VA Class:GA900

ATC Class:A02BC04

AHFS Class:

• Proton-pump Inhibitors 56:28.36

Generic Name(s):

• RABEprazole Sodium

Chemical Name:

• 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-benzimidazole sodium

Molecular Formula:

• C₁₈H₂₀N₃NaO₃S

Rabeprazole, commonly referred to as an acid or proton-pump inhibitor, is a gastric antisecretory agent.1,2,3,4,5,6

Gastroesophageal Reflux

Rabeprazole is used for the short-term (4-8 weeks) treatment of erosive or ulcerative esophagitis in patients with gastroesophageal reflux disease (GERD).1,2,3,15,18 The drug also is used as maintenance therapy following healing of erosive or ulcerative esophagitis to reduce recurrence of the disease.1,2,3 In addition, rabeprazole is used for the treatment of symptoms (e.g., heartburn) of GERD in patients without erosive or ulcerative esophagitis.1 Potential benefits in gastroesophageal reflux and esophagitis are thought to result principally from reduced acidity of gastric contents induced by the drug and resultant reduced irritation of esophageal mucosa; the drug can effectively relieve symptoms of esophagitis (e.g., heartburn) and promote healing of ulcerative and erosive lesions.1,2,3,15,16,18

Suppression of gastric acid secretion is considered by the American College of Gastroenterology (ACG) to be the mainstay of treatment for GERD, and a proton-pump inhibitor or histamine H₂-receptor antagonist is used to achieve acid suppression, control symptoms, and prevent complications of the disease.26 Because GERD is considered to be a chronic disease, the ACG states that many patients with GERD require long-term, even lifelong, treatment.26 The ACG states that proton-pump inhibitors are more effective (i.e., provide more frequent and more rapid symptomatic relief and healing of esophagitis) than histamine H₂-receptor antagonists in the treatment of GERD, and are effective and appropriate as maintenance therapy in many patients with the disease.26 Proton-pump inhibitors also provide greater control of acid reflux than do prokinetic agents (e.g., cisapride [no longer commercially available in the US], metoclopramide) without the risk of severe adverse effects associated with these agents.26

Efficacy of rabeprazole for treating acute GERD was established in 2 short-term (up to 8 weeks) controlled studies in adults;1,2,15,18 rabeprazole was more effective than placebo or ranitidine and at least as effective as omeprazole in healing lesions and providing symptomatic relief.1,2,3,15,18 Efficacy as maintenance therapy following healing of erosive or ulcerative esophagitis was established in two 52-week controlled studies in adults;1 maintenance of lesion healing and symptomatic relief were superior with rabeprazole versus placebo.1 Efficacy in patients with symptomatic GERD without erosive or ulcerative esophagitis was established in 2 short-term (4 weeks) controlled studies in patients with daytime and nocturnal heartburn, no endoscopic evidence of esophageal erosion, and 5 or more episodes of heartburn during the 7 days immediately prior to randomization.1 The percentage of daytime or nocturnal periods free of heartburn symptoms was greater, daily antacid consumption was substantially decreased, and other GERD-associated symptoms (regurgitation, belching, early satiety) were improved in patients receiving rabeprazole sodium 20 mg daily compared with those receiving placebo.1

Antacids may be used concomitantly as needed for pain relief.1,19

For further information on the treatment of GERD, see Uses: Gastroesophageal Reflux, in Omeprazole 56:28.36.

Duodenal Ulcer

Rabeprazole is used for the short-term (up to 4 weeks) treatment of active duodenal ulcers.1,2,3,17 Efficacy for treating acute duodenal ulcers was established in two 4-week studies;1,2,17,18 rabeprazole was more effective than placebo and at least as effective as omeprazole in healing ulcers and providing symptomatic relief.1,2,17,18 Antacids may be used concomitantly as needed for pain relief.1,19

Rabeprazole is used in combination with amoxicillin and clarithromycin (triple therapy) for the treatment of Helicobacter pylori infection and duodenal ulcer disease in individuals with active duodenal ulcer or a history of duodenal ulcer within the preceding 5 years.1 Efficacy of rabeprazole-based triple therapy for H. pylori eradication was established in a double-blind, parallel-group comparison study in patients with H. pylori infection; patients were stratified in a 1:1 ratio between those with peptic ulcer disease (active ulcer or a history of ulcer in the past 5 years) and symptomatic patients with no endoscopic evidence of peptic ulcer disease.1 Patients received 3, 7, or 10 days of therapy with rabeprazole (20 mg twice daily), amoxicillin (1 g twice daily), and clarithromycin (500 mg twice daily) or 10 days of therapy with omeprazole (20 mg twice daily), amoxicillin (1 g twice daily), and clarithromycin (500 mg twice daily).1 H. pylori eradication was defined as a negative ¹³C urea breath test 6 weeks or more after completion of the assigned regimen.1 H. pylori eradication rates achieved with the 7- and 10-day rabeprazole regimens (77.3 and 78.1%, respectively, by intent-to-treat analysis) were similar to those achieved with the 10-day omeprazole regimen (73.3%); eradication rates achieved with the 3-day rabeprazole regimen (27.3%) were inferior to those achieved with the other regimens.1 For a more complete discussion of H. pylori infection, including details about the efficacy of various regimens and rationale for drug selection, see Uses: Helicobacter pylori Infection, in Clarithromycin 8:12.12.92.

