevated serum gastrin levels and neoplastic changes or an increased risk of hip fracture, community-acquired pneumonia, Clostridium difficile infection, vitamin B12 anemia, iron malabsorption, and atrophic gastritis (TABLE 3).13-27
It is promising that data which demonstrate safe and effective use of these agents for longer than 10 years are available.2,28
TABLE 1
Similarities and differences among proton pump inhibitors2,8-12,25,34,35
| PANTOPRAZOLE PROTONIX | LANSOPRAZOLE PREVACID | ESOMEPRAZOLE NEXIUM | OMEPRAZOLE PRILOSEC, ZEGERID | RABEPRAZOLE ACIPHEX | NOTABLE SIMILARITIES AND DIFFERENCES | |
|---|---|---|---|---|---|---|
| Available strengths | 20 mg, 40 mg tabs 40 mg/vial 40 mg granules for suspension | 15 mg, 30 mg caps Packets for suspension, SoluTabs | 20 mg, 40 mg caps, per vial, packet for suspension | 10 mg, 20 mg, 40 mg caps 20 mg, 40 mg Zegerid packet 20 mg tab (OTC) | 20 mg tabs | Injectable options: Pantoprazole, esomeprazole Generic Prilosec and Protonix are available |
| Renal dose adjustment | No dosage adjustment needed | |||||
| Hepatic dose adjustment | > 40 mg/d not studied in hepatic impairment | Consider lower dose in severe hepatic impairment | Max 20 mg/d in severe hepatic impairment | Consider lower dose in hepatic impairment | Consider lower dose in severe hepatic impairment | No differences Consider decreased dose in hepatic impairment |
| Pregnancy category | B | B | B | C | B | All are pregnancy category B except omeprazole, which is C |
| Pediatric use | Safety and efficacy not established for patients < 18 yo | FDA approved for pediatric use except patients ≤ 2 yo | Safety and efficacy not established for patients ≤ 12 yo | FDA approved for pediatric use except patients ≤ 2 yo | Safety and efficacy not established for patients < 18 yo | Lansoprazole and omeprazole are FDA approved for pediatrics No PPI is approved for use in patients ≤ 2 yo |
| Major drug interactions** | ||||||
| Formulation stability | Do not break, crush, or chew tablets | Capsules can be opened and granules sprinkled onto soft food/beverage* or swallowed intact SoluTab and oral suspension packets can be dissolved with water | Capsules can be opened and granules sprinkled onto apple-sauce or swallowed intact Oral suspension packets can be dissolved with water | Capsules can be opened and granules sprinkled onto apple-sauce or swallowed intact Zegerid capsules should not be opened | Do not break, crush, or chew tablets | Suitable for NG administration: esomeprazole, omeprazole (Zegerid), lansoprazole Lansoprazole, omeprazole, and pantoprazole can be compounded into oral suspensions at retail pharmacies if the patient has difficulty swallowing tablets/capsules |
| Cost *** | $128 brand $100 generic | $122-$161 | $150-$165 | $115-$216 brand $64 (20 mg generic) $22 (#28 OTC) $15 (#28 OTC generic) No generic for 40 mg | $160 | Prilosec is the only PPI available OTC Prices at retail pharmacies may differ |
| Applicable soft foods and beverages are applesauce, cottage cheese, Ensure pudding, yogurt, strained pears, apple juice, tomato juice, or orange juice. | ||||||
| ** In addition to cytochrome P450 enzyme interactions, H2receptor antagonists and proton pump inhibitors can affect drugs that rely on acid for absorption (i.e., can decrease the absorption of bases like ketoconazole, iron, or cefpodoxime and increase the absorption of acids like diazepam). There have been case reports of elevated INRs with warfarin and the use of proton pump inhibitors. Omeprazole can raise levels of diazepam, warfarin, and phenytoin. | ||||||
| ***Cost information accessed at http://www.drugstore.com or http://www.cvs.com on March 10, 2008 and is for #30 unless otherwise specified. | ||||||
TABLE 2
Cost comparison of proton pump inhibitor regimens* for 8 conditions8-12,25,29
| PANTOPRAZOLE PROTONIX | LANSOPRAZOLE PREVACID | ESOMEPRAZOLE NEXIUM | OMEPRAZOLE PRILOSEC, ZEGERID | RABEPRAZOLE ACIPHEX | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| DOSAGE | PRICE | DOSAGE | PRICE | DOSAGE | PRICE | DOSAGE | PRICE | DOSAGE | PRICE | |
| GERD | 20 mg QD 4-8 wk | $128-$256 $110-$220 (G) | 15 mg QD up to 8 wk | $322 | 20 mg QD 4-8 wk | $165-$330 | 20 mg QD 4 wk | $142 $15 (OTC, G) | 20 mg QD 4-8 wk | $160-$320 |
| Erosive esophagitis associated with GERD | 40 mg QD 8-16 wk **40 mg QD IV 7-10 d | $256-$512 $220-$440 (G) | 30 mg QD 8-16 wk | $308-$616 | 20-40 mg QD 4-16 wk **20-40 mg QD IV up to 10 d | $150-$660 | 20 mg QD 4-8 wk | $142-$284 $15-$30 (OTC, G) | 20 mg QD 4-16 wk | $160-$640 |
| Maintenance of healing of erosive esophagitis | 40 mg QD up to 12 mo | $1536 or $1320 (G) /12 mo | 15 mg QD up to 12 mo | $1932/12 mo | 20 mg QD up to 6 mo | $990/6 mo | 20 mg QD up to 12 mo | $1704 or $180 (OTC, G)/12 mo | 20 mg QD up to 12 mo | $1920/12 mo |
| Hypersecretory conditions*** | 40 mg BID 80 mg BID IV 7-10 d | $256 $220 (G) | 60 mg QD | $309 | 40 mg BID | $300 | 60 mg QD | $426 or $45 (OTC, G) | 60 mg QD | $480 |
| Active duodenal ulcer | 40 mg QD 2-4 wk | $64-$128 $55-$110 (G) | 15 mg QD 4 wk | $161 | — | — | 20 mg QD 4-8 wk | $142-$284 $15-$30 (OTC, G) | 20 mg QD 4 wk | $160 |
| Active gastric ulcer | 40 mg QD up to 8 wk | $256 or $220 (G) | 30 mg QD up to 8 wk | $309 | — | — | 40 mg QD 4-8 wk | $216-$432$30-$60 (OTC, G) | 20 mg QD 3-6 wk | $112-$224 |
| Reduce risk of NSAID-associated gastric ulcer | 40 mg QD | $128 or $110(G)/mo | 15 mg QD up to 12 wk | $161/mo | 20-40 mg QD up to 6 mo | $150-$165/mo | 20 mg QD | $142 or $15 (OTC, G)/mo | — | — |
| Helicobacter pylori (Always part of a 3-drug combination) | 40 mg BID 10-14 d | $85-$120 $73-$103 (G) | 30 mg BID 10-14 d | $103-$144 | 40 mg QD 10-14 d | $50-$75 | 20 mg BID 10 d | $95 $15 (OTC, G) | 20 mg BID 7 d | $80 |
| * Doses in italics are from Ref. 29. | ||||||||||
| ** For GERD in patients with a history of erosive esophagitis. | ||||||||||
| *** Starting doses listed. Several years of therapy may be necessary. | ||||||||||
TABLE 3
Support vs refutation: Adverse events and long-term PPI therapy2,13-23,26,27
| POTENTIAL ADVERSE EVENT | PROPOSED MECHANISM | SUPPORT OR REFUTATION |
|---|---|---|
| Elevated serum gastrin levels and increased enterochromaffin-like (ECL) cells | PPIs elevate serum gastrin levels by interfering with negative feedback mechanism on gastrin release | Gastrin levels can be increased but typically remain within the normal range.2 Due to potential for gastrin to affect growth of tumors outside the gastrointestinal tract, further study of a potential relationship with stimulating tumor growth is needed.13 An increase in ECL cells has been seen in humans; neoplastic findings have not been seen in humans.2,13-15 |
| Vitamin B12 deficiency | Vitamin B12 depends on gastric acid to be released and absorbed from food. In the absence of gastric acid, there is potential for deficiency16 | There is no association between chronic PPI therapy and substantial reduction of vitamin B12.16 Consideration should be given to monitoring vitamin B12 levels periodically in patients who may be at higher risk for vitamin B12 deficiency.13 A small case-control study showed an association between vitamin B12deficiency and PPI/H2 antagonist therapy (OR=4.45, 95% CI 1.47-13.34). Other causes were not explored and data were not separated from the H2 antagonist group.16 |
| Risk of hip fracture | PPIs may inhibit bone resorption and reduce calcium absorption by inducing hypochlorhydria17 | In 2006, a nested, observational case-control study associating high-dose chronic PPI use with a higher incidence of hip fractures showed an adjusted OR=1.44 (95% CI 1.30-1.59) in patients on PPI therapy > 1 year.17 |
| Risk of community-acquired pneumonia (CAP) | Prolonged hypochlorhydria could lead to bacterial overgrowth | A case-control study had an adjusted OR=1.5 (95% CI 1.3-1.7) and the strongest association (OR=5; 95% CI 2.1-11.7) between PPI use and CAP was in patients who had started a PPI within the past 7 days.18 A higher percentage of case patients were on corticosteroid therapy and had concurrent chronic obstructive lung disease, diabetes mellitus, and heart disease. A small study of critically ill trauma patients did not find an increased risk of nosocomial infections in patients taking PPIs.19 A pediatric prospective study found 2 cases of pneumonia in follow-up of the control group of 95 patients, and 11 cases of pneumonia in 91 patients in the combined gastric acid suppression group (P=0.03).20 This trial did not differentiate between ranitidine and omeprazole and excluded patients with diseases identified as confounding variables in previous studies. |
| Risk of Clostridium difficile infection | Prolonged hypochlorhydria could lead to bacterial overgrowth | A case-control study found that the OR for a PPI exposure within the past 3 months and C difficile infection was 3.5 (95% CI 2.3-5.2).21 Previous antibiotic exposure within the same period was associated with an OR of 8.2 (95% CI 6.1-11.0). Notably, in this study, inflammatory bowel disease, renal failure, MRSA, cancer, pernicious anemia, and recent antibiotic use were all associated with a higher adjusted OR for increased risk of C difficile infection than PPI exposure. A 2nd cohort study found an unadjusted OR of 3.1 (95% CI 1.7-5.6) for PPIs and C difficile infection. Of note, higher unadjusted ORs were seen with both renal failure and MRSA.22 Another case-control study did not establish an association between PPI use and C difficile hospitalizations.23 |
| Atrophic gastritis | Unknown | One cohort study found atrophic gastritis can occur with chronic omeprazole therapy,26 but it should be noted that of 20 who patients developed atrophy, 18 were infected with H pylori (P < 0.001) and 2 were not infected (P=0.62). In a separate study, omeprazole was not associated with gastric atrophy after 3 years.27 |
Drug interactions
Two main types of drug interactions may occur with PPIs: those at the cytochrome P450 level, and those due to decreased absorption caused by acid suppression.
