AHFS Class:

• Proton-pump Inhibitors 56:28.36

Generic Name(s):

• Lansoprazole

Lansoprazole,1,2,4,9,20,21,23,25 commonly referred to as an acid- or proton-pump inhibitor, is a gastric antisecretory agent.1,3,4,5,6,8,9,10,12,13,15,17,19,21,22,23,24,36,103,104,125

Lansoprazole is used orally for the short-term treatment and symptomatic relief of active duodenal1,2,3,4,5,6,7,12,13,14 and benign gastric ulcer and as maintenance therapy following healing of duodenal ulcers.1 Lansoprazole also is used orally in combination with amoxicillin (dual therapy) or with clarithromycin and amoxicillin (triple therapy) for the treatment of Helicobacter pylori infection and duodenal ulcer disease.1,134,135 Lansoprazole also has been used in other multiple-drug regimens† for the treatment of H. pylori infection associated with peptic ulcer disease.126,129,131,135 Lansoprazole also is used orally for the treatment of nonsteroidal anti-inflammatory agent (NSAIA)-induced gastric ulcers in patients who continue NSAIA use,1 and for the prevention of NSAIA-induced gastric ulcers in patients with a documented history of gastric ulcer who require the use of an NSAIA.1 Oral lansoprazole also is used for short-term treatment and symptomatic relief of gastroesophageal reflux disease (e.g., erosive esophagitis),1,2,3,5,18,19,20,22,23 as maintenance therapy following healing of erosive esophagitis to reduce its recurrence1 and in the long-term treatment of pathologic GI hypersecretory conditions.1,2,3,5,7,24,25,26,27,28 Lansoprazole is used orally as self-medication for short-term treatment of frequent heartburn.191,192,194

Gastroesophageal Reflux

Acute Therapy

Lansoprazole is used orally to provide short-term (up to 8 weeks) treatment and symptomatic relief of all grades of erosive esophagitis in patients with gastroesophageal reflux disease (GERD).1,2,3,5,18,19,20,22,23 Oral lansoprazole also is used for the short-term (up to 8 weeks) treatment of symptomatic GERD (e.g., heartburn).1 Potential benefits of lansoprazole in gastroesophageal reflux and esophagitis 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.1,2,3,18,19,20,22,23

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.156 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.156 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.156

In a controlled study in patients with manifestations of GERD (e.g., heartburn) and the absence of erosive esophageal lesions, symptomatic improvement (reduction in frequency and severity of heartburn) with lansoprazole was greater than that with placebo.1 In this study in patients with endoscopically confirmed GERD, the median percentage of days without heartburn was 84, 82, or 13% at week 8 of therapy with lansoprazole 15 mg daily, lansoprazole 30 mg daily, or placebo, respectively; the median percentage of nights without heartburn in these respective treatment groups was 92, 80, or 36% at week 8.1 Administration of 30 mg of lansoprazole daily did not provide improved relief compared with 15 mg daily in this study.1

In controlled studies in patients with endoscopically evaluated GERD, reported rates of healing with lansoprazole were higher than those with placebo or an H₂-receptor antagonist 1,2,3,18,20,22,23 and at least as high as those with omeprazole.3,5,21,22 Generally, antacids were used concomitantly for pain relief.18,19,20,21,22 In a controlled study in patients with esophagitis, reported rates of healing were 91, 95, 94, or 53% at 8 weeks in patients receiving lansoprazole 15 mg daily, 30 mg daily, 60 mg daily, or placebo, respectively.2,8,22 Healing rates from controlled studies were 80-84 or 39-52% at 4 weeks and 91-92 or 53-70% at 8 weeks for lansoprazole 30 mg daily or ranitidine 150 mg twice daily, respectively.1,3,4,18 Patients receiving lansoprazole reported faster relief of daytime and nocturnal heartburn and self-administered less antacid than those receiving placebo or an H₂-receptor antagonist; however, since the recommended dosage of ranitidine for esophagitis is 150 mg four times daily and patients treated with ranitidine received only 150 mg twice daily, further study is needed to evaluate relative efficacy. 1,18,20,23 Lansoprazole also has been shown to be effective in promoting healing and providing symptomatic relief in a substantial proportion of patients failing to respond to usual or relatively high dosages of H₂-receptor antagonists.1,3,5,19

Although lansoprazole has been used IV for short-term (up to 7 days) treatment of erosive esophagitis in patients who are unable to take the drug orally, a parenteral dosage form no longer is commercially available in the US.170,195 In one controlled study in patients with erosive esophagitis receiving oral lansoprazole, the degree of inhibition of gastric acid secretion following IV administration of lansoprazole 30 mg daily for 7 days was similar to that achieved following repeated oral administration of the drug.170

Short-term lansoprazole therapy for the treatment of erosive esophagitis will not prevent recurrence of the disease following discontinuance of the drug.22,23 Most patients with erosive esophagitis respond to lansoprazole during an initial 8-week course of therapy;3,18,19,20,21,22,23 however, an additional 8 weeks of therapy may contribute to healing and symptomatic improvement in some patients (i.e., patients experiencing a recurrence of erosive esophagitis or patients who fail to heal after the initial course of therapy).1,3 If symptomatic GERD or severe esophagitis recur, the manufacturer states that additional 8-week courses of lansoprazole may be given.1 However, the ACG states that chronic, even lifelong, therapy with a proton-pump inhibitor is appropriate in many patients with GERD.156

Maintenance Therapy

Lansoprazole is used as maintenance therapy following healing of erosive esophagitis to reduce recurrence of the disease.1,126 In a multicenter, double-blind study, endoscopically documented remission of esophagitis was maintained at 6 months in 81, 93, or 27% of patients receiving lansoprazole 15 mg daily, 30 mg daily, or placebo, respectively, and such remission was maintained at 12 months in 79, 90, or 24% of patients, respectively.1 In another multicenter, double-blind study in patients with endoscopically confirmed healed esophagitis, remission of esophagitis was maintained at 6 months in 72, 72, or 13% of patients receiving lansoprazole 15 mg daily, 30 mg daily, or placebo, respectively, and at 12 months in 67, 55, or 13% of patients, respectively.1 Remission rates of esophagitis were independent of the patient's initial grade of erosive esophagitis and the daily dosage of lansoprazole (15 or 30 mg).1,126

Because GERD is a chronic condition, the ACG states that continuous therapy to control symptoms and prevent complications is appropriate, and chronic, even lifelong, use of a proton-pump inhibitor is effective and appropriate as maintenance therapy in many patients with GERD.156 The frequent marked improvement in symptoms associated with full dosage of a proton-pump inhibitor generally is followed by rapid recurrence of symptoms once the drug is discontinued,156,159 and reduced-dosage regimens (e.g., every other day, “weekend” dosage) have not been shown to be consistently effective for maintenance therapy.156,157,158

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

Self-medication

Lansoprazole is used orally in adults 18 years of age or older as self-medication for short-term (14 days) treatment of frequent (2 or more days per week) heartburn.191,192,194 Because 1-4 days may be required for complete relief of symptoms, lansoprazole for self-medication is not intended for the immediate relief of heartburn.191 However, some individuals may experience complete relief of symptoms within 24 hours of taking the first dose of lansoprazole.191 In 2 controlled studies in adults with frequent (2 or more days per week) heartburn, the percentage of days (24-hour periods) without heartburn during 14 days of treatment was greater with lansoprazole 15 mg daily than with placebo (59.9-64.7 versus 45-45.7%).192 The percentage of heartburn-free nights during the 14-day treatment period was 79.5-81.6% with lansoprazole therapy compared with 76.3-77% with placebo.192 On day 1 of treatment, 50.4-50.7% of lansoprazole-treated patients experienced no heartburn compared with 33-37.9% of those receiving placebo.192 In a controlled study in adults with frequent nocturnal heartburn, the percentage of heartburn-free nights during 14 days of treatment was greater with lansoprazole 15 or 30 mg (61.3-61.7%) compared with placebo (47.8%).194 The percentage of days (24-hour periods) without heartburn and the percentage of patients without heartburn on day 1 of treatment also were greater with lansoprazole therapy than with placebo.194

Gastric Ulcer

Acute Therapy

Lansoprazole is used for the short-term treatment and symptomatic relief of active benign gastric ulcer.1 Antacids may be used concomitantly as needed for pain relief.1 In controlled studies in patients with endoscopically confirmed gastric ulcers, reported rates of ulcer healing for lansoprazole were substantially higher than those for placebo.1 In a multicenter, double-blind study in patients with endoscopically confirmed gastric ulcer, reported rates of ulcer healing in patients receiving lansoprazole 15 or 30 mg each morning or placebo were 65, 58, or 38%, respectively, at 4 weeks and 92, 97, or 77%, respectively, at 8 weeks.1 Lansoprazole also produced greater reductions in daytime and nocturnal pain and antacid consumption than did placebo.1

Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of gastric ulcers,44,45,46,48,51,61,62,63,64,65,66,81,83,88,109,111,112,113,114 and the ACG, NIH, and most clinicians currently recommend that all patients with initial or recurrent gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.97,109,112,113,114 The choice of a particular regimen should be based on current data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.97,109,110,111,113,124 (See Duodenal Ulcer: Acute Therapy, in Uses.) 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.