Pathologic GI Hypersecretory Conditions

Rabeprazole is used in the long-term treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome).1,3 Experience in the treatment of these conditions is limited, but rabeprazole has been used effectively for up to 12 months; the optimum duration of treatment has not been clearly established.1

Crohn's Disease-associated Ulcers

Although evidence currently is limited, proton-pump inhibitors have been used for gastric acid-suppressive therapy as an adjunct in the symptomatic treatment of upper GI Crohn's disease†, including esophageal†, gastroduodenal†, and jejunoileal disease†.27,30 Most evidence of efficacy to date has been from case studies in patients with Crohn's-associated peptic ulcer disease unresponsive to other therapies (e.g., H₂-receptor antagonists, cytoprotective agents, antacids, and/or sucralfate).27,28,29,30,31,32,33 (See Uses: Crohn's Disease-associated Ulcers in Omeprazole 56:28.36.)

For further information on the management of Crohn's Disease, see Uses: Crohn's Disease, in Mesalamine 56:36.

Administration

Rabeprazole sodium is administered orally, generally once daily.1 Rabeprazole sodium tablets should not be chewed, crushed, or split.1 Food may delay the rate but does not affect the extent of GI absorption of the drug; therefore, rabeprazole generally may be given without regard to meals.1,20,23

Although the manufacturer currently recommends dosing rabeprazole after the morning meal for duodenal ulcers because clinical studies establishing efficacy for this use employed such dosing,1 other evidence indicates that the drug may be given without regard to meals in the morning or at bedtime.1,23,24,25 The possibility that time of administration could facilitate treatment compliance should be considered.24,25

When rabeprazole is used in combination with clarithromycin and amoxicillin (triple therapy) for the treatment of H. pylori infection, all 3 drugs should be taken twice daily with the morning and evening meals.1 Although concomitant administration of rabeprazole with clarithromycin and amoxicillin may result in increased peak plasma concentrations and areas under the plasma concentration-time curves (AUCs) of rabeprazole and 14-hydroxyclarithromycin (the active metabolite of clarithromycin), the increased exposure to these drugs is not expected to be clinically important.1

Dosage

Gastroesophageal Reflux

The recommended adult dosage of rabeprazole sodium for the short-term treatment of erosive or ulcerative esophagitis in patients with gastroesophageal reflux disease (GERD),1,2,15,18 maintenance therapy following healing of erosive or ulcerative esophagitis,1 and short-term treatment of symptomatic GERD in patients without erosive or ulcerative esophagitis is 20 mg once daily.1 The duration of therapy for acute treatment of erosive or ulcerative esophagitis in patients with GERD is 4-8 weeks;1,15 an additional 8-week course of therapy may be considered in patients if esophageal healing is incomplete after the first course of treatment.1 Controlled studies for maintenance therapy following healing of erosive or ulcerative esophagitis did not extend beyond 12 months.1 The manufacturer states that the duration of therapy for symptomatic GERD in patients without erosive or ulcerative esophagitis is 4 weeks;1 an additional 4-week course of therapy may be considered in patients whose symptoms have not completely resolved after the first course of treatment.1 However, the American College of Gastroenterology (ACG) states that chronic, even lifelong, therapy with a proton-pump inhibitor is appropriate in many patients with GERD.26

The recommended dosage of rabeprazole sodium for the short-term treatment of symptomatic GERD in adolescents 12 years of age and older is 20 mg once daily for up to 8 weeks.1

Duodenal Ulcer Disease

The recommended adult dosage of rabeprazole sodium for short-term treatment of duodenal ulcers is 20 mg daily,1,2,17,18 and the usual duration of therapy is 4 weeks;1,17 most patients heal within 4 weeks, but some may require additional therapy to achieve healing.1

When rabeprazole sodium is used in combination with clarithromycin and amoxicillin (triple therapy) for the treatment of H. pylori infection in patients with active duodenal ulcer or a history of duodenal ulcer in the preceding 5 years, the usual adult dosage of rabeprazole sodium is 20 mg twice daily for 7 days.1

Pathologic GI Hypersecretory Conditions

The recommended initial adult dosage of rabeprazole sodium for the treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome) is 60 mg once daily.1 Dosages up to 100 mg once daily or 60 mg twice daily have been used.1 Some patients may require divided doses.1 Dosage should be adjusted as necessary and continued for as long as clinically indicated.1 Some patients have been treated continuously with the drug for up to 1 year.1

Special Populations

Caution should be exercised in dosing patients with severe hepatic impairment,1,21 particularly because of the lack of clinical data in this patient population.1 However, accumulation of rabeprazole at the usual dosage of 20 mg daily is unlikely,21 and dosage adjustment is not necessary in those with mild to moderate hepatic impairment.1,21

Dosage adjustment also is not necessary in geriatric patients1 nor in patients with renal impairment.22,23

Contraindications

Known hypersensitivity to rabeprazole, other substituted benzimidazoles (e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole), or any ingredient in the formulation.1

Warnings/Precautions

Gastric Malignancy

Symptomatic response to therapy with rabeprazole does not preclude the occult presence of gastric neoplasm.1 Approximately 4% of patients had intestinal metaplasia during follow-up (up to 40 months), with no consistent changes noted.1

Clostridium difficile Infection

Available data suggest a possible association between use of proton-pump inhibitors and risk of Clostridium difficile infection, including C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis).335,336,339,340 In most observational studies to date, the risk of C. difficile infection in patients exposed to proton-pump inhibitors has ranged from 1.4-2.75 times that in patients not exposed to proton-pump inhibitors;335,339 however, some observational studies have found no increase in risk.335,337,338 Although many of the cases occurred in patients who had other risk factors for CDAD, including advanced age, comorbid conditions, and/or use of broad-spectrum anti-infectives, the US Food and Drug Administration (FDA) concluded that a contributory role for proton-pump inhibitors could not be definitively ruled out.335 The mechanism by which proton-pump inhibitors might increase the risk of CDAD has not been elucidated.338,341 Although it has been suggested that reduction of gastric acidity by gastric antisecretory agents might facilitate colonization with C. difficile , some studies have raised questions about this proposed mechanism or have suggested that the observed association is the result of confounding with other risk factors for CDAD.336,337,338,339,340,341 FDA also is reviewing the risk of CDAD in patients exposed to histamine H₂-receptor antagonists.335

CDAD can be serious in patients who have one or more risk factors for C. difficile infection and are receiving concomitant therapy with a proton-pump inhibitor; colectomy and, rarely, death have been reported.335 FDA recommends that patients receive proton-pump inhibitors at the lowest effective dosage and for the shortest possible time appropriate for their clinical condition.335 Patients experiencing persistent diarrhea should be evaluated for CDAD and should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.335,336

Respiratory Effects

Administration of proton-pump inhibitors has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia).35,36 (For further precautionary information about this adverse effect, see Community-acquired Pneumonia under Cautions: Respiratory Effects, in Omeprazole 56:28.36.)