PPIs are metabolized by both CYP 2C19 and CYP 3A4. Theoretically, any medication that can induce or inhibit either of these enzymes could affect PPI blood concentration levels.
Evidence suggests omeprazole and its enantiomer esomeprazole have the most potential of the PPIs for drug interactions, as they have been shown to increase blood concentration levels of phenytoin, benzodiazepines, carbamazepine, cilostazol, clarithomycin, and R-warfarin by inhibiting CYP 2C19.2,3,29 These interactions do not typically require a dose adjustment. However, more frequent monitoring may be appropriate.2,6
As a class, PPIs may decrease or increase the bioavailability of drugs whose absorption is dependent on gastric pH. Common medications that are pH dependent for absorption are the azole antifungals, ampicillin, cefpodoxime, indinavir, delavirdine, cyanocobalamin, iron, and digoxin.2,3,6 Digoxin absorption may be increased, resulting in elevated digoxin levels. Enteric-coated medications, which typically dissolve at a higher pH, may also be affected by PPI therapy.2
There may be a decrease in PPI efficacy if given concurrently with other antisecretory medications such as histamine 2 (H2) antagonists or misoprostol. This interaction is apparently due to the capability of PPIs to exert their effects only on actively secreting proton pumps.2,29
Step-up and step-down therapy
Step therapy was a much larger issue prior to the availability of generic omeprazole and pantoprazole. The relative novelty of these agents combined with higher cost of therapy and unknown long-term safety information as well as the availability of effective alternatives justified the argument for step-up therapy.
Health care systems and insurance providers encouraged short-term use of PPIs, either prior to H2 receptor antagonists (step-down therapy) or only after failure of H2 receptor antagonists (step-up therapy). Those who favored step-up therapy took into account the cost advantage of H2 receptor antagonists. Those who favored step-down therapy believed patients on H2 receptor antagonists may experience worsening control of the disease and would therefore need to utilize more health care resources, offsetting the lower costs of H2 receptor antagonists. Further, for indications like the treatment of H. pylori, compliance to therapy and corresponding efficacy may be compromised by the use of an H2 receptor antagonist in place of a PPI. Of the 2 approaches, cost effectiveness studies favor the step-down approach.30-33
Switch to an H2 blocker? Proponents of step-down therapy reasoned that many patients are placed on PPIs and continued indefinitely without re-evaluation. The only way to see if a PPI is still needed is to decrease the dose, switch to an H2 receptor antagonist, or completely discontinue acid-suppression therapy after symptom resolution.
At this time, omeprazole is the only PPI available OTC; it typically retails at $22 for 28 capsules. A generic version of the OTC omeprazole product has been approved. The cost is generally $13 to $15 for 28 capsules. Each H2 receptor antagonist is available as a generic, and OTC at half prescription strength. Of note, famotidine 20-mg tablets and ranitidine 150-mg and 300-mg tablets are available on many of the $4 prescription plans at retail pharmacies.
Your patient reports he has been taking omeprazole 20 mg daily, as you prescribed, for the past 2 weeks. His heart-burn symptoms have improved and he no longer needs to use Tums for breakthrough symptoms, as he did when he was taking Pepcid.
You considered pantoprazole and omeprazole because they are both available in generic form. Since there are no significant differences in efficacy of the 2 drugs for the treatment of GERD, you decided to prescribe pantoprazole because it will cost less for the patient, who has no prescription insurance. The pharmacy calls you, asking if generic omeprazole could be used instead due to the cost difference.
According to http://www.drugstore.com, generic pantoprazole would cost the patient $110 per month and generic omeprazole would cost the patient $63 per month.
Even though costs at local pharmacies vary and are often higher than online costs, the savings to the patient seemed significant enough to change
Equal efficacy
The first PPI, Prilosec, was approved in 1989, and 4 additional agents have become available. All are equally efficacious at equipotent doses.
Long-term safety
Although there has been concern about potential for several different adverse events with long-term PPI use, it is important to remember that the majority of these data are either conflicting or derived from case-control studies. The latter cannot prove cause and effect, but can describe potential associations that merit further investigation.
Step therapy
Whether to lower the PPI dose or switch to an H2 receptor antagonist should be considered in all patients and attempted in most patients who have been on PPIs long enough for adequate ulcer healing or who have been symptom-free.
Consider the cost to the patient
Given the similarities in interaction potential, adverse events, and efficacy, select the PPI on the basis of cost to the patient.
1. Top 200 Prescription Drugs of 2006. http://www.pharmacytimes.com/Article.cfm?Menu=1&ID=4629. Accessed August 28, 2007.
2. Berardi RR. A critical evaluation of proton pump inhibitors in the treatment of gastroesophageal reflux disease. Am J Manage Care. 2000;6(suppl):S491-505.
3. Guimaraes EV, Marguet C, Camargos PAM. Treatment of gastroesophageal reflux disease. J Pediatr (Rio J). 2006;82(5 Suppl):S133-145.
4. Hunt RH, Armstrong D, Yaghoobi M, et al. S-tenatoprazole-Na 30 mg, 60 mg and 90 mg versus esomeprazole (ESO) 40 mg in healthy male volunteers (hmv). Gastroenterology. 2007;132:A-488.
5. Klok RM, Postma MJ, Van Hout BA, Brouwers JRBJ. Meta-analysis: comparing the efficacy of proton pump inhibitors in short-term use. Aliment Pharmacol Ther. 2003;17:1237-1245.
6. McDonagh MS, Carson S. Drug Class Review on Proton Pump Inhibitors. 2006. http://www.ohsu.edu/drugeffectiveness/reports/final.cfm. Accessed December 18, 2007.
7. Dachs R, Darby-Stewart A, Graber M. Choosing one PPI treatment over another. Am Fam Phys. 2007;76:1273-1280.
8. Prilosec (package insert). Wilmington, DE: Astra-Zeneca LP; Sep 2006.
9. Prevacid (package insert). Lake Forest, IL: TAP Pharmaceuticals, Inc; Jun 2007.
10. Protonix (package insert). Philadelphia, PA: Wyeth Laboratories; Jun 2007.
11. Aciphex (package insert). Teaneck, NJ: Eisai, Inc; Aug 2003.
12. Nexium (package insert). Wilmington, DE: Astra-Zeneca LP; Apr 2007.
13. Jensen RT. Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol. 2006;98:4-19.
14. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2000;14:651-668.