NSAIA-induced Ulcers

Treatment

Lansoprazole is used for the treatment of NSAIA-induced gastric ulcers in patients who continue NSAIA use.1 In 2 controlled studies in patients with endoscopically confirmed NSAIA-associated gastric ulcer who continued their NSAIA use, substantially more patients receiving lansoprazole 30 mg daily experienced ulcer healing at 8 weeks compared with those receiving an active control drug.1 In one study, healing of gastric ulcers occurred in 60 and 79% of patients receiving lansoprazole, compared with 28 and 55% of those receiving an active control drug at 4 and 8 weeks, respectively.1 In the second study, ulcer healing occurred in 77% of patients receiving lansoprazole or in 50% of those receiving an active control drug at 4 and 8 weeks.1 However, there was no substantial difference in the number of patients experiencing symptomatic (e.g., abdominal pain) relief between those receiving lansoprazole and those receiving the active control.1

For treatment of NSAIA-induced ulcers, it is preferable to discontinue NSAIA therapy and initiate therapy with a drug (e.g., proton-pump inhibitor, histamine H₂-receptor antagonist) indicated for the treatment of ulcers.151,153 When NSAIA therapy must be continued, a proton-pump inhibitor is considered the drug of choice for treatment of ulcers since the efficacy of H₂-receptor antagonists is substantially decreased by continued use of NSAIAs.151,153 Treatment of H. pylori infection is recommended in patients receiving NSAIAs who have ulcers and are infected with this organism.151,153 For further information on 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.

Prevention

Lansoprazole is used for the prevention of NSAIA-induced gastric ulcers in patients with a documented history of gastric ulcer who require the use of an NSAIA.1 In a controlled study in patients with a history of gastric ulcer who required NSAIA therapy, lansoprazole 15 or 30 mg daily was more effective than placebo but less effective than misoprostol 200 mcg 4 times daily in preventing gastric ulcer recurrence at 4, 8, and 12 weeks of therapy.1,169,171 About one-half of the patients also had a history of duodenal ulcer.171 About 51, 93, 80, or 82% of those receiving placebo, misoprostol, or lansoprazole 15 or 30 mg, respectively, remained free of gastric ulcers at 12 weeks.1,169,171 In a subsequent subset analysis of patients receiving only naproxen or naproxen and aspirin (up to 325 mg daily), lansoprazole 15 or 30 mg daily was more effective than placebo and as effective as misoprostol in preventing gastric ulcer recurrence at 4, 8, and 12 weeks of therapy; about 33, 83, 89, or 83% of those receiving placebo, misoprostol, or lansoprazole 15 or 30 mg, respectively, remained free of gastric ulcers at 12 weeks.171 Serious NSAIA-related GI complications (e.g., bleeding, perforation, obstruction) were not reported during the study; however, the study was not designed to assess the effect of lansoprazole on the risk of such complications or on the risk of duodenal ulcers.171

Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving chronic NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.137,138,139,140,142,143,144,145,146,147,148,154,171 Results of studies to date are inconclusive concerning the relative risk of various NSAIAs in causing serious GI effects.137,138,139,142,143 In patients receiving prototypical NSAIAs and observed in clinical studies of several months' to 2-years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.137,142,143,171 These trends continue with long-term therapy and increase the likelihood of a serious GI event occurring at some time during the course of therapy.149,171 Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than tenfold higher risk for developing GI bleeding than patients without these risk factors.149,171 In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, high NSAIA dosage, smoking, alcoholism, older age, and poor general health status.149,150,151,153,154,171 In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal NSAIA-induced GI effects have been in such patients.136,137,140,141,142,143,171

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy.146,151,152,155 (See Misoprostol 56:28.28.) Alternatively, use of a proton-pump inhibitor (e.g., lansoprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy.1,146,151,152,153,155 Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of cyclooxygenase-2 (COX-2), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs.152 However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori -negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk.160,161 Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.160,161

Duodenal Ulcer

Acute Therapy

Lansoprazole is used for the short-term treatment of endoscopically or radiographically confirmed active duodenal ulcer.1,2,3,4,5,6,7,12,13,14 Antacids may be used concomitantly as needed for pain relief.1,12,13,14 In controlled studies in patients with endoscopically confirmed duodenal ulcers, reported rates of ulcer healing for lansoprazole were substantially higher than those for placebo.1,2,3,4,6,8,12 In a multicenter, double-blind study in patients with endoscopically confirmed duodenal ulcer, reported rates of ulcer healing for an oral lansoprazole dosage of 15 mg daily or placebo were 42 or 11%, respectively, at 2 weeks and 89 or 46%, respectively, at 4 weeks.1 A similar response was observed in patients receiving 30 or 60 mg of lansoprazole daily.1 Lansoprazole also produced greater reductions in daytime and nocturnal abdominal pain and antacid consumption than did placebo.1,2,3,12 Clinically important differences in the rates of ulcer healing between men and women receiving lansoprazole therapy do not appear to exist.1

Lansoprazole appears to be at least as effective as H₂-receptor antagonists or other proton-pump inhibitors (e.g., omeprazole) for short-term treatment of active duodenal ulcer.1,2,3,4,6,8,12,13 In a multicenter, controlled study in patients with endoscopically confirmed duodenal ulcers, 35 or 31% of ulcers were healed following 2 weeks of oral therapy with lansoprazole 20 mg daily or ranitidine 300 mg twice daily, respectively, and 92 or 71%, respectively, were healed after 4 weeks of therapy.1,12 A lansoprazole dosage of 30 mg daily was similarly effective.1,3,4,12 In another multicenter, controlled study in patients with endoscopically confirmed duodenal ulcers, 88 or 82% of ulcers were healed following 2 weeks of oral therapy with lansoprazole 30 mg daily or omeprazole 20 mg daily, respectively, and 98 or 97%, respectively, were healed after 4 weeks of therapy.14

Most patients with duodenal ulcer respond to lansoprazole therapy during the usual 4-week course of therapy.1,2,3,4,5,12,13,14 However, short-term lansoprazole therapy for the treatment of active duodenal disease will not prevent recurrence of the disease following acute healing and discontinuance of the drug.2,3

Lansoprazole is used in combination with amoxicillin and clarithromycin for the treatment of H. pylori infection and duodenal ulcer disease.1,134 Lansoprazole also is used in combination with amoxicillin for the treatment of H. pylori infection and duodenal ulcer disease in patients who are either allergic to or intolerant of clarithromycin or in whom clarithromycin resistance is known or suspected.1 Lansoprazole also has been used in other multiple-drug regimens† for the treatment of H. pylori infection and peptic ulcer disease.126,129,131,135 Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers;44,45,46,48,51,61,62,63,64,65,66,81,83,88,109,111,112,113,114 long-term H. pylori infection also has been implicated as a risk factor for gastric cancer.45,64,67,68,69,70,71,72,73,74,75,83,109,111 For additional information on the association of this infection with these and other GI conditions, see Helicobacter pylori Infection, under Uses, in Clarithromycin 8:12.12.92. Conventional antiulcer therapy with H₂-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori , and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year).44,51,66,109,111,112,113 The American College of Gastroenterology (ACG), the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.97,109,112,113,114,135 Although 3-drug regimens consisting of a bismuth salt (e.g., bismuth subsalicylate) and 2 anti-infective agents (e.g., tetracycline or amoxicillin plus metronidazole) administered for 10-14 days have been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori -associated peptic ulcer disease,44,45,46,48,49,50,60,76,77,78,80,81,83,88,89,92,109,112,113,114,115,124,135 current evidence principally from studies in Europe suggests that 1 week of such therapy provides comparable H. pylori eradication rates.109,113,114 Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, lansoprazole, H₂-receptor antagonist) also have been used successfully for H. pylori eradication,1,44,45,46,54,55,56,57,58,78,79,83,84,92,93,94,95,96,98,99,107,109,111,112,113,114,116,126,129,131,132,135 and the choice of a particular regimen should be based on current data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.97,109,110,111,113,124

Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., lansoprazole, omeprazole) in anti- H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance.1,109,113,135 Therefore, the ACG and many clinicians109,113,116,135 currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection.109,113,116,135

Therapy with an antisecretory drug and a single anti-infective agent (i.e., “dual therapy”) also has been used successfully for treatment of H. pylori infection.1,54,55,56,57,58,79,80,84,107,108,111,113,122,126,135 However, while some studies demonstrate that certain 2-drug anti- H. pylori regimens (e.g., clarithromycin-omeprazole, ranitidine bismuth citrate-omeprazole, amoxicillin-omeprazole) can successfully eradicate H. pylori infection and prevent recurrence of duodenal ulcer at least in the short term (e.g., at 6 months following completion of anti- H. pylori therapy),106,107,108,113,114,115,135 the ACG and some clinicians currently state that anti- H. pylori regimens consisting of at least 3 drugs (e.g., 2 anti-infective agents plus a proton-pump inhibitor) are recommended because of enhanced H. pylori eradication rates, decreased failures due to resistance, and shorter treatment periods compared with those apparently required with 2-drug regimens.44,49,106,109,111,115,126,134,135 Additional randomized, controlled studies comparing various anti- H. pylori regimens are needed to clarify optimum drug combinations, dosages, and durations of treatment for H. pylori infection.109,110,116,124,126,135 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.