Musculoskeletal Effects

Findings from several observational studies suggest that therapy with proton-pump inhibitors, particularly in high dosages (i.e., multiple daily doses) and/or for prolonged periods of time (i.e., one year or longer), may be associated with an increased risk of osteoporosis-related fractures of the hip, wrist, or spine.1,39,300,301,302,303,304,305 The magnitude of risk is unclear;39,300,301,302,303,304,305,310 causality has not been established.305 (See Cautions: Musculoskeletal Effects, in Omeprazole 56:28.36.) FDA is continuing to evaluate this safety concern.305 Although controlled studies are required to confirm these findings, patients should receive proton-pump inhibitors at the lowest effective dosage and for the shortest possible time appropriate for their clinical condition.1,39,301,303,305,307 Individuals who are at risk for osteoporosis-related fractures should receive an adequate intake of calcium and vitamin D and should have their bone health assessed and managed according to current standards of care.1,39,303,305,307

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients receiving long-term therapy (for at least 3 months or, in most cases, for longer than one year) with proton-pump inhibitors, including rabeprazole.1,317,318,319,320,321,322,323,324,325,326,327,328,329,330 Clinically serious adverse effects associated with hypomagnesemia, which are similar to manifestations of hypocalcemia, include tetany, seizures, tremors, carpopedal spasm, arrhythmias (e.g., atrial fibrillation, supraventricular tachycardia), and abnormal QT interval.1,318,319,321,322,323,325,327,328,329 Other reported adverse effects include paresthesia, muscle weakness, muscle cramps, lethargy, fatigue, and unsteadiness.319,320,321,325,330 In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuance of the proton-pump inhibitor.1,317,319,321,322,323,324,325,326,327,330 Following discontinuance of the proton-pump inhibitor, hypomagnesemia resolved within a median of one week; upon rechallenge, hypomagnesemia recurred within a median of 2 weeks.327

In patients expected to receive long-term therapy with a proton-pump inhibitor or in those receiving a proton-pump inhibitor concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), clinicians should consider measurement of serum magnesium concentrations prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.1,319,326,327,328,330 (See Cautions: Hypomagnesemia and also Cautions: Precautions and Contraindications, in Omeprazole 56:28.36.)

Specific Populations

Pregnancy

Category B. (See Users Guide.)1

Lactation

It is unknown whether rabeprazole is distributed into milk; discontinue nursing or drug because of potential risk in nursing infants.1

Pediatric Use

Efficacy and safety of rabeprazole for short-term treatment of symptomatic GERD in adolescents 12-16 years of age are supported by controlled clinical trials in adults and additional safety and pharmacokinetic studies in adolescents.1 The pharmacokinetic and adverse effect profiles of rabeprazole in adolescents with symptomatic or endoscopically diagnosed GERD were similar to those in adults.1 Safety and efficacy of rabeprazole for uses other than short-term treatment of symptomatic GERD have not been established in pediatric patients.1

Safety and efficacy of the drug in children younger than 12 years of age have not been established.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Severe Hepatic Impairment

Use with caution.1,21 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving rabeprazole in controlled clinical trials and reported more frequently with rabeprazole than with placebo include pain,1 pharyngitis,1 flatulence,1 infection,1 and constipation.1

Rabeprazole is extensively metabolized, mainly via hepatic cytochrome P-450 (CYP) 3A and 2C19 isoenzymes.1,7,8,9

Drugs that Cause Hypomagnesemia

Potential pharmacologic interaction (possible increased risk of hypomagnesemia).327 In patients receiving diuretics (i.e., loop or thiazide diuretics) or other drugs that may cause hypomagnesemia, monitoring of magnesium concentrations should be considered prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.1,327 (See Hypomagnesemia under Cautions: Warnings/Precautions.)

Gastric pH-Dependent Drugs

Potential pharmacokinetic interaction; increased or decreased drug absorption at increased gastric pH values (e.g., digoxin, ketoconazole).1 Increased monitoring during concomitant use with rabeprazole.1

Antiretroviral Agents

Atazanavir

Potential pharmacokinetic interaction (possible altered oral absorption of atazanavir at increased gastric pH, resulting in decreased plasma atazanavir concentrations).1 Concomitant use of omeprazole 40 mg once daily and atazanavir (with or without low-dose ritonavir) results in a substantial decrease in plasma concentrations of atazanavir and possible loss of the therapeutic effect of the antiretroviral agent.42 The manufacturer of rabeprazole states that concomitant administration with atazanavir is not recommended.1 If atazanavir is administered in an antiretroviral treatment-naive patient receiving a proton-pump inhibitor, a ritonavir-boosted regimen of 300 mg of atazanavir once daily with ritonavir 100 mg once daily with food is recommended.42 The dose of the proton-pump inhibitor should be administered approximately 12 hours before ritonavir-boosted atazanavir; the dose of the proton-pump inhibitor should not exceed omeprazole 20 mg daily (or equivalent).41,42 Concomitant use of proton-pump inhibitors with atazanavir is not recommended in antiretroviral treatment-experienced patients.41,42