15. Robinson M. Review article: current perspectives on hypergastrinaemia and enterochromaffin-like cell hyperplasia. Aliment Pharmacol Ther. 1999;13 (Suppl 5):5-10.
16. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of B12 deficiency in older adults. J Clin Epidemiol. 2004;57:422-428.
17. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947-2953.
18. Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump inhibitors and the risk of community-acquired pneumonia. Arch Intern Med. 2007;167:950-955.
19. Mallow S, Rebuck JA, Osler T, Ahern J, Healey MA, Rogers FB. Do proton pump inhibitors increase the incidence of nosocomial pneumonia and related infectious complications when compared with histamine-2 receptor antagonists in critically ill trauma patients? Curr Surg. 2004;61:452-458.
20. Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, Passariello A, Manguso F, Morelli L, Guarino A. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006;117:e817-e820.
21. Dial S, Delaney C, Schneider V, Suissa S. Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ. 2006;175:745-748.
22. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171(1):33-38.
23. Lowe DO, Mamdani MM, Kopp A, Low DE, Juurlink DN. Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study. Clin Infect Dis. 2006;43:1272-1276.
24. Health Canada reviewing new safety information on cardiac events in patients taking Losec (omeprazole) or Nexium (esomeprazole). http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2007/2007_95_e.html. Accessed on August 28, 2007.
25. Vanderhoff BT, Tahboub RM. Proton pump inhibitors: an update. Am Fam Phys. 2002;66:273-280.
26. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med. 1996;334:1018-1022.
27. Lundell L, Miettinen P, Myrvold HE, et al. Lack of effect of acid suppression therapy on gastric atrophy. Gastroenterology. 1999;117:319-326.
28. Hassall E, Kerr W, El-Serag HB. Characteristics of children receiving proton pump inhibitors continuously for up to 11 years duration. J Pediatr. 2007;150:262-267.
29. Clinical Pharmacology. http://cpip.gsm.com. Accessed on August 17, 2007.
30. Inadomi JM, et al. Step-down management of gastroesophageal disease. Gastroenterology. 2001;121:1095-1100.
31. Tytgat GNJ. Review article: management of mild and severe gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2003;17(Suppl 2):52-56.
32. Ofman JJ, Dorn GH, Fennerty MB, Fass R. The clinical and economic impact of competing management strategies for gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2002;16:261-273.
33. Gerson LB, Robbins AS, Garber A, Hornberger J, Tridafilopoulos G. A cost-effectiveness analysis of prescribing strategies in the management of gastroesophageal reflux disease. Am J Gastroenterol. 2000;95:395-407.
34. Zimmermann AE, Walters JK, Katona BG, Souney PF, Levine D. Review of omeprazole use in the treatment of acid-related disorders in children. Clin Ther. 2001;23:660-679.
35. Humphries TJ, Merritt GJ. Review article: drug interactions with agents used to treat acid-related diseases. Aliment Pharmacol Ther. 1999;23(Suppl 3):18-26.
Treatment strategy
- Choose the least expensive product available to the patient.
- Differences in drug interactions, efficacy, and adverse events are not significant. (A)
Dose and duration
- Use PPIs at the lowest effective dose for the minimum duration. (C)
- Since many indications for PPI therapy are for a finite duration, attempt to “step down” therapy to a lower dose or try switching to an H2 receptor antagonist periodically, to achieve the goal of minimum effective dose. (C)
- If stress ulcer prophylaxis was started in the hospital, re-evaluate the need for continued use of PPIs after hospital discharge. (C)
Safety
- PPIs have been on the market for more than 15 years and have a good adverse-event profile, which is comparable to placebo. (A)
- Limited data which attempt to link PPIs to several rare adverse events do not establish a cause-effect relationship. (B)
Strength of recommendation (SOR)
- Good quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
A 33-year-old man returns to see you about his bothersome heartburn, which tends to occur after lunch and dinner. He says the trouble began about 2 weeks ago. Chewing Tums tablets after meals relieves his symptoms, but he does not like the chalky taste or frequent dosing. He tried OTC Pepcid, but it relieved his symptoms only occasionally. He says he has not lost weight or had nausea, vomiting, bleeding, or dysphagia. Since you saw him the previous month, he has been trying to exercise and watch his diet, to help manage his hypertension, as you advised. His blood pressure has improved, but his heartburn has not.
THE DILEMMA
You decide to start a PPI, but wonder whether there are significant differences in PPIs, and whether there are long-term health consequences.
The last time you wrote a prescription for a proton pump inhibitor, what came to mind? Did you write a prescription for the PPI you always use? Did you prescribe Prilosec because it is available in generic form? Did you decide on Prevacid because the patient had responded well to it before? Did you consider cost, even if the patient was insured? Was your main concern side effects?
Nexium, Prevacid, and Protonix were among the 25 most commonly dispensed medications in 2006.1 With multiple indications, high clinical efficacy, low incidence of adverse events, convenient dosing, and few drug interactions, it is understandable why PPIs are popular with physicians and patients. Use of prescription PPIs has continued to increase even after Prilosec OTC became available.
TABLES 1–3 give recommended dosing for PPI indications, formulations, drug interactions, cost, and adverse event profiles.
Drug action and efficacy. PPIs have a pharmacokinetic elimination half-life of 30 minutes to 2 hours, but once-daily dosing is possible due to long-lasting inactivation of the proton pump.2
Genetic polymorphism. Up to 6% of Caucasian and 23% of Asian patients are CYP P450 2C19 poor metabolizers.2,3 This is the common hepatic clearance pathway for currently available PPIs. However, due to PPI efficacy, low potential for drug interactions, and infrequent adverse events, this genetic polymorphism is not likely to affect the vast majority of patients on PPI therapy.
Are differences clinically significant? Many trials have compared PPIs using a variety of surrogate endpoints. A new PPI, S-tenatoprazole [not available in the US] has shown greater acid suppression than esomeprazole.4 However, no single agent has proven more efficacious than other PPIs at equipotent doses.5,6 Even though lansoprazole and omeprazole have the most FDA-approved indications, this should not discourage you from using any PPI for a variety of gastrointestinal indications. For example, lansoprazole and esomeprazole are the only PPIs approved for healing or risk reduction of NSAID-related gastric ulcers. Yet other PPIs have been used for this indication without any reason to suspect lack of effectiveness. A meta-analysis of 41 randomized, double-blind studies evaluated head-to-head clinical trials for many conditions, including Helicobacter pylori, gastroesophageal reflux disease (GERD) and peptic ulcer disease.5 No clinically important differences were noted when equipotent doses were used.5-7
Only 1 difference in the treatment of GERD was noted between esomeprazole 40 mg and omeprazole 20 mg in the pooled results (relative risk 1.18; 95% confidence interval 1.14-1.23). This is not surprising because the 2 medications were not given at equipotent doses.