Maintenance Therapy

Lansoprazole is used as maintenance therapy following healing of duodenal ulcers to reduce ulcer recurrence.1 In 2 controlled studies of patients with endoscopically documented healed duodenal ulcers, those receiving lansoprazole 15 or 30 mg daily remained healed substantially longer, and experienced substantially fewer recurrences than those receiving placebo over a 12 month period.1 In one study, 90, 87, and 84% of patients receiving lansoprazole 15 mg daily, and 49, 41, and 39% of patients receiving placebo, remained in endoscopically documented remission over 3, 6, and 12 months, respectively.1 In another study, 94, 94, and 85% of patients receiving lansoprazole 30 mg daily and 87, 79, and 70% of those receiving lansoprazole 15 mg daily were still in endoscopically documented remission at 3, 6, and 12 months, respectively.1 In comparison, only 33% of those receiving placebo remained in endoscopically documented remission over 3 months, and none were in remission at 6 or 12 months.1 There was no substantial difference between lansoprazole 15 or 30 mg daily in maintaining remission.1

Pathologic GI Hypersecretory Conditions

Lansoprazole is used for the long-term treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas, systemic mastocytosis).1,2,3,5,7,24,25,26,27,28 The drug reduces gastric acid secretion and associated symptoms (including diarrhea, anorexia, and pain) in patients with these conditions.1,4,24,25,26,27,28 In dosages ranging from 15 mg every other day to 180 mg daily, lansoprazole can maintain basal acid secretion below 5 or 10 mEq/hour in patients who have or have not undergone gastric surgery, respectively.1,3,4,10,24,25,26,27 Lansoprazole therapy has been continued in some patients for longer than 4 years.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.162,163,164,166,167 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).163,164 (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

Lansoprazole is administered orally.1,134 Lansoprazole also has been administered by IV infusion; however, a parenteral dosage form no longer is commercially available in the US.170,195

If a dose of lansoprazole is missed, the dose should be taken as soon as possible.1 However, if the next scheduled dose is due, the missed dose should be omitted, and the next dose taken at the regularly scheduled time.1 A double dose should not be administered to make up for a missed dose.1

Oral Administration

Lansoprazole is administered orally as capsules or orally disintegrating tablets.1,134,191 To avoid decomposition of lansoprazole in the acidic pH of the stomach, the commercially available delayed-release capsules contain enteric-coated granules of the drug, and the orally disintegrating tablets contain enteric-coated microgranules of the drug.1,193 The contents of the capsules should not be chewed or crushed, nor should the orally disintegrating tablets be broken, cut, or chewed.1,191

Lansoprazole usually is administered once daily,1,15,191 generally in the morning;2,3,4,5,12,13,14,18,19,20,21,191 however, the manufacturer states that administration of the drug in 2 equally divided doses in the morning and evening may improve efficacy in patients receiving more than 120 mg daily.1,43 When lansoprazole is used in combination with amoxicillin1 or with clarithromycin and amoxicillin1,134 for the treatment of Helicobacter pylori infection associated with duodenal ulcer, lansoprazole is given in 2 or 3 divided doses daily.1,134

Following administration of lansoprazole with meals, the rate and extent of GI absorption are reduced.1,3,4,5 Therefore, lansoprazole should be taken before meals.1,3,43,191 Since an acidic environment in the parietal cell canaliculi is required for conversion of proton-pump inhibitors (e.g., lansoprazole) to their active sulfenamide metabolites, the American College of Gastroenterology suggests that proton-pump inhibitors are most effective when given about 30 minutes prior to meals and that effectiveness may be compromised if these drugs are administered during the basal state (e.g., to fasting patients at bedtime) or concomitantly with other antisecretory agents (e.g., anticholinergics, histamine H₂-receptor antagonists, somatostatin analogs, misoprostol).8,109 Lansoprazole may be administered concomitantly with antacids1,2,3,4,134 but should be administered at least 30 minutes before sucralfate (see Drug Interactions).1,134

Extemporaneously Compounded Oral Suspension

An extemporaneously compounded 3 mg/mL oral suspension of lansoprazole has been prepared using the commercially available capsules and an 8.4% sodium bicarbonate vehicle.255,256 An extemporaneous suspension also has been prepared by pulverizing one 30-mg enteric-coated microgranule tablet in 10 mL of Ora-Blend to provide a suspension containing 3 mg/mL.257

Standardize 4 Safety

Standardized concentrations for an extemporaneously prepared oral suspension of lansoprazole have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Multidisciplinary expert panels were convened to determine recommended standard concentrations. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web]252 .

Oral Capsules

Lansoprazole capsules may be swallowed whole.1 Alternatively, the contents of a capsule may be sprinkled on a tablespoonful of a suitable soft food and swallowed without chewing; mixed with apple, orange, or tomato juice and consumed; or mixed with apple juice and given via a nasogastric tube.1

In patients who have difficulty swallowing capsules, the contents of a capsule may be sprinkled on a tablespoonful of applesauce, liquid dietary supplement (e.g., Ensure^®) pudding, cottage cheese, yogurt, or strained pears and ingested immediately without a clinically important effect on the drug's bioavailability.1,40,43 The granules should not be chewed or crushed.1 The manufacturer states that administration of lansoprazole mixed in other foods has not been evaluated clinically and is not recommended.1

Alternatively, the contents of a capsule may be emptied into a small volume (i.e., 60 mL, about 2 ounces) of apple, orange, or tomato juice, mixed briefly, and swallowed immediately.1 To ensure complete consumption of the dose, the glass should be rinsed with 120 mL or more of juice, and the contents swallowed immediately.1 The manufacturer states that administration of lansoprazole mixed in other beverages has not been evaluated clinically and is not recommended.1

For patients with a nasogastric tube, the contents of a capsule can be mixed with 40 mL of apple juice in a syringe and administered immediately (i.e., within 3-5 minutes) without any clinically important effect on the drug's bioavailability;1,127 the manufacturer states that other liquids should not be used.1 To facilitate delivery of the entire dose and to maintain patency of the nasogastric tube, the syringe and tube should be flushed with additional apple juice.1,127

The manufacturer states that lansoprazole capsules for self-medication should be swallowed whole with a glass of water; the capsules should not be crushed or chewed.191

Orally Disintegrating Tablets

Lansoprazole orally disintegrating tablets containing enteric-coated microgranules of the drug may be allowed to disintegrate on the tongue and then swallowed without chewing; alternatively, a tablet may be dispersed in a compatible liquid and administered orally using an oral syringe or given via a nasogastric tube.1 The orally disintegrating tablets should not be broken or cut.1

For oral administration, the orally disintegrating tablet should be placed on the tongue and allowed to disintegrate (usually in less than 1 minute) with or without water, and the particles swallowed without chewing.1

For administration using an oral syringe, a 15- or 30-mg orally disintegrating tablet should be placed in an oral syringe, about 4 or 10 mL, respectively, of water should be drawn into the syringe, and the syringe should be shaken gently to ensure rapid dispersal of the particles.1 The contents of the syringe should be administered within 15 minutes of preparation.1 An additional 2 mL (for a 15-mg dose) or 5 mL (for a 30-mg dose) of water should be drawn into the syringe, mixed gently, and the entire contents ingested to ensure complete consumption of the dose.1

For administration via a nasogastric tube, a 15- or 30-mg orally disintegrating tablet should be placed in a syringe, about 4 or 10 mL, respectively, of water should be drawn into the syringe, and the syringe should be shaken gently to ensure rapid dispersal of the particles.1 The contents of the syringe should be administered through a nasogastric tube (8 French or larger) within 15 minutes of preparation.1 An additional 5 mL of water should be drawn into the syringe, mixed gently, and used to flush the nasogastric tube.1

Dosage

Adult Dosage

Gastroesophageal Reflux

For the short-term treatment of symptomatic gastroesophageal reflux disease (GERD), the usual adult dosage of lansoprazole is 15 mg once daily for up to 8 weeks.1