Fosamprenavir

Concomitant use of esomeprazole with fosamprenavir (with or without ritonavir) did not substantially affect concentrations of amprenavir (active metabolite of fosamprenavir).345 No dosage adjustment is required when proton-pump inhibitors are used concomitantly with fosamprenavir (with or without ritonavir).41,345

Lopinavir

Concomitant use of omeprazole with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) did not have a clinically important effect on plasma concentrations or area under the concentration-time curve (AUC) of lopinavir.41,344 No dosage adjustment is required when proton-pump inhibitors are used concomitantly with lopinavir/ritonavir.41

Raltegravir

Pharmacokinetic interaction with omeprazole (substantially increased peak plasma concentration and AUC of raltegravir); however, no dosage adjustment is recommended when proton-pump inhibitors are used concomitantly with raltegravir.41,348

Rilpivirine

Pharmacokinetic interaction with omeprazole (decreased plasma concentrations and AUC of rilpivirine).41,343 Concomitant use of other proton-pump inhibitors also may result in decreased plasma concentrations of rilpivirine.343 Concomitant use of rilpivirine and proton-pump inhibitors is contraindicated.41,343

Saquinavir

Potential pharmacokinetic interaction (increased peak plasma concentration and AUC of saquinavir).41,346 Concomitant use of omeprazole 40 mg once daily and ritonavir-boosted saquinavir (saquinavir 1 g twice daily and ritonavir 100 mg twice daily) increased the peak plasma concentration and AUC of saquinavir by 75 and 82%, respectively.41,346 Caution is advised if proton-pump inhibitors are used concomitantly with ritonavir-boosted saquinavir, and patients should be monitored for saquinavir toxicity.41,346

Clopidogrel

Potential pharmacokinetic interaction (decreased plasma concentration of the active metabolite of clopidogrel) and pharmacodynamic interaction (reduced antiplatelet effects) between proton-pump inhibitors and clopidogrel.47,219,220,221,224,226,227,228,229 Clopidogrel is metabolized to its active metabolite by cytochrome P-450 (CYP) isoenzyme 2C19 (CYP2C19).47,224,228 Concurrent use of omeprazole or esomeprazole, which inhibit CYP2C19, with clopidogrel reduces exposure to the active metabolite of clopidogrel and decreases platelet inhibitory effects.223,224,225,228,232,233,236,350 Although the clinical importance has not been fully elucidated, a reduction in the effectiveness of clopidogrel in preventing cardiovascular events is possible.219,220,221,224,229,230,234,235,236,237,238,240 Proton-pump inhibitors vary in their potency for inhibiting CYP2C19.219,220,221,224,232 The change in inhibition of adenosine diphosphate (ADP)-induced platelet aggregation associated with concomitant use of proton-pump inhibitors is related to the change in exposure to the active metabolite of clopidogrel.350,351 In pharmacokinetic and pharmacodynamic studies in healthy individuals, dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole.224,350,351

The decision to use a proton-pump inhibitor concomitantly with clopidogrel should be based on the assessed risks and benefits in individual patients.237,240,243,248,250 The American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) states that the reduction in GI bleeding risk with proton-pump inhibitors is substantial in patients with risk factors for GI bleeding (e.g., advanced a concomitant use of warfarin, corticosteroids, or nonsteroidal anti-inflammatory agents [NSAIAs]; H. pylori infection) and may outweigh any potential reduction in the cardiovascular efficacy of antiplatelet treatment associated with a drug-drug interaction.311 In contrast, ACCF/ACG/AHA states that patients without such risk factors receive little if any absolute risk reduction from proton-pump inhibitor therapy, and the risk/benefit balance may favor use of antiplatelet therapy without a proton-pump inhibitor in these patients.311

If concomitant therapy with a proton-pump inhibitor and clopidogrel is considered necessary, use of an agent with little or no CYP2C19-inhibitory activity should be considered.47,48,49,224,230,350 Alternatively, treatment with a histamine H₂-receptor antagonist (ranitidine, famotidine, nizatidine) may be considered, although such agents may not be as effective as a proton-pump inhibitor in providing gastric protection;47,48,230 cimetidine should not be used since it also is a potent CYP2C19 inhibitor.232,233 There currently is no evidence that histamine H₂-receptor antagonists (other than cimetidine) or other drugs that reduce gastric acid (e.g., antacids) interfere with the antiplatelet effects of clopidogrel.225,232 For further information on interactions between proton-pump inhibitors and clopidogrel, see Drug Interactions: Proton-Pump Inhibitors, in Clopidogrel Bisulfate 20:12.18.

Cyclosporine

Potential pharmacokinetic interaction (inhibition of cyclosporine metabolism).1

Digoxin

Hypomagnesemia (e.g., resulting from long-term use of proton-pump inhibitors) sensitizes the myocardium to digoxin and, thus, may increase the risk of digoxin-induced cardiotoxic effects.327,331 In patients receiving digoxin, monitoring of magnesium concentrations should be considered prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.1,327

Methotrexate

Potential pharmacokinetic interaction (increased serum methotrexate concentrations, possibly resulting in toxicity) when proton-pump inhibitors, including rabeprazole, are used concomitantly with methotrexate.1,333,334 Increased serum concentrations and delayed clearance of methotrexate and/or its metabolite hydroxymethotrexate, with or without symptoms of methotrexate toxicity, have been reported in patients receiving methotrexate (usually at doses of 300 mg/m² to 12 g/m²) concomitantly with a proton-pump inhibitor.1,333 Although most of the reported cases occurred in patients receiving high doses of methotrexate,1,333 toxicity also has been reported in patients receiving low dosages of methotrexate (e.g., 15 mg per week) concomitantly with a proton-pump inhibitor.333 No formal studies of interactions between high-dose methotrexate and proton-pump inhibitors have been conducted to date.1,333