All PPIs are well tolerated. The most common adverse effects are headache, diarrhea, and abdominal pain.8-12 The side-effect profile is consistent among PPIs. An exception is dose-related increases in the frequency of diarrhea reported with lansoprazole (ranging from 1.4% to 7.4%) and higher dose omeprazole therapy.2,8
Although considered relatively safe, several considerations have arisen from clinical trials. Some (occurrence of rebound acid hypersecretion after PPI discontinuation) are better documented than others.13 Additional data are needed to determine whether there is any significant association with PPI-induced elevated serum gastrin levels and neoplastic changes or an increased risk of hip fracture, community-acquired pneumonia, Clostridium difficile infection, vitamin B12 anemia, iron malabsorption, and atrophic gastritis (TABLE 3).13-27
It is promising that data which demonstrate safe and effective use of these agents for longer than 10 years are available.2,28
TABLE 1
Similarities and differences among proton pump inhibitors2,8-12,25,34,35
| PANTOPRAZOLE PROTONIX | LANSOPRAZOLE PREVACID | ESOMEPRAZOLE NEXIUM | OMEPRAZOLE PRILOSEC, ZEGERID | RABEPRAZOLE ACIPHEX | NOTABLE SIMILARITIES AND DIFFERENCES | |
|---|---|---|---|---|---|---|
| Available strengths | 20 mg, 40 mg tabs 40 mg/vial 40 mg granules for suspension | 15 mg, 30 mg caps Packets for suspension, SoluTabs | 20 mg, 40 mg caps, per vial, packet for suspension | 10 mg, 20 mg, 40 mg caps 20 mg, 40 mg Zegerid packet 20 mg tab (OTC) | 20 mg tabs | Injectable options: Pantoprazole, esomeprazole Generic Prilosec and Protonix are available |
| Renal dose adjustment | No dosage adjustment needed | |||||
| Hepatic dose adjustment | > 40 mg/d not studied in hepatic impairment | Consider lower dose in severe hepatic impairment | Max 20 mg/d in severe hepatic impairment | Consider lower dose in hepatic impairment | Consider lower dose in severe hepatic impairment | No differences Consider decreased dose in hepatic impairment |
| Pregnancy category | B | B | B | C | B | All are pregnancy category B except omeprazole, which is C |
| Pediatric use | Safety and efficacy not established for patients < 18 yo | FDA approved for pediatric use except patients ≤ 2 yo | Safety and efficacy not established for patients ≤ 12 yo | FDA approved for pediatric use except patients ≤ 2 yo | Safety and efficacy not established for patients < 18 yo | Lansoprazole and omeprazole are FDA approved for pediatrics No PPI is approved for use in patients ≤ 2 yo |
| Major drug interactions** | ||||||
| Formulation stability | Do not break, crush, or chew tablets | Capsules can be opened and granules sprinkled onto soft food/beverage* or swallowed intact SoluTab and oral suspension packets can be dissolved with water | Capsules can be opened and granules sprinkled onto apple-sauce or swallowed intact Oral suspension packets can be dissolved with water | Capsules can be opened and granules sprinkled onto apple-sauce or swallowed intact Zegerid capsules should not be opened | Do not break, crush, or chew tablets | Suitable for NG administration: esomeprazole, omeprazole (Zegerid), lansoprazole Lansoprazole, omeprazole, and pantoprazole can be compounded into oral suspensions at retail pharmacies if the patient has difficulty swallowing tablets/capsules |
| Cost *** | $128 brand $100 generic | $122-$161 | $150-$165 | $115-$216 brand $64 (20 mg generic) $22 (#28 OTC) $15 (#28 OTC generic) No generic for 40 mg | $160 | Prilosec is the only PPI available OTC Prices at retail pharmacies may differ |
| Applicable soft foods and beverages are applesauce, cottage cheese, Ensure pudding, yogurt, strained pears, apple juice, tomato juice, or orange juice. | ||||||
| ** In addition to cytochrome P450 enzyme interactions, H2receptor antagonists and proton pump inhibitors can affect drugs that rely on acid for absorption (i.e., can decrease the absorption of bases like ketoconazole, iron, or cefpodoxime and increase the absorption of acids like diazepam). There have been case reports of elevated INRs with warfarin and the use of proton pump inhibitors. Omeprazole can raise levels of diazepam, warfarin, and phenytoin. | ||||||
| ***Cost information accessed at http://www.drugstore.com or http://www.cvs.com on March 10, 2008 and is for #30 unless otherwise specified. | ||||||
TABLE 2
Cost comparison of proton pump inhibitor regimens* for 8 conditions8-12,25,29
| PANTOPRAZOLE PROTONIX | LANSOPRAZOLE PREVACID | ESOMEPRAZOLE NEXIUM | OMEPRAZOLE PRILOSEC, ZEGERID | RABEPRAZOLE ACIPHEX | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| DOSAGE | PRICE | DOSAGE | PRICE | DOSAGE | PRICE | DOSAGE | PRICE | DOSAGE | PRICE | |
| GERD | 20 mg QD 4-8 wk | $128-$256 $110-$220 (G) | 15 mg QD up to 8 wk | $322 | 20 mg QD 4-8 wk | $165-$330 | 20 mg QD 4 wk | $142 $15 (OTC, G) | 20 mg QD 4-8 wk | $160-$320 |
| Erosive esophagitis associated with GERD | 40 mg QD 8-16 wk **40 mg QD IV 7-10 d | $256-$512 $220-$440 (G) | 30 mg QD 8-16 wk | $308-$616 | 20-40 mg QD 4-16 wk **20-40 mg QD IV up to 10 d | $150-$660 | 20 mg QD 4-8 wk | $142-$284 $15-$30 (OTC, G) | 20 mg QD 4-16 wk | $160-$640 |
| Maintenance of healing of erosive esophagitis | 40 mg QD up to 12 mo | $1536 or $1320 (G) /12 mo | 15 mg QD up to 12 mo | $1932/12 mo | 20 mg QD up to 6 mo | $990/6 mo | 20 mg QD up to 12 mo | $1704 or $180 (OTC, G)/12 mo | 20 mg QD up to 12 mo | $1920/12 mo |
| Hypersecretory conditions*** | 40 mg BID 80 mg BID IV 7-10 d | $256 $220 (G) | 60 mg QD | $309 | 40 mg BID | $300 | 60 mg QD | $426 or $45 (OTC, G) | 60 mg QD | $480 |
| Active duodenal ulcer | 40 mg QD 2-4 wk | $64-$128 $55-$110 (G) | 15 mg QD 4 wk | $161 | — | — | 20 mg QD 4-8 wk | $142-$284 $15-$30 (OTC, G) | 20 mg QD 4 wk | $160 |
| Active gastric ulcer | 40 mg QD up to 8 wk | $256 or $220 (G) | 30 mg QD up to 8 wk | $309 | — | — | 40 mg QD 4-8 wk | $216-$432$30-$60 (OTC, G) | 20 mg QD 3-6 wk | $112-$224 |
| Reduce risk of NSAID-associated gastric ulcer | 40 mg QD | $128 or $110(G)/mo | 15 mg QD up to 12 wk | $161/mo | 20-40 mg QD up to 6 mo | $150-$165/mo | 20 mg QD | $142 or $15 (OTC, G)/mo | — | — |
| Helicobacter pylori (Always part of a 3-drug combination) | 40 mg BID 10-14 d | $85-$120 $73-$103 (G) | 30 mg BID 10-14 d | $103-$144 | 40 mg QD 10-14 d | $50-$75 | 20 mg BID 10 d | $95 $15 (OTC, G) | 20 mg BID 7 d | $80 |
| * Doses in italics are from Ref. 29. | ||||||||||
| ** For GERD in patients with a history of erosive esophagitis. | ||||||||||
| *** Starting doses listed. Several years of therapy may be necessary. | ||||||||||
TABLE 3
Support vs refutation: Adverse events and long-term PPI therapy2,13-23,26,27
| POTENTIAL ADVERSE EVENT | PROPOSED MECHANISM | SUPPORT OR REFUTATION |
|---|---|---|
| Elevated serum gastrin levels and increased enterochromaffin-like (ECL) cells | PPIs elevate serum gastrin levels by interfering with negative feedback mechanism on gastrin release | Gastrin levels can be increased but typically remain within the normal range.2 Due to potential for gastrin to affect growth of tumors outside the gastrointestinal tract, further study of a potential relationship with stimulating tumor growth is needed.13 An increase in ECL cells has been seen in humans; neoplastic findings have not been seen in humans.2,13-15 |
| Vitamin B12 deficiency | Vitamin B12 depends on gastric acid to be released and absorbed from food. In the absence of gastric acid, there is potential for deficiency16 | There is no association between chronic PPI therapy and substantial reduction of vitamin B12.16 Consideration should be given to monitoring vitamin B12 levels periodically in patients who may be at higher risk for vitamin B12 deficiency.13 A small case-control study showed an association between vitamin B12deficiency and PPI/H2 antagonist therapy (OR=4.45, 95% CI 1.47-13.34). Other causes were not explored and data were not separated from the H2 antagonist group.16 |
| Risk of hip fracture | PPIs may inhibit bone resorption and reduce calcium absorption by inducing hypochlorhydria17 | In 2006, a nested, observational case-control study associating high-dose chronic PPI use with a higher incidence of hip fractures showed an adjusted OR=1.44 (95% CI 1.30-1.59) in patients on PPI therapy > 1 year.17 |
| Risk of community-acquired pneumonia (CAP) | Prolonged hypochlorhydria could lead to bacterial overgrowth | A case-control study had an adjusted OR=1.5 (95% CI 1.3-1.7) and the strongest association (OR=5; 95% CI 2.1-11.7) between PPI use and CAP was in patients who had started a PPI within the past 7 days.18 A higher percentage of case patients were on corticosteroid therapy and had concurrent chronic obstructive lung disease, diabetes mellitus, and heart disease. A small study of critically ill trauma patients did not find an increased risk of nosocomial infections in patients taking PPIs.19 A pediatric prospective study found 2 cases of pneumonia in follow-up of the control group of 95 patients, and 11 cases of pneumonia in 91 patients in the combined gastric acid suppression group (P=0.03).20 This trial did not differentiate between ranitidine and omeprazole and excluded patients with diseases identified as confounding variables in previous studies. |
| Risk of Clostridium difficile infection | Prolonged hypochlorhydria could lead to bacterial overgrowth | A case-control study found that the OR for a PPI exposure within the past 3 months and C difficile infection was 3.5 (95% CI 2.3-5.2).21 Previous antibiotic exposure within the same period was associated with an OR of 8.2 (95% CI 6.1-11.0). Notably, in this study, inflammatory bowel disease, renal failure, MRSA, cancer, pernicious anemia, and recent antibiotic use were all associated with a higher adjusted OR for increased risk of C difficile infection than PPI exposure. A 2nd cohort study found an unadjusted OR of 3.1 (95% CI 1.7-5.6) for PPIs and C difficile infection. Of note, higher unadjusted ORs were seen with both renal failure and MRSA.22 Another case-control study did not establish an association between PPI use and C difficile hospitalizations.23 |
| Atrophic gastritis | Unknown | One cohort study found atrophic gastritis can occur with chronic omeprazole therapy,26 but it should be noted that of 20 who patients developed atrophy, 18 were infected with H pylori (P < 0.001) and 2 were not infected (P=0.62). In a separate study, omeprazole was not associated with gastric atrophy after 3 years.27 |
Drug interactions
Two main types of drug interactions may occur with PPIs: those at the cytochrome P450 level, and those due to decreased absorption caused by acid suppression.