For the short-term symptomatic treatment of all grades of erosive esophagitis, the usual adult dosage of lansoprazole is 30 mg once daily.1,2,3,5,22 Therapy is continued until healing occurs, usually within 8 weeks; an additional 8 weeks of therapy (up to 16 weeks for a single course) may contribute to healing and symptomatic improvement in some patients.1 If the erosive esophagitis recurs, the manufacturer states that an additional 8-week course of lansoprazole may be given.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.156

For maintenance therapy following healing of erosive esophagitis to reduce recurrence, the usual adult dosage of lansoprazole is 15 mg daily.1 Safety and efficacy of lansoprazole maintenance therapy for longer than 1 year have not been established.1

For self-medication to relieve symptoms of frequent heartburn in adults 18 years of age or older, a lansoprazole dosage of 15 mg once daily in the morning for 14 days is recommended.191 For self-medication , the manufacturer recommends that the dosage of lansoprazole not exceed 15 mg in 24 hours.191 In addition, the drug should not be used for self-medication for longer than 14 days of continuous use and individuals should not exceed one course of therapy every 4 months unless otherwise directed by a clinician.191

Gastric Ulcer

For the short-term treatment of active benign gastric ulcer, the usual adult dosage of lansoprazole is 30 mg daily for up to 8 weeks.1,2

Nonsteroidal Anti-inflammatory Agent (NSAIA)-induced Ulcers

For the treatment of nonsteroidal anti-inflammatory agent (NSAIA)-associated gastric ulcers in patients continuing NSAIA use, the usual adult dosage of lansoprazole is 30 mg once daily for 8 weeks.1

For prevention of NSAIA-associated gastric ulcers in patients with a documented history of gastric ulcer who require the use of an NSAIA, the usual adult dosage of lansoprazole is 15 mg once daily for up to 12 weeks.1 Efficacy of lansoprazole for periods exceeding 12 weeks in preventing of NSAIA-induced gastric ulcers has not been studied.1,171

Duodenal Ulcer

For the short-term treatment of active duodenal ulcer, the usual adult dosage of lansoprazole is 15 mg once daily.1,2,3,4,5,6,12,13,14 Although an oral dosage of 30 mg daily often was administered in clinical studies,1,2,3,5 the manufacturer states that dosages of 30 or even 60 mg daily were no more effective at healing active duodenal ulcers than 15 mg daily.1 Therapy should be continued up to 4 weeks or until healing occurs.1

When lansoprazole is used in combination with amoxicillin and clarithromycin (triple therapy) for the treatment of H. pylori infection in patients with active duodenal ulcer, the usual adult dosage is 30 mg every 12 hours (morning and evening) for 10 or 14 days.1,134 When lansoprazole is used in combination with amoxicillin (dual therapy) for the treatment of H. pylori infection in patients with active duodenal ulcer, the usual adult dosage is 30 mg every 8 hours for 14 days.1

For maintenance therapy following healing of duodenal ulcer to reduce recurrence, the usual adult dosage of lansoprazole is 15 mg daily.1 Safety and efficacy of lansoprazole maintenance therapy for longer than 1 year have not been established.1

Pathologic GI Hypersecretory Conditions

For the long-term treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas, systemic mastocytosis), dosages of lansoprazole should be individualized according to patient response and tolerance.1,2,3,5 The usual initial adult dosage is 60 mg once daily.1,2,24,25,28 Subsequent lansoprazole dosage should be adjusted as tolerated and necessary to adequately suppress gastric acid secretion, and therapy continued as long as clinically necessary.1

Oral dosages ranging from 15 mg every other day to 180 mg daily have been necessary to maintain basal gastric acid secretion at less than 10 mEq/hour in patients without a history of gastric surgery and less than 5 mEq/hour in those who have undergone gastric surgery;1,3,4,10,24,25,26,27,43 generally, determination of gastric acid secretion during the hour prior to a dose is useful in establishing optimum dosage.2,25,27 The manufacturer recommends that daily dosages exceeding 120 mg be administered in 2 equally divided doses in the morning and evening.1,7,43 Lansoprazole has been given continuously for longer than 4 years in some patients with Zollinger-Ellison syndrome.1,2

Pediatric Dosage

Gastroesophageal Reflux

For the short-term treatment of symptomatic GERD or erosive esophagitis in children 1-11 years of age, the usual oral dosage of lansoprazole for children weighing 30 kg or less is 15 mg once daily for up to 12 weeks; dosage for children weighing more than 30 kg is 30 mg once daily for up to 12 weeks.1 Dosage in children 1-11 years of age has been increased to up to 30 mg twice daily in patients remaining symptomatic after 2 or more weeks of treatment.1

For children 12-17 years of age, the usual oral dosage of lansoprazole for treatment of nonerosive GERD is 15 mg daily for up to 8 weeks, and that for erosive esophagitis is 30 mg daily for up to 8 weeks.1

Special Populations

The manufacturer states that lansoprazole dosage adjustment is not necessary in geriatric patients.1,33,34 Although pharmacokinetics of lansoprazole may be altered slightly in patients with renal impairment, dosage adjustment is not necessary.1,24,36 However, the commercially available daily administration pack containing lansoprazole, amoxicillin, and clarithromycin (Prevpac^®)is not recommended for use in patients with creatinine clearance values less than 30 mL/minute.134 In patients with severe hepatic impairment, lansoprazole dosage reduction should be considered.1,22,24,36,134 (See Specific Populations under Cautions: Warnings/Precautions.)

Contraindications

Known severe hypersensitivity to lansoprazole or any ingredient in the formulation.1,191,254

Warnings/Precautions

Gastric Malignancy

Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy.1,134

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).176,177 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.1,178,300,301,302,303,304,305 The magnitude of risk is unclear;178,300,301,302,303,304,305,310 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.1,178,301,303,305,307 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.1,178,303,305,307

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 lansoprazole.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.)

Phenylketonuria

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that each 15- or 30-mg Prevacid^® SoluTab^® orally disintegrating tablet contains aspartame (NutraSweet^®), which is metabolized in the GI tract to provide about 2.5 or 5.1 mg, respectively, of phenylalanine following oral administration.1,172,173,174,175

Specific Populations

Pregnancy

Category B.1 (See Users Guide.)

Lactation

Lansoprazole or its metabolites are distributed into milk in rats; it is not known whether lansoprazole is distributed into human milk.1,134 The manufacturer states that a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,134

Pediatric Use

Safety and efficacy of oral lansoprazole in pediatric patients 1-17 years of age have been established for short-term treatment of symptomatic gastroesophageal reflux disease (GERD) and erosive esophagitis.1 In an open-label study in children 1-11 years of age, symptomatic improvement occurred following 8-12 weeks of lansoprazole therapy in 76% of children with symptomatic GERD; in a limited subset of children with endoscopically documented erosive esophagitis, rates of symptomatic improvement and healing were 81 and 100%, respectively.1 Lansoprazole was initiated at a dosage of 15 mg daily in children weighing 30 kg or less and a dosage of 30 mg daily in those weighing more than 30 kg; dosage could be increased up to 30 mg twice daily in children who continued to experience symptoms 2 or more weeks after initiating therapy with the drug.1 In an open-label study in adolescents 12-17 years of age with GERD, symptomatic improvement occurred following 8 weeks of therapy with lansoprazole 15 mg daily in 71% of those with nonerosive disease; in a smaller group of adolescents with erosive esophagitis, rates of symptomatic improvement and healing were 78 and 96%, respectively, following 8-12 weeks of therapy with lansoprazole 30 mg daily.1 The most commonly reported adverse effects in pediatric patients receiving lansoprazole include headache, abdominal pain, constipation, nausea, and dizziness.1

Efficacy of oral lansoprazole has not been established in infants younger than 1 year of age.1 In a controlled study in infants 1 month to younger than 1 year of age with symptomatic GERD, lansoprazole was no more effective than placebo in reducing feeding-associated episodes of crying, fussing, or irritability; in both the placebo and lansoprazole groups, the response rate was 54%.1

Safety and efficacy of lansoprazole for self-medication of frequent heartburn have not been established in children younger than 18 years of age.191,193

Geriatric Use

The frequency of adverse effects in geriatric patients appears to be similar to that in younger patients.1 Clearance of lansoprazole may be decreased in geriatric patients, but accumulation of the drug does not occur with once-daily dosing and dosage adjustment is not necessary.1,134

Hepatic Impairment

Systemic exposure to lansoprazole, as measured by area under the serum concentration-time curve (AUC), may be increased by up to 500% in patients with chronic hepatic impairment.1,134 Dosage reduction should be considered in patients with severe hepatic impairment.1,22,24,36,134

Renal Impairment

Although the pharmacokinetics of lansoprazole may be altered slightly in patients with renal impairment, dosage adjustment is not necessary.1,24,36

Common Adverse Effects

Adverse effects occurring in 1% or more of patients receiving oral lansoprazole and more frequently than with placebo include abdominal pain,1,134 diarrhea,1,134 nausea,1,134 and constipation.1,134