The manufacturer of rabeprazole states that temporary discontinuance of proton-pump inhibitor therapy may be considered in some patients receiving high-dose methotrexate therapy.1 Some clinicians recommend either withholding proton-pump inhibitor therapy for several days before and after methotrexate administration or substituting a histamine H₂-receptor antagonist for the proton-pump inhibitor when acid suppressive therapy is indicated during methotrexate therapy.333,334 Pending further evaluation, some clinicians state that these recommendations should extend to patients receiving low-dose methotrexate.334

Sucralfate

Potential pharmacokinetic interaction.34 Concomitant administration of lansoprazole or omeprazole with sucralfate resulted in delayed absorption and decreased bioavailability of these proton-pump inhibitors.34 Administer proton-pump inhibitors at least 30 minutes before sucralfate.34

Warfarin

Increases in the international normalized ratio (INR) and prothrombin time have been reported in patients receiving warfarin concomitantly with a proton-pump inhibitor, including rabeprazole.1 Because such increases may lead to abnormal bleeding and death, monitoring of INR and prothrombin time may be necessary during concomitant use with rabeprazole.1

Description

Rabeprazole, a proton-pump inhibitor, is a gastric antisecretory agent structurally and pharmacologically related to lansoprazole and omeprazole.1,2,3,4,5,6 The drugs are substituted benzimidazoles1,2,3,4,5,6 and are chemically and pharmacologically unrelated to H₂-receptor antagonists, antimuscarinics, or prostaglandin analogs.1,2,3

Rabeprazole binds to hydrogen-potassium ATPase in gastric parietal cells; inactivation of this enzyme system (also known as the proton, hydrogen, or acid pump) blocks the final step in the secretion of hydrochloric acid by these cells, resulting in potent, long-lasting inhibition of gastric acid secretion.1,2,3,4,5,6 The antisecretory effect is apparent within 1 hour following oral administration,23 with the median inhibitory effect on 24-hour gastric acidity being 88% of maximal after the first dose.1

Because the rabeprazole molecule is acid labile, the delayed-release, enteric-coated tablet formulation increases oral bioavailability.1 Rabeprazole is extensively metabolized, mainly via hepatic cytochrome P-450 (CYP) 3A and 2C19 isoenzymes.1,7,8,9

Rabeprazole can suppress gastric Helicobacter pylori in patients with duodenal ulcer and/or reflux esophagitis infected with the organism,2,3,10,11 probably via binding to the bacteria and resultant inhibition of urease activity.12,13,14 Combined therapy with rabeprazole and one or more appropriate anti-infectives (e.g., clarithromycin, amoxicillin) can effectively eradicate H. pylori gastric infection.2,3,10,11

Increased gastric pH during rabeprazole therapy stimulates gastrin secretion via a negative feedback mechanism1,5,6 and results in enterochromaffin-like cell (ECL) hyperplasia.1 Although rats have demonstrated carcinoid lesions,1,23 no clinical sequelae (e.g., no adenomatoid, dysplastic, or neoplastic changes) have occurred to date in patients receiving the drug for up to 1 year.1

Therapy with proton-pump inhibitors, particularly in high dosages and/or for prolonged periods of time, may be associated with an increased risk of osteoporosis-related fractures of the hip, wrist, or spine.1,39,300,301,302,303,304,305 (See Musculoskeletal Effects under Cautions: Warnings/Precautions.) The mechanism by which these drugs may increase risk of such fractures has not been elucidated but may involve decreased insoluble calcium absorption secondary to increased gastric pH.39,300,301,302,303,304,307,308

Advice to Patients

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.23

Necessity of swallowing tablets whole, without crushing or chewing.1

Importance of continuing rabeprazole therapy for the entire treatment course, unless directed otherwise.1

Importance of advising patients that use of multiple daily doses of the drug for an extended period of time may increase the risk of fractures of the hip, wrist, or spine.1,305

Risk of hypomagnesemia; importance of advising patients to immediately report and seek care for any cardiovascular or neurologic manifestations (e.g., palpitations, dizziness, seizures, tetany).1

Possible increased risk of Clostridium difficile infection; importance of contacting a clinician if persistent watery stools, abdominal pain, and fever occur.335

Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Eisai Inc. and Janssen Pharmaceuticals Inc. AcipHex^® (rabeprazole sodium) delayed-release tablets prescribing information. Woodcliff Lake and Titusville, NJ; 2012 May

2. Prakash A, Faulds D. Rabeprazole. Drugs . 1998; 55:261-7. [PubMed 9506245]

3. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders. Drugs . 1998; 56:307-35. [PubMed 9777309]

4. Morii M, Hamatani K, Takeguchi N. The proton pump inhibitor, E3810, binds to the N -terminal half of the α-subunit og gastric H+,K(+)-ATPase. Biochem Pharmacol . 1995; 16:1729-34.

5. Williams MP, Sercombe J, Hamilton MI et al. A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther . 1998; 12:1079-89. [PubMed 9845397]

6. Lew EA, Barbuti RC, Kovacs TO et al. An ascending single-dose safety and tolerance study of an oral formulation of rabeprazole (E3810). Aliment Pharmacol Ther . 1998; 12:667-72. [PubMed 9701531]

7. VandenBranden M, Ring BJ, Binkley SN et al. Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor. Pharmacogenetics . 1996; 6:81-91. [PubMed 8845864]

8. Yasuda S, Horai Y, Tomono Y et al. Comparison of the kinetic disposition and metabolism of E3810, a new proton inhibitor, and omeprazole in relation to S-mephenytoin 4'-hydroxylation status. Clin Pharmacol Ther . 1995; 58:143-54. [PubMed 7648764]

9. Ishizaki T, Chiba K, Manabe K et al. Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S -mephenytoin 4'-hydroxylation. Clin Pharmacol Ther . 1995; 58:155-64. [PubMed 7648765]