PPIs are metabolized by both CYP 2C19 and CYP 3A4. Theoretically, any medication that can induce or inhibit either of these enzymes could affect PPI blood concentration levels.
Evidence suggests omeprazole and its enantiomer esomeprazole have the most potential of the PPIs for drug interactions, as they have been shown to increase blood concentration levels of phenytoin, benzodiazepines, carbamazepine, cilostazol, clarithomycin, and R-warfarin by inhibiting CYP 2C19.2,3,29 These interactions do not typically require a dose adjustment. However, more frequent monitoring may be appropriate.2,6
As a class, PPIs may decrease or increase the bioavailability of drugs whose absorption is dependent on gastric pH. Common medications that are pH dependent for absorption are the azole antifungals, ampicillin, cefpodoxime, indinavir, delavirdine, cyanocobalamin, iron, and digoxin.2,3,6 Digoxin absorption may be increased, resulting in elevated digoxin levels. Enteric-coated medications, which typically dissolve at a higher pH, may also be affected by PPI therapy.2
There may be a decrease in PPI efficacy if given concurrently with other antisecretory medications such as histamine 2 (H2) antagonists or misoprostol. This interaction is apparently due to the capability of PPIs to exert their effects only on actively secreting proton pumps.2,29
Step-up and step-down therapy
Step therapy was a much larger issue prior to the availability of generic omeprazole and pantoprazole. The relative novelty of these agents combined with higher cost of therapy and unknown long-term safety information as well as the availability of effective alternatives justified the argument for step-up therapy.
Health care systems and insurance providers encouraged short-term use of PPIs, either prior to H2 receptor antagonists (step-down therapy) or only after failure of H2 receptor antagonists (step-up therapy). Those who favored step-up therapy took into account the cost advantage of H2 receptor antagonists. Those who favored step-down therapy believed patients on H2 receptor antagonists may experience worsening control of the disease and would therefore need to utilize more health care resources, offsetting the lower costs of H2 receptor antagonists. Further, for indications like the treatment of H. pylori, compliance to therapy and corresponding efficacy may be compromised by the use of an H2 receptor antagonist in place of a PPI. Of the 2 approaches, cost effectiveness studies favor the step-down approach.30-33
Switch to an H2 blocker? Proponents of step-down therapy reasoned that many patients are placed on PPIs and continued indefinitely without re-evaluation. The only way to see if a PPI is still needed is to decrease the dose, switch to an H2 receptor antagonist, or completely discontinue acid-suppression therapy after symptom resolution.
At this time, omeprazole is the only PPI available OTC; it typically retails at $22 for 28 capsules. A generic version of the OTC omeprazole product has been approved. The cost is generally $13 to $15 for 28 capsules. Each H2 receptor antagonist is available as a generic, and OTC at half prescription strength. Of note, famotidine 20-mg tablets and ranitidine 150-mg and 300-mg tablets are available on many of the $4 prescription plans at retail pharmacies.
Your patient reports he has been taking omeprazole 20 mg daily, as you prescribed, for the past 2 weeks. His heart-burn symptoms have improved and he no longer needs to use Tums for breakthrough symptoms, as he did when he was taking Pepcid.
You considered pantoprazole and omeprazole because they are both available in generic form. Since there are no significant differences in efficacy of the 2 drugs for the treatment of GERD, you decided to prescribe pantoprazole because it will cost less for the patient, who has no prescription insurance. The pharmacy calls you, asking if generic omeprazole could be used instead due to the cost difference.
According to http://www.drugstore.com, generic pantoprazole would cost the patient $110 per month and generic omeprazole would cost the patient $63 per month.
Even though costs at local pharmacies vary and are often higher than online costs, the savings to the patient seemed significant enough to change
Equal efficacy
The first PPI, Prilosec, was approved in 1989, and 4 additional agents have become available. All are equally efficacious at equipotent doses.
Long-term safety
Although there has been concern about potential for several different adverse events with long-term PPI use, it is important to remember that the majority of these data are either conflicting or derived from case-control studies. The latter cannot prove cause and effect, but can describe potential associations that merit further investigation.
Step therapy
Whether to lower the PPI dose or switch to an H2 receptor antagonist should be considered in all patients and attempted in most patients who have been on PPIs long enough for adequate ulcer healing or who have been symptom-free.
Consider the cost to the patient
Given the similarities in interaction potential, adverse events, and efficacy, select the PPI on the basis of cost to the patient.
Treatment strategy
- Choose the least expensive product available to the patient.
- Differences in drug interactions, efficacy, and adverse events are not significant. (A)
Dose and duration
- Use PPIs at the lowest effective dose for the minimum duration. (C)
- Since many indications for PPI therapy are for a finite duration, attempt to “step down” therapy to a lower dose or try switching to an H2 receptor antagonist periodically, to achieve the goal of minimum effective dose. (C)
- If stress ulcer prophylaxis was started in the hospital, re-evaluate the need for continued use of PPIs after hospital discharge. (C)
Safety
- PPIs have been on the market for more than 15 years and have a good adverse-event profile, which is comparable to placebo. (A)
- Limited data which attempt to link PPIs to several rare adverse events do not establish a cause-effect relationship. (B)
Strength of recommendation (SOR)
- Good quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
A 33-year-old man returns to see you about his bothersome heartburn, which tends to occur after lunch and dinner. He says the trouble began about 2 weeks ago. Chewing Tums tablets after meals relieves his symptoms, but he does not like the chalky taste or frequent dosing. He tried OTC Pepcid, but it relieved his symptoms only occasionally. He says he has not lost weight or had nausea, vomiting, bleeding, or dysphagia. Since you saw him the previous month, he has been trying to exercise and watch his diet, to help manage his hypertension, as you advised. His blood pressure has improved, but his heartburn has not.
THE DILEMMA
You decide to start a PPI, but wonder whether there are significant differences in PPIs, and whether there are long-term health consequences.
The last time you wrote a prescription for a proton pump inhibitor, what came to mind? Did you write a prescription for the PPI you always use? Did you prescribe Prilosec because it is available in generic form? Did you decide on Prevacid because the patient had responded well to it before? Did you consider cost, even if the patient was insured? Was your main concern side effects?
Nexium, Prevacid, and Protonix were among the 25 most commonly dispensed medications in 2006.1 With multiple indications, high clinical efficacy, low incidence of adverse events, convenient dosing, and few drug interactions, it is understandable why PPIs are popular with physicians and patients. Use of prescription PPIs has continued to increase even after Prilosec OTC became available.
TABLES 1–3 give recommended dosing for PPI indications, formulations, drug interactions, cost, and adverse event profiles.
Drug action and efficacy. PPIs have a pharmacokinetic elimination half-life of 30 minutes to 2 hours, but once-daily dosing is possible due to long-lasting inactivation of the proton pump.2
Genetic polymorphism. Up to 6% of Caucasian and 23% of Asian patients are CYP P450 2C19 poor metabolizers.2,3 This is the common hepatic clearance pathway for currently available PPIs. However, due to PPI efficacy, low potential for drug interactions, and infrequent adverse events, this genetic polymorphism is not likely to affect the vast majority of patients on PPI therapy.
Are differences clinically significant? Many trials have compared PPIs using a variety of surrogate endpoints. A new PPI, S-tenatoprazole [not available in the US] has shown greater acid suppression than esomeprazole.4 However, no single agent has proven more efficacious than other PPIs at equipotent doses.5,6 Even though lansoprazole and omeprazole have the most FDA-approved indications, this should not discourage you from using any PPI for a variety of gastrointestinal indications. For example, lansoprazole and esomeprazole are the only PPIs approved for healing or risk reduction of NSAID-related gastric ulcers. Yet other PPIs have been used for this indication without any reason to suspect lack of effectiveness. A meta-analysis of 41 randomized, double-blind studies evaluated head-to-head clinical trials for many conditions, including Helicobacter pylori, gastroesophageal reflux disease (GERD) and peptic ulcer disease.5 No clinically important differences were noted when equipotent doses were used.5-7
Only 1 difference in the treatment of GERD was noted between esomeprazole 40 mg and omeprazole 20 mg in the pooled results (relative risk 1.18; 95% confidence interval 1.14-1.23). This is not surprising because the 2 medications were not given at equipotent doses.