Drugs Metabolized by Hepatic Microsomal Enzymes

Lansoprazole is metabolized by cytochrome P-450 (CYP) isoenzymes 2C19 and 3A.1,134 In studies in healthy individuals, clinically important interactions were not observed between lansoprazole and other drugs (e.g., antipyrine, clarithromycin, diazepam, ibuprofen, indomethacin, phenytoin, prednisone, propranolol, warfarin) metabolized by CYP isoenzymes, including the 1A2, 2C9, 2C19, 2D6, and 3A isoenzymes.1,134

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

Pharmacokinetic interaction is theoretically possible when lansoprazole is used concomitantly with gastric pH-dependent drugs (e.g., ampicillin esters, digoxin, iron salts, ketoconazole); altered drug absorption at increased gastric pH values.1,134

Amoxicillin

Clinically important interaction is unlikely.1,134

Antacids

Efficacy of lansoprazole is not altered by concomitant administration of antacids.1,134

Antiretroviral Agents

Atazanavir

Potential pharmacokinetic interaction with atazanavir (possible altered oral absorption of atazanavir at increased gastric pH, resulting in decreased plasma atazanavir concentrations).1,134 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.180 The manufacturer of lansoprazole states that concomitant administration with atazanavir is not recommended.1,134 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.180 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).179,180 Concomitant use of proton-pump inhibitors with atazanavir is not recommended in antiretroviral treatment-experienced patients.179,180

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).179,345

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.179,344 No dosage adjustment is required when proton-pump inhibitors are used concomitantly with lopinavir/ritonavir.179

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.179,348

Rilpivirine

Pharmacokinetic interaction with omeprazole (decreased plasma concentrations and AUC of rilpivirine).179,343 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.179,343

Saquinavir

Potential pharmacokinetic interaction (increased peak plasma concentration and AUC of saquinavir).179,346 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.179,346 Caution is advised if proton-pump inhibitors are used concomitantly with ritonavir-boosted saquinavir, and patients should be monitored for saquinavir toxicity.179,346

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.182,183,184,186,224,226,227,228,229 Clopidogrel is metabolized to its active metabolite by CYP2C19.186,224,228 Concurrent use of omeprazole or esomeprazole, which inhibit CYP2C19, with clopidogrel reduces exposure to the active metabolite of clopidogrel and decreases platelet inhibitory effects.186,224,225,228,232,233,236,311,350 Although the clinical importance has not been fully elucidated, a reduction in the effectiveness of clopidogrel in preventing cardiovascular events is possible.186,187,224,225,228,229,230,235,236,237,238,240,311 Proton-pump inhibitors vary in their potency for inhibiting CYP2C19.182,183,184,224,232,253 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.1,350,351 In pharmacokinetic and pharmacodynamic studies in healthy individuals, concomitant use of dexlansoprazole, lansoprazole, or pantoprazole had less effect on the antiplatelet activity of clopidogrel than did concomitant use of omeprazole or esomeprazole.224,350,351 In individuals who were extensive metabolizers of CYP2C19 substrates, use of lansoprazole (30 mg once daily) concomitantly with clopidogrel (75 mg once daily) for 9 days reduced exposure to the active metabolite of clopidogrel by about 14% compared with use of clopidogrel alone.1,350 The observed effects of lansoprazole on metabolite exposure and clopidogrel-induced platelet inhibition were not considered clinically important,1,350 and the manufacturer of lansoprazole states that no adjustment of clopidogrel dosage is necessary if clopidogrel is used concomitantly with recommended dosages of lansoprazole.1

The decision to use a proton-pump inhibitor concomitantly with clopidogrel should be based on the assessed risks and benefits in individual patients.312,313,314,315,316 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.186,187,224,230,253,350 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;186,187,230 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.

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 lansoprazole, 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 In patients with rheumatoid arthritis receiving low-dose methotrexate (7.5-15 mg weekly), concomitant use of lansoprazole (30 mg daily) and naproxen (500 mg twice daily) for 7 days had no effect on the pharmacokinetics of methotrexate or 7-hydroxymethotrexate.1 However, no formal studies of interactions between high-dose methotrexate and proton-pump inhibitors have been conducted to date.1,333

The manufacturer of lansoprazole 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.1,134 Concomitant administration of lansoprazole with sucralfate resulted in delayed absorption and decreased (by 17%) bioavailability of lansoprazole.1,134 Lansoprazole should be administered at least 30 minutes before sucralfate.1,134

Tacrolimus

Potential pharmacokinetic interaction (increased whole blood concentrations of tacrolimus), particularly in transplant patients who are intermediate or poor metabolizers of CYP2C19 substrates.1

Theophylline

Potential pharmacokinetic interaction.1,134 Concomitant administration of theophylline and lansoprazole may result in a slight (10%) increase in theophylline clearance.1,134 The interaction is unlikely to be clinically important, although some patients may require adjustment of theophylline dosage when lansoprazole therapy is initiated or discontinued.1,134

Warfarin

When warfarin was administered concomitantly with single or multiple doses of lansoprazole 60 mg in healthy individuals, the pharmacokinetics of warfarin and the prothrombin time were not altered; however, increased international normalized ratio (INR) and prothrombin time have been reported in patients receiving warfarin concomitantly with proton-pump inhibitors, including lansoprazole.1,134 The INR and prothrombin time may need to be monitored when lansoprazole is used concomitantly with warfarin.1,134

Description

Lansoprazole is a substituted benzimidazole gastric antisecretory agent.1,2,4,9,20,21,23,25 Lansoprazole is structurally and pharmacologically related to dexlansoprazole, esomeprazole, omeprazole, pantoprazole, and rabeprazole; lansoprazole differs structurally from omeprazole by the presence of a trifluoroethoxy group in position 4 of the pyridine ring and the absence of methyl and methoxy groups on the pyridine and benzimidazole rings, respectively.1,2,4,9,21,23,25,190 The drugs are chemically and pharmacologically unrelated to H₂-receptor antagonists, antimuscarinics, or prostaglandin analogs.1,2,7 Lansoprazole is a racemic mixture of R - and S -isomers.188,189 Both isomers inhibit hydrogen/potassium adenosine triphosphatase (H⁺K⁺-exchanging ATPase), but plasma clearance of the R -isomer (dexlansoprazole) is slower than that of the S -isomer; following oral administration of racemic lansoprazole, plasma concentrations of the R -isomer are markedly higher than those of the S -isomer.188,189

Lansoprazole binds to H⁺K⁺-exchanging 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.1,2,4,9,18,33 Therefore, gastric antisecretory agents such as lansoprazole are commonly referred to as acid- or proton-pump inhibitors.1,3,4,5,6,8,9,10,12,13,15,17,19,21,22,23,24,36,103,104,125 Lansoprazole, a weak base, does not directly inhibit this enzyme system, but instead, it concentrates under the acid conditions of the parietal cell secretory canaliculi, where the drug undergoes rearrangement to active sulfenamide metabolites; these active metabolites then react with the sulfhydryl groups of H⁺K⁺-exchanging ATPase inactivating the proton pump.2,4,9,19,33 Because the sulfenamide metabolites form an irreversible covalent bond to H⁺K⁺-exchanging ATPase, acid secretion is inhibited until additional enzyme is synthesized, resulting in a prolonged duration of action.9,21,24,25,33,43,125

Lansoprazole inhibits basal and stimulated gastric acid secretion; in addition, because the drug inhibits the final step in the secretory pathway, it inhibits such secretion regardless of the stimulus.1,2,3,4 The degree of inhibition of gastric acid secretion is related to the dose and duration of therapy, but lansoprazole is a more potent inhibitor of such secretion than are H₂-receptor antagonists.1,2,3,4,5 Following oral administration of 15 or 30 mg of lansoprazole, inhibition of gastric acid secretion is apparent within 2-3 or 1-2 hours, respectively.1,5 After multiple daily doses, increased gastric pH is apparent within 1 hour of administration of 30 mg of lansoprazole and within 1-2 hours after administration of 15 mg of the drug.1

Although lansoprazole has a short terminal plasma half-life,4,33 the drug has a long duration of action (secondary to the prolonged presence of active lansoprazole metabolites within the parietal cell where they bind to H⁺K⁺-exchanging ATPase). 1,2,9 Following continuous oral administration of 15 or 30 mg of lansoprazole, the percent of time during a 24-hour period that the gastric pH exceeds 4 is 49 or 66%, respectively.1 Inhibition of basal gastric secretion is 71% after an initial oral dose of 30 mg and 80% or greater after 7 days of oral administration of 30 mg of lansoprazole daily.4 Stimulated gastric secretion initially is reduced 81% after an oral dose of 30 mg of lansoprazole and gastric secretion is reduced 88% after 7 days of oral administration of 30 mg of lansoprazole daily.4 Oral administration of lansoprazole 60 mg produced almost complete inhibition of gastric acid secretion in some patients.2 Following discontinuance of lansoprazole therapy, gastric acid secretion returns to baseline over a 2- to 4-day period, without rebound gastric acidity.1,4,5