10. Miwa H, Ohkura R, Murai T et al. Impact of rabeprazole, a new proton pump inhibitor, in triple therapy for Helicobacter pylori infection-comparison with omeprazole and lansoprazole. Aliment Pharmacol Ther . 1999; 13:741-6. [PubMed 10383502]

11. Stack WA, Knifton A, Thirwell D et al. Safety and efficacy of rabeprazole in combination with four antibiotic regimens for eradication of Helicobacter pylori in patients with chronic gastritis with or without peptic ulceration. Am J Gastroenterol . 1998; 93:1909-13. [PubMed 9772054]

12. Tsuchiya M, Imamura L, Park JB et al. Helicobacter pylori urease inhibition by rabeprazole, a proton pump inhibitor. Biol Pharm Bull . 1995; 18:1053-6. [PubMed 8535394]

13. Park JB, Imamura L, Kobashi K. Kinetic studies of Helicobacter pylori urease inhibition by a novel proton pump inhibitor, rabeprazole. Biol Pharm Bull . 1996; 19:182-7. [PubMed 8850302]

14. Hirai M, Azuma T, Ito S et al. A proton pump inhibitor, E3810, has antibacterial activity through niding to Helicobacter pylori . J Gastroenterol . 1995; 30:461-4. [PubMed 7550855]

15. Dekkers CP, Beker JA, Thjodleifsson B et al for the European Rabeprazole Study Group. Double-blind comparison (correction of double-blind, placebo-controlled comparison) of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of erosive or ulcerative gastro-oesophageal reflux disease. Aliment Pharmacol Ther . 1999; 13:49-57. [PubMed 9892879]

16. National Institutes of Health Consensus Development Group. Gastroesophageal reflux disease (hiatal hernia and heartburn). NIH Publication No. 94-882; 1994 Sep.

17. Dekkers CP, Beker JA, Thjodleifsson B et al. Comparison of rabeprazole 20 mg versus omperazole 20 mg in the treatment of active duodenal ulcer: a European multicentre study. Aliment Pharmacol Ther . 1999; 13:179-86. [PubMed 10102948]

18. Cloud ML, Enas N, Humphries TJ et al for the Rabeprazole Study Group. Rabeprazole in treatment of acid peptic diseases: results of three placebo-controlled dose-response clinical trials in duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease (GERD). Dig Dis Sci . 1998; 43:993-1000. [PubMed 9590413]

19. Yasuda S, Higashi S, Murakami M et al. Antacids have no influence on the pharmacokinetics of rabeprazole, a new proton pump inhibitor, in healthy volunteers. Int J Clin Pharmacol Ther . 1999; 37:249-53. [PubMed 10363624]

20. Yasuda S, Ohnishi A, Ogawa T et al. Pharmacokinetic properties of E3810, a new proton pump inhibitor, in healthy male volunteers. Int J Clin Pharmacol Ther . 1994; 32:466-73. [PubMed 7820329]

21. Hoyumpa AM, Trevino-Alanis H, Grimes I et al. Rabeprazole: pharmacokinetics in patients with stable, compensated cirrhosis. Clin Ther . 1999; 21:691-701. [PubMed 10363734]

22. Keane WF, Swan SK, Grimes I et al. Rabeprazole: pharmacokinetics and tolerability in patients with stable, end-stage renal failure. J Clin Pharmacol . 1999; 39:927-33. [PubMed 10471983]

23. Eisai Inc. Teaneck, NJ: Personal communication.

24. Shinomura Y, Kanayama S, Miyazaki Y et al. A clinical study of the effects of E3810 (rabeprazole sodium) for the treatment of gastric and duodenal ulcers: a comparison of post-breakfast and bedtime dosing regimens. Mod Physician . 1994; 14:69-84.

25. Eisai Ltd. and Janssen-Cilag Pharmaceutica Inc. Pariet^® (rabeprazole sodium) gastro-resistant tablets product monograph. London, 1998 Sep.

26. DeVault KR, Castell DO, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol . 1999; 94:1434-42. [PubMed 10364004]

27. Hanauer SB, Sandborn W, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults: Practice Guidelines. Am J Gastroenterol . 2001; 96:635-43. [PubMed 11280528]

28. Valori RM, Cockel R. Omeprazole for duodenal ulceration in Crohn's disease. Br Med J . 1990; 300:438-9.

29. Bianchi G, Ardizzone S, Petrillo M et al. Omeprazole for peptic ulcer in Crohn's disease. Am J Gastroenterol . 1991; 86: 245-6. [PubMed 1992643]

30. Przemioslo RT, Mee AS. Omeprazole in possible esophageal Crohn's disease. Dig Dis Sci . 1994; 39:1594-5. [PubMed 8026276]

31. Dickinson JB. Is omeprazole helpful in inflammatory bowel disease? J Clin Gastroenterol . 1994; 18:317-9.

32. Abrahao LJ Jr., Abrahao LJ, Vargas C et al. [Gastoduodenal Crohn's disease—report of 4 cases and review of the literature]. (Portuguese; with English abstract.) Arq Gastroenterol . 2001; 38:57-62.

33. Freston JW. Review article: role of proton pump inhibitors in non- H. pylori -related ulcers. Aliment Pharmacol Ther . 20001; 15(Suppl 2):2-5.

34. TAP. Prevacid^® (lansoprazole) delayed-release capsules, for delayed-release oral suspension and delayed-release orally disintegrating tablets prescribing information. Lake Forest, IL; 2004 Jul.

35. Laheij RJF, Sturkenboom MCJM, Hassing RJ et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA . 2004; 292:1955-60. [PubMed 15507580]

36. Gregor JC. Acid suppression and pneumonia.; a clinical indication for rational prescribing. JAMA . 2004; 292:2012-3. [PubMed 15507589]

37. AstraZeneca, Nexium® (esomeprazole magnesium) delayed-release capsules prescribing information. Wilmington, DE; 2001 Aug.