All PPIs are well tolerated. The most common adverse effects are headache, diarrhea, and abdominal pain.8-12 The side-effect profile is consistent among PPIs. An exception is dose-related increases in the frequency of diarrhea reported with lansoprazole (ranging from 1.4% to 7.4%) and higher dose omeprazole therapy.2,8
Although considered relatively safe, several considerations have arisen from clinical trials. Some (occurrence of rebound acid hypersecretion after PPI discontinuation) are better documented than others.13 Additional data are needed to determine whether there is any significant association with PPI-induced elevated serum gastrin levels and neoplastic changes or an increased risk of hip fracture, community-acquired pneumonia, Clostridium difficile infection, vitamin B12 anemia, iron malabsorption, and atrophic gastritis (TABLE 3).13-27
It is promising that data which demonstrate safe and effective use of these agents for longer than 10 years are available.2,28
TABLE 1
Similarities and differences among proton pump inhibitors2,8-12,25,34,35
| PANTOPRAZOLE PROTONIX | LANSOPRAZOLE PREVACID | ESOMEPRAZOLE NEXIUM | OMEPRAZOLE PRILOSEC, ZEGERID | RABEPRAZOLE ACIPHEX | NOTABLE SIMILARITIES AND DIFFERENCES | |
|---|---|---|---|---|---|---|
| Available strengths | 20 mg, 40 mg tabs 40 mg/vial 40 mg granules for suspension | 15 mg, 30 mg caps Packets for suspension, SoluTabs | 20 mg, 40 mg caps, per vial, packet for suspension | 10 mg, 20 mg, 40 mg caps 20 mg, 40 mg Zegerid packet 20 mg tab (OTC) | 20 mg tabs | Injectable options: Pantoprazole, esomeprazole Generic Prilosec and Protonix are available |
| Renal dose adjustment | No dosage adjustment needed | |||||
| Hepatic dose adjustment | > 40 mg/d not studied in hepatic impairment | Consider lower dose in severe hepatic impairment | Max 20 mg/d in severe hepatic impairment | Consider lower dose in hepatic impairment | Consider lower dose in severe hepatic impairment | No differences Consider decreased dose in hepatic impairment |
| Pregnancy category | B | B | B | C | B | All are pregnancy category B except omeprazole, which is C |
| Pediatric use | Safety and efficacy not established for patients < 18 yo | FDA approved for pediatric use except patients ≤ 2 yo | Safety and efficacy not established for patients ≤ 12 yo | FDA approved for pediatric use except patients ≤ 2 yo | Safety and efficacy not established for patients < 18 yo | Lansoprazole and omeprazole are FDA approved for pediatrics No PPI is approved for use in patients ≤ 2 yo |
| Major drug interactions** | ||||||
| Formulation stability | Do not break, crush, or chew tablets | Capsules can be opened and granules sprinkled onto soft food/beverage* or swallowed intact SoluTab and oral suspension packets can be dissolved with water | Capsules can be opened and granules sprinkled onto apple-sauce or swallowed intact Oral suspension packets can be dissolved with water | Capsules can be opened and granules sprinkled onto apple-sauce or swallowed intact Zegerid capsules should not be opened | Do not break, crush, or chew tablets | Suitable for NG administration: esomeprazole, omeprazole (Zegerid), lansoprazole Lansoprazole, omeprazole, and pantoprazole can be compounded into oral suspensions at retail pharmacies if the patient has difficulty swallowing tablets/capsules |
| Cost *** | $128 brand $100 generic | $122-$161 | $150-$165 | $115-$216 brand $64 (20 mg generic) $22 (#28 OTC) $15 (#28 OTC generic) No generic for 40 mg | $160 | Prilosec is the only PPI available OTC Prices at retail pharmacies may differ |
| Applicable soft foods and beverages are applesauce, cottage cheese, Ensure pudding, yogurt, strained pears, apple juice, tomato juice, or orange juice. | ||||||
| ** In addition to cytochrome P450 enzyme interactions, H2receptor antagonists and proton pump inhibitors can affect drugs that rely on acid for absorption (i.e., can decrease the absorption of bases like ketoconazole, iron, or cefpodoxime and increase the absorption of acids like diazepam). There have been case reports of elevated INRs with warfarin and the use of proton pump inhibitors. Omeprazole can raise levels of diazepam, warfarin, and phenytoin. | ||||||
| ***Cost information accessed at http://www.drugstore.com or http://www.cvs.com on March 10, 2008 and is for #30 unless otherwise specified. | ||||||
TABLE 2
Cost comparison of proton pump inhibitor regimens* for 8 conditions8-12,25,29
| PANTOPRAZOLE PROTONIX | LANSOPRAZOLE PREVACID | ESOMEPRAZOLE NEXIUM | OMEPRAZOLE PRILOSEC, ZEGERID | RABEPRAZOLE ACIPHEX | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| DOSAGE | PRICE | DOSAGE | PRICE | DOSAGE | PRICE | DOSAGE | PRICE | DOSAGE | PRICE | |
| GERD | 20 mg QD 4-8 wk | $128-$256 $110-$220 (G) | 15 mg QD up to 8 wk | $322 | 20 mg QD 4-8 wk | $165-$330 | 20 mg QD 4 wk | $142 $15 (OTC, G) | 20 mg QD 4-8 wk | $160-$320 |
| Erosive esophagitis associated with GERD | 40 mg QD 8-16 wk **40 mg QD IV 7-10 d | $256-$512 $220-$440 (G) | 30 mg QD 8-16 wk | $308-$616 | 20-40 mg QD 4-16 wk **20-40 mg QD IV up to 10 d | $150-$660 | 20 mg QD 4-8 wk | $142-$284 $15-$30 (OTC, G) | 20 mg QD 4-16 wk | $160-$640 |
| Maintenance of healing of erosive esophagitis | 40 mg QD up to 12 mo | $1536 or $1320 (G) /12 mo | 15 mg QD up to 12 mo | $1932/12 mo | 20 mg QD up to 6 mo | $990/6 mo | 20 mg QD up to 12 mo | $1704 or $180 (OTC, G)/12 mo | 20 mg QD up to 12 mo | $1920/12 mo |
| Hypersecretory conditions*** | 40 mg BID 80 mg BID IV 7-10 d | $256 $220 (G) | 60 mg QD | $309 | 40 mg BID | $300 | 60 mg QD | $426 or $45 (OTC, G) | 60 mg QD | $480 |
| Active duodenal ulcer | 40 mg QD 2-4 wk | $64-$128 $55-$110 (G) | 15 mg QD 4 wk | $161 | — | — | 20 mg QD 4-8 wk | $142-$284 $15-$30 (OTC, G) | 20 mg QD 4 wk | $160 |
| Active gastric ulcer | 40 mg QD up to 8 wk | $256 or $220 (G) | 30 mg QD up to 8 wk | $309 | — | — | 40 mg QD 4-8 wk | $216-$432$30-$60 (OTC, G) | 20 mg QD 3-6 wk | $112-$224 |
| Reduce risk of NSAID-associated gastric ulcer | 40 mg QD | $128 or $110(G)/mo | 15 mg QD up to 12 wk | $161/mo | 20-40 mg QD up to 6 mo | $150-$165/mo | 20 mg QD | $142 or $15 (OTC, G)/mo | — | — |
| Helicobacter pylori (Always part of a 3-drug combination) | 40 mg BID 10-14 d | $85-$120 $73-$103 (G) | 30 mg BID 10-14 d | $103-$144 | 40 mg QD 10-14 d | $50-$75 | 20 mg BID 10 d | $95 $15 (OTC, G) | 20 mg BID 7 d | $80 |
| * Doses in italics are from Ref. 29. | ||||||||||
| ** For GERD in patients with a history of erosive esophagitis. | ||||||||||
| *** Starting doses listed. Several years of therapy may be necessary. | ||||||||||
TABLE 3
Support vs refutation: Adverse events and long-term PPI therapy2,13-23,26,27
| POTENTIAL ADVERSE EVENT | PROPOSED MECHANISM | SUPPORT OR REFUTATION |
|---|---|---|
| Elevated serum gastrin levels and increased enterochromaffin-like (ECL) cells | PPIs elevate serum gastrin levels by interfering with negative feedback mechanism on gastrin release | Gastrin levels can be increased but typically remain within the normal range.2 Due to potential for gastrin to affect growth of tumors outside the gastrointestinal tract, further study of a potential relationship with stimulating tumor growth is needed.13 An increase in ECL cells has been seen in humans; neoplastic findings have not been seen in humans.2,13-15 |
| Vitamin B12 deficiency | Vitamin B12 depends on gastric acid to be released and absorbed from food. In the absence of gastric acid, there is potential for deficiency16 | There is no association between chronic PPI therapy and substantial reduction of vitamin B12.16 Consideration should be given to monitoring vitamin B12 levels periodically in patients who may be at higher risk for vitamin B12 deficiency.13 A small case-control study showed an association between vitamin B12deficiency and PPI/H2 antagonist therapy (OR=4.45, 95% CI 1.47-13.34). Other causes were not explored and data were not separated from the H2 antagonist group.16 |
| Risk of hip fracture | PPIs may inhibit bone resorption and reduce calcium absorption by inducing hypochlorhydria17 | In 2006, a nested, observational case-control study associating high-dose chronic PPI use with a higher incidence of hip fractures showed an adjusted OR=1.44 (95% CI 1.30-1.59) in patients on PPI therapy > 1 year.17 |