The degree of inhibition of gastric acid secretion is similar following oral or IV administration (a parenteral formulation no longer is commercially available in the US) of lansoprazole 30 mg daily for 7 days in healthy individuals.170 Following oral or IV administration of the drug, the percent of time during a 24-hour period that the gastric pH exceeds 4 is about 67 or 71%, respectively, after an initial dose of 30 mg and about 78 or 80%, respectively, after 5 days of administration of lansoprazole 30 mg daily in healthy individuals.170

Lansoprazole increases plasma gastrin concentrations; this increase occurs in response to a negative feedback mechanism resulting from decreased gastric acid secretion.1,2,3,4 Although a single oral dose of 30 mg of lansoprazole did not affect serum gastrin levels in healthy adults, patients with gastric ulcer receiving 30-60 mg of lansoprazole once daily for 2 months developed a 50-100% increase from baseline in median fasting serum gastrin concentration; however, median serum gastrin levels remained within the normal range.1,3 Serum gastrin concentrations reach a plateau within 2 months of lansoprazole therapy and return to pretreatment values within 1-12 weeks after discontinuing therapy with the drug.1,2 Although marked hypergastrinemia with subsequent enterochromaffin-like (ECL) cell proliferation and carcinoid lesions have been observed in animal studies, no evidence of similar ECL cell effects were observed in patients receiving the drug for periods of at least one year.1,171 Longer-term study and experience are needed to rule out the possibility of an increased risk of gastric tumors in patients receiving prolonged lansoprazole therapy.1,2,3,4,5,8,12,18,23,24,25,41

Lansoprazole also decreases pepsin secretion and activity and increases serum pepsinogen; however, these effects are not as pronounced as the drug's inhibition of gastric acid secretion.1,3 Suppression of pepsin activity appears to be secondary to increased gastric pH, as conversion of the inactive precursor pepsinogen to pepsin requires an acidic gastric milieu.2 Pepsin output is inhibited in healthy adults receiving 30 mg of lansoprazole daily for 7 days in the morning or evening by 42-58 or 67-88%, respectively.2 When the dose is increased to 60 mg daily, no additional inhibition of pepsin secretion is observed.2 Pepsin activity also is inhibited by lansoprazole 30 mg daily administered in the morning or evening by 23 or 35%, respectively.2 Lansoprazole also substantially prolongs gastric emptying of digestible solids,1 but does not appear to affect lower esophageal sphincter pressure.1,43

Lansoprazole can suppress Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis ) in patients with gastric or duodenal ulcers infected with the organism.3,5,6,10,11,16,103,104 Combined therapy with lansoprazole and one or more appropriate anti-infectives (e.g., amoxicillin, clarithromycin) can effectively eradicate H. pylori gastric infection.1,3,16,103,104,134 (See Duodenal Ulcer: Acute Therapy, in Uses.)

Lansoprazole is extensively metabolized in the liver.1,189,190 Cytochrome P-450 (CYP) isoenzymes 2C19 and 3A4 are involved in the metabolism of the drug.189,190 Following single-dose oral administration of lansoprazole, approximately one-third of the administered dose is eliminated in urine and two-thirds in feces; unchanged drug is not recovered in urine.1,134

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.1,178,300,301,302,303,304,305 (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.178,300,301,302,303,304,307,308

Advice to Patients

Importance of instructing patients regarding proper administration of delayed-release oral preparations (see Oral Administration under Dosage and Administration: Administration).1 Necessity of swallowing the preparation without crushing or chewing the delayed-release granules.1,134 Importance of administering lansoprazole delayed-release oral preparations before eating.1,134

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.305,1

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

Advise patients that self-medication with lansoprazole is not intended for immediate relief of heartburn; the drug may relieve symptoms within 24 hours, but 1-4 days may be required for complete relief.191

Importance of not using lansoprazole for self-medication for longer than 14 days of continuous use and of not exceeding one course of therapy every 4 months unless otherwise directed by a clinician.191,305 Advise patients to discontinue use of lansoprazole as self-medication and to consult a clinician if their heartburn persists or worsens or if they need to use the drug for longer than 14 days or require more than one course of therapy every 4 months.191

Advise patients to consult a clinician before using lansoprazole for self-medication if they have liver disease, have had heartburn for longer than 3 months, or are experiencing heartburn with lightheadedness, dizziness, or sweating; chest or shoulder pain with shortness of breath, sweating, lightheadedness, or pain spreading to the arms, neck, or shoulders; frequent chest pain; frequent wheezing (especially with heartburn); unexplained weight loss; nausea or vomiting; or stomach pain.191 Advise patients with difficulty or pain with swallowing, those vomiting blood, and those with bloody or blackened stools that they should not use lansoprazole for self-medication and should consult a clinician.191

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

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1,134,191 Antacid administration is permissible with lansoprazole delayed-release preparations.1,134

Importance of informing patients with phenylketonuria that lansoprazole delayed-release orally disintegrating tablets contain aspartame.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,134,191

Importance of informing patients of other important precautionary information.1,134 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Takeda Pharmaceuticals America, Inc. Prevacid^® (lansoprazole) delayed-release capsules and delayed-release oral disintegrating tablets prescribing information. Deerfield, IL; 2012 May.

2. Barradell LB, Faulds D, McTavish D. Lansoprazole: a review of its pharmacodynamic and pharmacokinetic properties and its therapeutic efficacy in acid-related disorders. Drugs . 1992; 44:225-50. [PubMed 1382017]

3. Spencer CM, Faulds D. Lansoprazole: a reappraisal of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy in acid-related disorders. Drugs . 1994; 48:403-30.

4. Landes BD, Petite JP, Flouvat B. Clinical pharmacokinetics of lansoprazole. Clin Pharmacokinet . 1995; 28:458-70. [PubMed 7656504]

5. Anon. Lansoprazole. Med Lett Drugs Ther . 1995; 37:63. [PubMed 7603391]

6. Anon. Update on proton-pump inhibitors. Intl Pharm J . 1994; 8:193-5.

7. Tap Pharmaceuticals, Inc. Product information form for American hospital formulary service: Prevacid^® (lansoprazole) delayed-release capsules. Deerfield, IL; 1995 May 10.

8. Shamburek RD, Schubert ML. Pharmacology of gastric acid inhibition. Bailliere's Clin Gastroenterol . 1993; 7:23-54.

9. Sachs G, Shin JM, Besancon M et al. The continuing development of gastric acid pump inhibitors. Altern Pharmacol Ther . 1993; 7(Suppl 1):4-12.

10. Nagata K, Takagi E, Tsuda M et al. Inhibitory action of lansoprazole and its analogs against helicobacter pylori : inhibition of growth is not related to inhibition of urease. Antimicrob Agents Chemother . 1995; 39:567-70. [PubMed 7726537]

11. Verdü EF, Fraser R, Armstrong D et al. Effects of omeprazole and lansoprazole on 24-hour intragastric pH in helicobacter pylori -positive volunteers. Scand J Gastroenterol . 1994; 29:1065-9. [PubMed 7886393]

12. Lanza F, Goff J, Scowcroft C et al. Double-blind comparison of lansoprazole, ranitidine, and placebo in the treatment of acute duodenal ulcer. Am J Gastroenterol . 1994; 89:1191-200. [PubMed 8053433]

13. Hawkey CJ, Long RG, Bardham KD et al. Improved symptom relief and duodenal ulcer healing with lansoprazole, a new proton pump inhibitor, compared with ranitidine. Gut . 1993; 34:1458-62. [PubMed 8244121]

14. Ekstrom P, Carling L, Unge P et al. Lansoprazole versus omeprazole in active duodenal ulcer. Scand J Gastroenterol . 1995; 30:210-5. [PubMed 7770708]

15. Hongo M, Ohara S, Hirasawa Y et al. Effect of lansoprazole on intragastric pH: comparison between morning and evening dosing. Dig Dis Sci . 1992; 37:882-90. [PubMed 1534047]

16. De Korwin JD, Joubert M, Bazin N et al. Lansoprazole versus lansoprazole plus antibiotics in the treatment of helicobacter pylori gastric infection. Gastroenterology . 1991; 100(Suppl):A67.

17. Mauch F, Bode G, Malfertheiner P. Identification and characterization of an ATPase system of Helicobacter pylori and the effect of proton pump inhibitors. Am J Gastroenterol . 1993; 88:1801-2. [PubMed 8213737]

18. Robinson M, Sahba B, Avner D et al. A comparison of lansoprazole and ranitidine in the treatment of ercsive oesophagitis. Aliment Pharmacol Ther . 1995; 9:25-31. [PubMed 7766740]

19. Robinson M, Campbell DR, Sontag S et al. Treatment of erosive reflux esophagitis resistant to H₂-receptor antagonist therapy. Dig Dis Sci . 1995; 40:590-7. [PubMed 7895551]

20. Feldman M, Harford WV, Fisher RS et al. Treatment of reflux esophagitis resistant to H2-receptor antagonists with lansoprazole, a new H⁺K⁺-ATPase inhibitor: a controlled, double-blind study. Am J Gastroenterol . 1993; 88:1212-7. [PubMed 8101695]

21. Hatlebank JG, Berstad A, Carling L et al. Lnasoprazole versus omeprazole in short-term treatment of reflux oesophagitis. Scan J Gastroenterol . 1993; 28:224-8.