38. TAP. Prevacid^® (lansoprazole) delayed-release capsules, for delayed-release oral suspension and delayed-release orally disintegrating tablets prescribing information. Lake Forest, IL; 2003 Aug.

39. Yang Y-X, Lewis JD, Epstein S et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA . 2006; 296:2947-53. [PubMed 17190895]

41. Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (Mar 29, 2012). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website. [Web]

42. Bristol-Myers Squibb. Reyataz^® (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2012 Mar.

43. Gilard M, Arnaud B, Cornily JC et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin. JACC . 2008; 51:256-60, doi:10.1016/j.jacc.2007.06.064. Accessed 2008 Dec 8. Available from website. [Web][PubMed 18206732]

44. Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. JACC . 2008; 52:1038-9. Letter. [PubMed 18786491]

45. MEDCO. New study: A common class of GI medications reduce protection against heart attack in patients taking widely prescribed cardiovascular drug. Franklin Lakes, NJ; 2008 Nov 11. Press release from website. [Web]

46. Gilard M, Cornily JC, Boschat J. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. JACC . 2008; 52:1039. Reply.

47. . PPI interactions with clopidogrel revisited. Med Lett Drugs Ther . 2009; 51:13-4.

48. Juurlink DN, Gomes T, Ko DT et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ . 2009; 180:713-8. [PubMedCentral][PubMed 19176635]

49. Food and Drug Administration. Information on clopidogrel bisulfate (marketed as Plavix). Rockville, MD; 2010 Oct 27. From FDA website. [Web]

219. Gilard M, Arnaud B, Cornily JC et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin. JACC . 2008; 51:256-60, doi:10.1016/j.jacc.2007.06.064. Accessed 2008 Dec 8. Available from website. [Web][PubMed 18206732]

220. Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. JACC . 2008; 52:1038-9. Letter. [PubMed 18786491]

221. MEDCO. New study: A common class of GI medications reduce protection against heart attack in patients taking widely prescribed cardiovascular drug. Franklin Lakes, NJ; 2008 Nov 11. Press release from website. [Web]

223. . PPI interactions with clopidogrel revisited. Med Lett Drugs Ther . 2009; 51:13-4.

224. Sanofi-Aventis/Bristol-Myers Squibb. Plavix^®, (clopidogrel bisulfate) tablets prescribing information. New York, NY; 2011 Dec.

225. Food and Drug Administration. Early communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix). Rockville, MD; 2009 Jan 26. From FDA website. [Web]

226. Siller-Matula JM, Spiel AO, Lang IM et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J . 2009; 157:148.e1-5.

227. Gilard M, Arnaud B, Le Gal G et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost . 2006; 4:2508-9. [PubMed 16898956]

228. Anon. PPI interactions with clopidogrel. Med Lett Drugs Ther . 2009; 51:2-3.

229. Aubert RE, Epstein RS, Teagarden JR et al. Proton pump inhibitors effect on clopidogrel effectiveness: The clopidogrel Medco outcomes study. Circulation . 2008; 118:S_815, Abstract 3998.

230. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel. CMAJ . 2009; 180:699-700. [PubMedCentral][PubMed 19332744]

232. Food and Drug Administration. Information for heathcare professionals: Update to the labeling of clopidogrel bisulfate (marketed as Plavix) to alert heathcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). Rockville, MD; 2009 Nov 17. From FDA website. [Web]

233. Food and Drug Administration. Follow-up to the January 26, 2009 Early Communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed as Prilosec and Prilosec OTC). Rockville, MD; 2009 Nov 17. From FDA website. [Web]

234. Juurlink DN, Gomes T, Ko DT et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ . 2009; 180:713-8. [PubMedCentral][PubMed 19176635]

235. Ho PM, Maddox TM, Wang L et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA . 2009; 301:937-44. [PubMed 19258584]

236. Norgard NB, Mathews KD, Wall GC. Drug-drug interaction between clopidogrel and the proton pump inhibitors. Ann Pharmacother . 2009; 43:1266-74. [PubMed 19470853]

237. Last EJ, Sheehan AH. Review of recent evidence: potential interaction between clopidogrel and proton pump inhibitors. Am J Health Syst Pharm . 2009; 66:2117-22. [PubMed 19923312]

238. Stanek EJ, Aubert RE, Flockhart DA et al. A national study of the effect of individual proton pump inhibitors on cardiovascular outcomes in patients treated with clopidogrel following coronary stenting: the Clopidogrel Medco Outcomes Study. Available from website. Accessed 2009 Dec 15. [Web]

240. Stockl KM, Le L, Zakharyan A et al. Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med . 2010; 170:704-10. [PubMed 20421557]

243. Juurlink DN. Proton pump inhibitors and clopidogrel: putting the interaction in perspective. Circulation . 2009; 120:2310-2. [PubMed 19933929]

248. Khalique SC, Cheng-Lai A. Drug interaction between clopidogrel and proton pump inhibitors. Cardiol Rev . 2009 Jul-Aug; 17:198-200.

250. Rude MK, Chey WD. Proton-pump inhibitors, clopidogrel, and cardiovascular adverse events: fact, fiction, or something in between?. Gastroenterology . 2009; 137:1168-71. [PubMed 19635603]

300. Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int . 2006; 79:76-83. [PubMed 16927047]

301. Corley DA, Kubo A, Zhao W et al. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology . 2010; 139:93-101. [PubMedCentral][PubMed 20353792]

302. Yu EW, Blackwell T, Ensrud KE et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int . 2008; 83:251-9. [PubMedCentral][PubMed 18813868]

303. Gray SL, LaCroix AZ, Larson J et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. Arch Intern Med . 2010; 170:765-71. [PubMedCentral][PubMed 20458083]

304. Targownik LE, Lix LM, Metge CJ et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ . 2008; 179:319-26. [PubMedCentral][PubMed 18695179]

305. Food and Drug Administration. Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. May 25, 2010. From FDA web site. [Web]

307. Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology . 2010; :.