| Risk of community-acquired pneumonia (CAP) | Prolonged hypochlorhydria could lead to bacterial overgrowth | A case-control study had an adjusted OR=1.5 (95% CI 1.3-1.7) and the strongest association (OR=5; 95% CI 2.1-11.7) between PPI use and CAP was in patients who had started a PPI within the past 7 days.18 A higher percentage of case patients were on corticosteroid therapy and had concurrent chronic obstructive lung disease, diabetes mellitus, and heart disease. A small study of critically ill trauma patients did not find an increased risk of nosocomial infections in patients taking PPIs.19 A pediatric prospective study found 2 cases of pneumonia in follow-up of the control group of 95 patients, and 11 cases of pneumonia in 91 patients in the combined gastric acid suppression group (P=0.03).20 This trial did not differentiate between ranitidine and omeprazole and excluded patients with diseases identified as confounding variables in previous studies. |
| Risk of Clostridium difficile infection | Prolonged hypochlorhydria could lead to bacterial overgrowth | A case-control study found that the OR for a PPI exposure within the past 3 months and C difficile infection was 3.5 (95% CI 2.3-5.2).21 Previous antibiotic exposure within the same period was associated with an OR of 8.2 (95% CI 6.1-11.0). Notably, in this study, inflammatory bowel disease, renal failure, MRSA, cancer, pernicious anemia, and recent antibiotic use were all associated with a higher adjusted OR for increased risk of C difficile infection than PPI exposure. A 2nd cohort study found an unadjusted OR of 3.1 (95% CI 1.7-5.6) for PPIs and C difficile infection. Of note, higher unadjusted ORs were seen with both renal failure and MRSA.22 Another case-control study did not establish an association between PPI use and C difficile hospitalizations.23 |
| Atrophic gastritis | Unknown | One cohort study found atrophic gastritis can occur with chronic omeprazole therapy,26 but it should be noted that of 20 who patients developed atrophy, 18 were infected with H pylori (P < 0.001) and 2 were not infected (P=0.62). In a separate study, omeprazole was not associated with gastric atrophy after 3 years.27 |
Drug interactions
Two main types of drug interactions may occur with PPIs: those at the cytochrome P450 level, and those due to decreased absorption caused by acid suppression.
PPIs are metabolized by both CYP 2C19 and CYP 3A4. Theoretically, any medication that can induce or inhibit either of these enzymes could affect PPI blood concentration levels.
Evidence suggests omeprazole and its enantiomer esomeprazole have the most potential of the PPIs for drug interactions, as they have been shown to increase blood concentration levels of phenytoin, benzodiazepines, carbamazepine, cilostazol, clarithomycin, and R-warfarin by inhibiting CYP 2C19.2,3,29 These interactions do not typically require a dose adjustment. However, more frequent monitoring may be appropriate.2,6
As a class, PPIs may decrease or increase the bioavailability of drugs whose absorption is dependent on gastric pH. Common medications that are pH dependent for absorption are the azole antifungals, ampicillin, cefpodoxime, indinavir, delavirdine, cyanocobalamin, iron, and digoxin.2,3,6 Digoxin absorption may be increased, resulting in elevated digoxin levels. Enteric-coated medications, which typically dissolve at a higher pH, may also be affected by PPI therapy.2
There may be a decrease in PPI efficacy if given concurrently with other antisecretory medications such as histamine 2 (H2) antagonists or misoprostol. This interaction is apparently due to the capability of PPIs to exert their effects only on actively secreting proton pumps.2,29
Step-up and step-down therapy
Step therapy was a much larger issue prior to the availability of generic omeprazole and pantoprazole. The relative novelty of these agents combined with higher cost of therapy and unknown long-term safety information as well as the availability of effective alternatives justified the argument for step-up therapy.
Health care systems and insurance providers encouraged short-term use of PPIs, either prior to H2 receptor antagonists (step-down therapy) or only after failure of H2 receptor antagonists (step-up therapy). Those who favored step-up therapy took into account the cost advantage of H2 receptor antagonists. Those who favored step-down therapy believed patients on H2 receptor antagonists may experience worsening control of the disease and would therefore need to utilize more health care resources, offsetting the lower costs of H2 receptor antagonists. Further, for indications like the treatment of H. pylori, compliance to therapy and corresponding efficacy may be compromised by the use of an H2 receptor antagonist in place of a PPI. Of the 2 approaches, cost effectiveness studies favor the step-down approach.30-33
Switch to an H2 blocker? Proponents of step-down therapy reasoned that many patients are placed on PPIs and continued indefinitely without re-evaluation. The only way to see if a PPI is still needed is to decrease the dose, switch to an H2 receptor antagonist, or completely discontinue acid-suppression therapy after symptom resolution.
At this time, omeprazole is the only PPI available OTC; it typically retails at $22 for 28 capsules. A generic version of the OTC omeprazole product has been approved. The cost is generally $13 to $15 for 28 capsules. Each H2 receptor antagonist is available as a generic, and OTC at half prescription strength. Of note, famotidine 20-mg tablets and ranitidine 150-mg and 300-mg tablets are available on many of the $4 prescription plans at retail pharmacies.
Your patient reports he has been taking omeprazole 20 mg daily, as you prescribed, for the past 2 weeks. His heart-burn symptoms have improved and he no longer needs to use Tums for breakthrough symptoms, as he did when he was taking Pepcid.
You considered pantoprazole and omeprazole because they are both available in generic form. Since there are no significant differences in efficacy of the 2 drugs for the treatment of GERD, you decided to prescribe pantoprazole because it will cost less for the patient, who has no prescription insurance. The pharmacy calls you, asking if generic omeprazole could be used instead due to the cost difference.
According to http://www.drugstore.com, generic pantoprazole would cost the patient $110 per month and generic omeprazole would cost the patient $63 per month.
Even though costs at local pharmacies vary and are often higher than online costs, the savings to the patient seemed significant enough to change
Equal efficacy
The first PPI, Prilosec, was approved in 1989, and 4 additional agents have become available. All are equally efficacious at equipotent doses.
Long-term safety
Although there has been concern about potential for several different adverse events with long-term PPI use, it is important to remember that the majority of these data are either conflicting or derived from case-control studies. The latter cannot prove cause and effect, but can describe potential associations that merit further investigation.
Step therapy
Whether to lower the PPI dose or switch to an H2 receptor antagonist should be considered in all patients and attempted in most patients who have been on PPIs long enough for adequate ulcer healing or who have been symptom-free.
Consider the cost to the patient
Given the similarities in interaction potential, adverse events, and efficacy, select the PPI on the basis of cost to the patient.
1. Top 200 Prescription Drugs of 2006. http://www.pharmacytimes.com/Article.cfm?Menu=1&ID=4629. Accessed August 28, 2007.
2. Berardi RR. A critical evaluation of proton pump inhibitors in the treatment of gastroesophageal reflux disease. Am J Manage Care. 2000;6(suppl):S491-505.
3. Guimaraes EV, Marguet C, Camargos PAM. Treatment of gastroesophageal reflux disease. J Pediatr (Rio J). 2006;82(5 Suppl):S133-145.
4. Hunt RH, Armstrong D, Yaghoobi M, et al. S-tenatoprazole-Na 30 mg, 60 mg and 90 mg versus esomeprazole (ESO) 40 mg in healthy male volunteers (hmv). Gastroenterology. 2007;132:A-488.
5. Klok RM, Postma MJ, Van Hout BA, Brouwers JRBJ. Meta-analysis: comparing the efficacy of proton pump inhibitors in short-term use. Aliment Pharmacol Ther. 2003;17:1237-1245.