22. Berstad A, Hatlebakk JG. Lansoprazole in the treatment of reflux oesophagitis: a survey of clinical studies. Aliment Pharmacol Ther . 1993; 7(Suppl 1):34-6. [PubMed 8490077]

23. Howden CW, Castell dO, Cohen S et al. The rationale for continuous maintenance treatment of reflux esophagitis. Arch Intern Med . 1995; 155:1465-71. [PubMed 7605147]

24. Jensen RT, Metz DC, Koviack PD et al. Prospective study of the long-term efficacy and safety of lansoprazole in patients with the Zolinger-Ellison syndrome. Ailment Pharmacol Ther . 1993; 7(Suppl 1):41-50.

25. Metz DC, Pisegna JR, Ringham GL et al. Prospective study of efficacy and safety of lansoprazole in Zollinger-Ellison syndrome. Dig Dis Sci . 1993; 38:245-56. [PubMed 8425437]

26. Jensen RT, Fraker DL. Zollinger-Ellison syndrome: advances in treatment of gastric hypersecretion and the gastrinoma. JAMA . 1994; 271:1429-35. [PubMed 7513768]

27. Metz DC, Pisegna JR, Fishbeyn VA et al. Control of gastric acid hypersecretion in the management of patients with Zolinger-Ellison syndrome. World J Surg . 1993; 17:468-80. [PubMed 8362529]

28. Hirschowitz BJ, Hohnen J, Shaw S. Zollinger-Ellison syndrome treated wtih lansoprazole. Gastroenterolog . 1993; 104:A100.

29. Cavanaugh JH, Winters EP, Cohen A et al. Lack of effect of lansoprazole on steady state warfarin metabolism. Gastroenterology . 1991; 100:A40.

30. Granneman g, Winters EP, Locke CS et al. Lack of effect of concomitant lansoprazole on steady-state theophylline pharmacokinetics. Gastroenterology . 1991; 100:A75.

31. Cavanaugh JH, Schneck DW, Mukherji D et al. Lack of effect of concomitant lansoprazole on single-dose prorpranolol pharmacokinetics and pharmacodynamics. Gastroenterology . 1994; 106:A4.

32. Mukherji D, Cavanaugh JH. Lack of effect of concomitant multi-dose lansoprazole on single-dose phenytoin pharmacokinetics in subjects. Gastroenterology . 1994; 106:A103.

33. Hussein Z, Granneman GR, Mukherjee D et al. Age-related differences in the pharmacokinetics and pharmacodynamics of lansoprazole. Br J Clin Pharmacol . 1993; 36:391-8. [PubMed 12959285]

34. Flouvat B, Delhotal-Landes B, Cournot A et al. Single and multiple dose pharmacokinetics of lansoprazole in elderly subjects. Br J Clin Pharmacol . 1993; 36:467-9. [PubMed 12959297]

35. Lefebvre RA, Flouvat B, Karola-Tamisier S et al. Influence of lansoprazole treatment on diazepam plasma concentrations. Clin Pharmacol Ther . 1992; 52:458-63. [PubMed 1424419]

36. Delhotal-Landes B, Flouvat B, Duchier J et al. Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity. Eur J Clin Pharmacol . 1993; 45:367-71. [PubMed 8299672]

37. Shamburek RD, Schubert ML. Pharmacology of gastric acid inhibition. Bailliére's Clin Gastroenterol . 1993; 7:23-54.

38. Cerulli MA, Cloud ML, Offen WW et al. Nizatidine as maintenance therapy of duodenal ulcer disease in remission. Scand J Gastroenterol . 1987; 22(Suppl 136):79-83.

39. Hentschel E, Schütze K, Reichel W et al. Nizatidine versus ranitidine in the prevention of duodenal ulcer relapse: six-month interim results of a European multicentre study. Scand J Gastroenterol . 1987; 22(Suppl 136):84-8.

40. Chun AHC, Eason CJ, Shi HH et al. Lansoprazole: an alternative method of administration of a capsule dosage formulation. Clin Ther . 1995; 17:441-7. [PubMed 7585848]

41. Eissele R, Brunner G, Fischer B et al. Evaluation of enterochromaffin-like (ECL)-cell hyperplasia during long-term treatment with the proton pump inhibitor lansoprazole. Gastroenterology . 1993; 104:A74.

42. Rodrigues AD, Freston JW. PPI effects on the cytochrome P₄₅₀system: implications to significant drug interactions. In: Giuli R, ed. The esophageal mucosa, 300 questions - 300 answers. Amsterdam: Elsevier Science; 1994:460-4.

43. Tap Pharmaceuticals, Inc., Deerfield, IL: Personal communication.

44. Ateshkadi A, Lam NP, Johnson CA. Helicobacter pylori and peptic ulcer disease. Clin Pharm . 1993; 12:34-48. [PubMed 8428432]

45. Blaser MJ. Helicobacter pylori: its role in disease. Clin Infect . 1992; 15:386-91.

46. Marshall BJ. Treatment strategies for Helicobacter pylori infection. Gastroenterol Clin North Am . 1993; 22:183-98. [PubMed 8449566]

47. Israel DM, Hassall E. Treatment and long-term follow-up of Helicobacter pylori-associated duodenal ulcer disease in children. J Pediatr . 1993; 123:53-8. [PubMed 8320625]

48. Murray DM, DuPont HL, Cooperstock M et al. Evaluation of new anti-infective drugs for the treatment of gastritis and peptic ulcer disease associated with infection by Helicobacter pylori. Clin Infect Dis . 1992; 15(Suppl 1):S268-73.

49. Chiba N, Rao BV, Rademaker JW et al. Meta-analysis of the efficacy of antibiotic therapy in eradicating Helicobacter pylori. Am J Gastroenterol . 1992; 87:1716-27. [PubMed 1449132]

50. Glassman MS. Helicobacter pylori infection in children. A clinical overview. Clin Pediatr (Phila) . 1992; 31:481-7. [PubMed 1643767]

51. Peterson WL. Helicobacter pylori and peptic ulcer disease. N Engl J Med . 1991; 324:1043-8. [PubMed 2005942]

52. Logan RP, Gummett PA, Misiewicz JJ et al. One week eradication regimen for Helicobacter pylori . Lancet . 1991; 338:1249-52. [PubMed 1682653]

53. Burette A, Glupczynski Y. On: The who's and when's of therapy for Helicobacter pylori . 1991; 86:924-5. Letter.

54. Bayerdorffer E, Mannes GA, Sommer A et al. Long-term follow-up after eradication of Helicobacter pylori with a combination of omeprazole and amoxycillin. Scand J Gastroenterol Suppl . 1993; 196:19-25. [PubMed 8341987]

55. Unge P, Ekstrom P. Effects of combination therapy with omeprazole and an antibiotic on H. pylori and duodenal ulcer disease. Scand J Gastroenterol Suppl . 1993; 196:17-8.

56. Hunt RH. Hp and pH: implications for the eradication of Helicobacter pylori. Scand J Gastroenterol Suppl . 1993; 196:12-6. [PubMed 8341986]

57. Malfertheiner P. Compliance, adverse events and antibiotic resistance in Helicobacter pylori treatment. Scand J Gastroenterol Suppl . 1993; 196:34-7. [PubMed 8341989]

58. Bell GD, Powell U. Eradication of Helicobacter pylori and its effect in peptic ulcer disease. Scand J Gastroenterol Suppl . 1993; 196:7-11. [PubMed 8341990]

59. Adamek RJ, Wegener M, Opferkuch W et al. Successful Helicobacter pylori eradication: a systemic effect of antibiotics? Am J Gastroenterol . 1993; 88:792-3. Letter.

60. Bianchi Porro G, Parente F, Lazzaroni M. Short and long term outcome of Helicobacter pylori positive resistant duodenal ulcers treated with colloidal bismuth subcitrate plus antibiotics or sucralfate alone. Gut . 1993; 34:466-9. [PubMed 8491391]

61. Graham DY, Go MF. Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated. Clin Infect Dis . 1993; 17:293-4. [PubMed 8399892]

62. Murray DM, DuPont HL. Reply. (Evaluation of new antiinfective drugs for Helicobacter pylori infection: revisited and updated.) Clin Infect Dis . 1993; 17:294-5.