308. Targownik LE, Lix LM, Leung S et al. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology . 2010; 138:896-904. [PubMed 19931262]

310. Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy . 2008; 28:951-9. [PubMed 18657011]

311. Abraham NS, Hlatky MA, Antman EM et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use. A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. JACC. 2010; 56: Published online Nov 8, 2010.

317. Furlanetto TW, Faulhaber GA. Hypomagnesemia and Proton Pump Inhibitors: Below the Tip of the Iceberg. Arch Intern Med . 2011; :. [PubMed 21555654]

318. Fernández-Fernández FJ, Sesma P, Caínzos-Romero T et al. Intermittent use of pantoprazole and famotidine in severe hypomagnesaemia due to omeprazole. Neth J Med . 2010; 68:329-30. [PubMed 21071783]

319. Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM . 2010; 103:387-95. [PubMed 20378675]

320. Shabajee N, Lamb EJ, Sturgess I et al. Omeprazole and refractory hypomagnesaemia. BMJ . 2008; 337:a425. [PubMedCentral][PubMed 18617497]

321. . In brief: PPI's and hypomagnesemia. Med Lett Drugs Ther . 2011; 53:25.

322. Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol (Oxf) . 2008; 69:338-41. [PubMed 18221401]

323. Broeren MA, Geerdink EA, Vader HL et al. Hypomagnesemia induced by several proton-pump inhibitors. Ann Intern Med . 2009; 151:755-6. [PubMed 19920278]

324. Metz DC, Sostek MB, Ruszniewski P et al. Effects of esomeprazole on acid output in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion. Am J Gastroenterol . 2007; 102:2648-54. [PubMed 17764495]

325. Kuipers MT, Thang HD, Arntzenius AB. Hypomagnesaemia due to use of proton pump inhibitors--a review. Neth J Med . 2009; 67:169-72. [PubMed 19581665]

326. Epstein M, McGrath S, Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med . 2006; 355:1834-6. [PubMed 17065651]

327. US Food and Drug Administration. FDA drug safety communication: Low magnesium levels can be associated with long-term use of proton pump inhibitor drugs (PPIs). Rockville, MD; 2011 March 2. From FDA website. [Web]

328. US Food and Drug Administration. Proton pump inhibitor drugs (PPIs): Drug safety communication- Low magnesium levels can be associated with long-term use. Rockville, MD; 2011 March 2. From FDA website. [Web]

329. Hoorn EJ, van der Hoek J, de Man RA et al. A case series of proton pump inhibitor-induced hypomagnesemia. Am J Kidney Dis . 2010; 56:112-6. [PubMed 20189276]

330. Regolisti G, Cabassi A, Parenti E et al. Severe hypomagnesemia during long-term treatment with a proton pump inhibitor. Am J Kidney Dis . 2010; 56:168-74. [PubMed 20493607]

331. GlaxoSmithKline. Lanoxin^® (digoxin) tablets prescribing information. Research Triangle Park, NC; 2009 Aug.

333. Bezabeh S, Mackey AC, Kluetz P et al. Accumulating evidence for a drug-drug interaction between methotrexate and proton pump inhibitors. Oncologist . 2012; 17:550-4. [PubMedCentral][PubMed 22477728]

334. Horn JR, Hansten PD. Methotrexate and proton pump inhibitors. Pharm Times . 2012; 78(4). Published online 2012 Apr 9. [Web]

335. Food and Drug Administration. Drug safety communication: Clostridium difficile -associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). Rockville, MD; 2012 Feb 8. From FDA website. Accessed 2012 May 3l. [Web]

336. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol . 2010; 31:431-55. [PubMed 20307191]

337. Shah S, Lewis A, Leopold D et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM . 2000; 93:175-81. [PubMed 10751237]

338. Leonard AD, Ho KM, Flexman J. Proton pump inhibitors and diarrhoea related to Clostridium difficile infection in hospitalised patients: a case-control study. Intern Med J . 2012; 42:591-4. [PubMed 22616966]

339. Kwok CS, Arthur AK, Anibueze CI et al. Risk of Clostridium difficile Infection With Acid Suppressing Drugs and Antibiotics: Meta-Analysis. Am J Gastroenterol . 2012; 107:1011-9. [PubMed 22525304]

340. Dial S, Delaney JA, Barkun AN et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA . 2005; 294:2989-95. [PubMed 16414946]

341. Nerandzic MM, Pultz MJ, Donskey CJ. Examination of potential mechanisms to explain the association between proton pump inhibitors and Clostridium difficile infection. Antimicrob Agents Chemother . 2009; 53:4133-7. [PubMedCentral][PubMed 19667292]

343. Tibotec Therapeutics. Edurant^® (rilpivirine) tablets prescribing information. Raritan, NJ; 2011 May.

344. Abbott Laboratories. Kaletra^® (lopinavir/ritonavir) oral tablets and solution prescribing information. North Chicago, IL; 2012 May.

345. ViiV Healthcare. Lexiva^® (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2012 Apr.

346. Genentech USA. Invirase^® (saquinavir mesylate) capsules and tablets prescribing information. South San Francisco, CA; 2012 Feb.

348. Merck Sharp & Dohme. Isentress^® (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.

350. Frelinger AL, Lee RD, Mulford DJ et al. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol . 2012; 59:1304-11. [PubMed 22464259]

351. Angiolillo DJ, Gibson CM, Cheng S et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther . 2011; 89:65-74. [PubMed 20844485]