6. McDonagh MS, Carson S. Drug Class Review on Proton Pump Inhibitors. 2006. http://www.ohsu.edu/drugeffectiveness/reports/final.cfm. Accessed December 18, 2007.
7. Dachs R, Darby-Stewart A, Graber M. Choosing one PPI treatment over another. Am Fam Phys. 2007;76:1273-1280.
8. Prilosec (package insert). Wilmington, DE: Astra-Zeneca LP; Sep 2006.
9. Prevacid (package insert). Lake Forest, IL: TAP Pharmaceuticals, Inc; Jun 2007.
10. Protonix (package insert). Philadelphia, PA: Wyeth Laboratories; Jun 2007.
11. Aciphex (package insert). Teaneck, NJ: Eisai, Inc; Aug 2003.
12. Nexium (package insert). Wilmington, DE: Astra-Zeneca LP; Apr 2007.
13. Jensen RT. Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol. 2006;98:4-19.
14. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2000;14:651-668.
15. Robinson M. Review article: current perspectives on hypergastrinaemia and enterochromaffin-like cell hyperplasia. Aliment Pharmacol Ther. 1999;13 (Suppl 5):5-10.
16. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of B12 deficiency in older adults. J Clin Epidemiol. 2004;57:422-428.
17. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947-2953.
18. Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump inhibitors and the risk of community-acquired pneumonia. Arch Intern Med. 2007;167:950-955.
19. Mallow S, Rebuck JA, Osler T, Ahern J, Healey MA, Rogers FB. Do proton pump inhibitors increase the incidence of nosocomial pneumonia and related infectious complications when compared with histamine-2 receptor antagonists in critically ill trauma patients? Curr Surg. 2004;61:452-458.
20. Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, Passariello A, Manguso F, Morelli L, Guarino A. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006;117:e817-e820.
21. Dial S, Delaney C, Schneider V, Suissa S. Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ. 2006;175:745-748.
22. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171(1):33-38.
23. Lowe DO, Mamdani MM, Kopp A, Low DE, Juurlink DN. Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study. Clin Infect Dis. 2006;43:1272-1276.
24. Health Canada reviewing new safety information on cardiac events in patients taking Losec (omeprazole) or Nexium (esomeprazole). http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2007/2007_95_e.html. Accessed on August 28, 2007.
25. Vanderhoff BT, Tahboub RM. Proton pump inhibitors: an update. Am Fam Phys. 2002;66:273-280.
26. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med. 1996;334:1018-1022.
27. Lundell L, Miettinen P, Myrvold HE, et al. Lack of effect of acid suppression therapy on gastric atrophy. Gastroenterology. 1999;117:319-326.
28. Hassall E, Kerr W, El-Serag HB. Characteristics of children receiving proton pump inhibitors continuously for up to 11 years duration. J Pediatr. 2007;150:262-267.
29. Clinical Pharmacology. http://cpip.gsm.com. Accessed on August 17, 2007.
30. Inadomi JM, et al. Step-down management of gastroesophageal disease. Gastroenterology. 2001;121:1095-1100.
31. Tytgat GNJ. Review article: management of mild and severe gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2003;17(Suppl 2):52-56.
32. Ofman JJ, Dorn GH, Fennerty MB, Fass R. The clinical and economic impact of competing management strategies for gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2002;16:261-273.
33. Gerson LB, Robbins AS, Garber A, Hornberger J, Tridafilopoulos G. A cost-effectiveness analysis of prescribing strategies in the management of gastroesophageal reflux disease. Am J Gastroenterol. 2000;95:395-407.
34. Zimmermann AE, Walters JK, Katona BG, Souney PF, Levine D. Review of omeprazole use in the treatment of acid-related disorders in children. Clin Ther. 2001;23:660-679.
35. Humphries TJ, Merritt GJ. Review article: drug interactions with agents used to treat acid-related diseases. Aliment Pharmacol Ther. 1999;23(Suppl 3):18-26.
1. Top 200 Prescription Drugs of 2006. http://www.pharmacytimes.com/Article.cfm?Menu=1&ID=4629. Accessed August 28, 2007.
2. Berardi RR. A critical evaluation of proton pump inhibitors in the treatment of gastroesophageal reflux disease. Am J Manage Care. 2000;6(suppl):S491-505.
3. Guimaraes EV, Marguet C, Camargos PAM. Treatment of gastroesophageal reflux disease. J Pediatr (Rio J). 2006;82(5 Suppl):S133-145.
4. Hunt RH, Armstrong D, Yaghoobi M, et al. S-tenatoprazole-Na 30 mg, 60 mg and 90 mg versus esomeprazole (ESO) 40 mg in healthy male volunteers (hmv). Gastroenterology. 2007;132:A-488.
5. Klok RM, Postma MJ, Van Hout BA, Brouwers JRBJ. Meta-analysis: comparing the efficacy of proton pump inhibitors in short-term use. Aliment Pharmacol Ther. 2003;17:1237-1245.
6. McDonagh MS, Carson S. Drug Class Review on Proton Pump Inhibitors. 2006. http://www.ohsu.edu/drugeffectiveness/reports/final.cfm. Accessed December 18, 2007.
7. Dachs R, Darby-Stewart A, Graber M. Choosing one PPI treatment over another. Am Fam Phys. 2007;76:1273-1280.
8. Prilosec (package insert). Wilmington, DE: Astra-Zeneca LP; Sep 2006.
9. Prevacid (package insert). Lake Forest, IL: TAP Pharmaceuticals, Inc; Jun 2007.
10. Protonix (package insert). Philadelphia, PA: Wyeth Laboratories; Jun 2007.
11. Aciphex (package insert). Teaneck, NJ: Eisai, Inc; Aug 2003.
12. Nexium (package insert). Wilmington, DE: Astra-Zeneca LP; Apr 2007.
13. Jensen RT. Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol. 2006;98:4-19.
14. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2000;14:651-668.
15. Robinson M. Review article: current perspectives on hypergastrinaemia and enterochromaffin-like cell hyperplasia. Aliment Pharmacol Ther. 1999;13 (Suppl 5):5-10.
16. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of B12 deficiency in older adults. J Clin Epidemiol. 2004;57:422-428.
17. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947-2953.
18. Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump inhibitors and the risk of community-acquired pneumonia. Arch Intern Med. 2007;167:950-955.
19. Mallow S, Rebuck JA, Osler T, Ahern J, Healey MA, Rogers FB. Do proton pump inhibitors increase the incidence of nosocomial pneumonia and related infectious complications when compared with histamine-2 receptor antagonists in critically ill trauma patients? Curr Surg. 2004;61:452-458.
20. Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, Passariello A, Manguso F, Morelli L, Guarino A. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006;117:e817-e820.
21. Dial S, Delaney C, Schneider V, Suissa S. Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ. 2006;175:745-748.
22. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171(1):33-38.
23. Lowe DO, Mamdani MM, Kopp A, Low DE, Juurlink DN. Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study. Clin Infect Dis. 2006;43:1272-1276.
24. Health Canada reviewing new safety information on cardiac events in patients taking Losec (omeprazole) or Nexium (esomeprazole). http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2007/2007_95_e.html. Accessed on August 28, 2007.
25. Vanderhoff BT, Tahboub RM. Proton pump inhibitors: an update. Am Fam Phys. 2002;66:273-280.
26. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med. 1996;334:1018-1022.
27. Lundell L, Miettinen P, Myrvold HE, et al. Lack of effect of acid suppression therapy on gastric atrophy. Gastroenterology. 1999;117:319-326.
28. Hassall E, Kerr W, El-Serag HB. Characteristics of children receiving proton pump inhibitors continuously for up to 11 years duration. J Pediatr. 2007;150:262-267.
29. Clinical Pharmacology. http://cpip.gsm.com. Accessed on August 17, 2007.
30. Inadomi JM, et al. Step-down management of gastroesophageal disease. Gastroenterology. 2001;121:1095-1100.
31. Tytgat GNJ. Review article: management of mild and severe gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2003;17(Suppl 2):52-56.
32. Ofman JJ, Dorn GH, Fennerty MB, Fass R. The clinical and economic impact of competing management strategies for gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2002;16:261-273.
33. Gerson LB, Robbins AS, Garber A, Hornberger J, Tridafilopoulos G. A cost-effectiveness analysis of prescribing strategies in the management of gastroesophageal reflux disease. Am J Gastroenterol. 2000;95:395-407.
34. Zimmermann AE, Walters JK, Katona BG, Souney PF, Levine D. Review of omeprazole use in the treatment of acid-related disorders in children. Clin Ther. 2001;23:660-679.
35. Humphries TJ, Merritt GJ. Review article: drug interactions with agents used to treat acid-related diseases. Aliment Pharmacol Ther. 1999;23(Suppl 3):18-26.