63. George LL, Borody TJ, Andrews P et al. Cure of duodenal ulcer after eradication of H. pylori. Med J Aust . 1990; 153:145-9. [PubMed 1974027]

64. Farrell MK. Dr. Apley meets Helicobacter pylori. J Pediatr Gastroenterol Nutr . 1993; 16:118-9. [PubMed 8450375]

65. Fiocca R, Solcia E, Santoro B. Duodenal ulcer relapse after eradication of Helicobacter pylori. Lancet . 1991; 337:1614. [PubMed 1675746]

66. Marshall BJ. Campylobacter pylori: its link to gastritis and peptic ulcer disease. Clin Infect Dis . 1990; 12(Suppl 1):S87-93.

67. Nomura A, Stemmermann GN, Chyou PH et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med . 1991; 325:1132-6. [PubMed 1891021]

68. Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med . 1991; 325:1127-31. [PubMed 1891020]

69. The EUROGAST Study Group. An international association between Helicobacter pylori infection and gastric cancer. Lancet . 1993; 341:1359-62. [PubMed 8098787]

70. Talley NJ, Zinsmeister AR, Weaver A et al. Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst . 1991; 83:1734-9. [PubMed 1770552]

71. Forman D, Newell DG, Fullerton F et al. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ . 1991; 302:1302-5. [PubMed 2059685]

72. Forman D. Helicobacter pylori infection: a novel risk factor in the etiology of gastric cancer. J Natl Cancer Inst . 1991; 83:1702-3. [PubMed 1770545]

73. Parsonnet J. Helicobacter pylori and gastric cancer. Gastroenterol Clin North Am . 1993; 22:89-104. [PubMed 8449573]

74. Correa P. Is gastric carcinoma an infectious disease? N Engl J Med . 1991; 325:1170-1.

75. Isaacson PG, Spencer J. Is gastric lymphoma an infectious disease? Hum Pathol . 1993; 24:569-70.

76. Borody T, Andrews P, Mancuso N et al. Helicobacter pylori reinfection 4 years post-eradication. Lancet . 1992; 339:1295. [PubMed 1349686]

77. Hixson LJ, Kelley CL, Jones WN et al. Current trends in the pharmacotherapy for peptic ulcer disease. Arch Intern Med . 1992; 152:726-32. [PubMed 1558429]

78. Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer with eradication of Helicobacter pylori. Lancet . 1990; 335:1233-5. [PubMed 1971318]

79. Hunt RH. pH and Hp—gastric acid secretion and Helicobacter pylori: implications for ulcer healing and eradication of the organism. Am J Gastroenterol . 1993; 88:481-3. [PubMed 8470623]

80. Hentschel E, Brandstatter G, Dragosics B et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med . 1993; 328:308-12. [PubMed 8419816]

81. Graham DY, Lew GM, Evans DG et al. Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing: a randomized controlled trial. Ann Intern Med . 1991; 115:266-9. [PubMed 1854110]

82. Reviewers' comments (personal observations) on Helicobacter pylori ; 1993 Oct 26.

83. Marshall BJ. Helicobacter pylori . Am J Gastroenterol . 1994; 89(Suppl):S116-28.

84. Labenz J, Gyenes E, Rühl GH et al. Amoxicillin plus omeprazole versus triple therapy for eradication of Helicobacter pylori in duodenal ulcer disease: a prospective, randomized, and controlled study. Gut . 1993; 34:1167-70. [PubMed 8406147]

85. Labenz J, Gyenes E, Rühl GH et al. Omeprazole plus amoxicillin: efficacy of various treatment regimens to eradicate Helicobacter pylori . Am J Gastroenterol . 1993; 88:491-5. [PubMed 8470626]

86. Bell GD, Powell KU, Burridge SM et al. Helicobacter pylori eradication: efficacy and side effect profile of a combination of omeprazole, amoxycillin and metronidazole compared with four alternative regimens. Q J Med . 1993; 86:743-50. [PubMed 8265776]

87. Labenz J, Rühl GH, Bertrams J et al. Medium- and high-dose omeprazole plus amoxicillin for eradication of Helicobacter pylori in duodenal ulcer disease. Dig Dis Sci . 1994; 39:1483-7. [PubMed 8026260]

88. Labenz J, Börsch G. Highly significant change of the clinical course of relapsing and complicated peptic ulcer disease after cure of Helicobacter pylori infection. Am J Gastroenterol . 1994; 89: 1785-8.

89. Wang WM, Chen CY, Jan CM et al. Long-term follow-up and serological study after triple therapy of Helicobacter pylori -associated duodenal ulcer. Am J Gastroenterol . 1994; 89:1793-6. [PubMed 7942669]

90. Savarino V, Sandro Mela G, Zentilin P et al. Acid inhibition and amoxicillin activity against Helicobacter pylori . Am J Gastroenterol . 1993; 88:1975-6. [PubMed 8237959]

91. Labenz J, Börsch G. Acid inhibition and amoxicillin activity against Helicobacter pylori : response to Savarino et al . Am J Gastroenterol . 1993; 88:1976. [PubMed 8292199]

92. Anon. Drugs for treatment of peptic ulcers. Med Lett Drugs Ther . 1994; 36:65-7. [PubMed 7912812]

93. Freston JW. Emerging strategies for managing peptic ulcer disease. Scand J Gastroenterol Suppl . 1994; 201:49-54. [PubMed 8047824]

94. Axon ATR. The role of acid inhibition in the treatment of Helicobacter pylori infection. Scand J Gastroenterol Suppl . 1994; 201:16-23. [PubMed 8047818]

95. Labenz J, Rühl GH, Bertrams J et al. Medium- or high-dose omeprazole plus amoxicillin eradicates Helicobacter pylori in gastric ulcer disease. Am J Gastroenterol . 1994; 89:726-30. [PubMed 8172146]

96. Labenz J, Borsch G. Evidence for the essential role of Helicobacter pylori in gastric ulcer disease. Gut . 1994; 35:19-22. [PubMed 8307443]

97. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. Helicobacter pylori in peptic ulcer disease. JAMA . 1994; 272:65-9. [PubMed 8007082]

98. Fennerty MB. Helicobacter pylori . Ann Intern Med . 1994; 154:721-7.

99. Adamek RJ, Wegener M, Labenz J et al. Medium-term results of oral and intravenous omeprazole/amoxicillin Helicobacter pylori eradication therapy. Am J Gastroenterol . 1994; 89:39-42. [PubMed 8273795]

100. Peura DA, Graham DY. Helicobacter pylori: consensus reached: peptic ulcer is on the way to becoming an historic disease. Am J Gastroenterol . 1994; 89:1137-9. [PubMed 8053422]

101. Cotton P. NIH consensus panel urges antimicrobials for ulcer patients, skeptics concur with caveats. JAMA . 1994; 271:808-9. [PubMed 8114221]

102. Feldman M. The acid test. Making clinical sense of the consensus conference on Helicobacter pylori . JAMA . 1994; 272:70-1. [PubMed 8007084]

103. Harris AW, Gummett PA, Logan RPH et al. Eradication of Helicobacter pylori with lansoprazole and clarithromycin. Aliment Pharmacol Ther . 1995; 9:201-4. [PubMed 7605863]

104. Lamouliatte H. Effect of lansoprazole on Helicobacter pylori . Clin Ther . 1993; 15(Suppl B):32-6. [PubMed 8205593]

105. Sloane R, Cohen H. Common-sense management of Helicobacter pylori -associated gastroduodenal disease. Personal views. Gastroenterol Clin North Am . 1993; 22:199-206. [PubMed 8449567]

106. Abbott Laboratories. Biaxin^® (clarithromycin) Filmtab^® tablets and granules for oral suspension prescribing information. Abbott Park, IL; 1996 Apr.

107. Markham A, McTavish D. Clarithromycin and omeprazole: as Helicobacter pylori eradication therapy in patients with H. pylori-associated gastric disorders. Drugs . 1996; 51:161-78. [PubMed 8741237]

108. Sung JJY, Chung SCS, Ling TKW et al. Dual therapy versus triple therapy for Helicobacter pylori -associated duodenal ulcers. Dig Dis Sci . 1996; 41:453-7. [PubMed 8617114]

109. Soll AH. Medical treatment of peptic ulcer disease. JAMA . 1996; 275:622-9. [PubMed 8594244]

110. Soll AH. Practice guidelines for treatment of peptic ulcer disease. JAMA . 1996; 276:1136-7.

111. Reviewers' comments (personal observations) on the Aminopenicillins General Statement 8:12.16.

112. Walsh JH, Peterson WL. The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. N Engl J Med . 1995; 333:984-91. [PubMed 7666920]

113. Hackelsberger A, Malfertheiner P. A risk-benefit assessment of drugs used in the eradication of Helicobacter pylori infection. Drug Saf . 1996; 15:30-52. [PubMed 8862962]

114. Rauws EAJ, van der Hulst RWM. Current guidelines for the eradication of Helicobacter pylori in peptic ulcer disease. Drugs . 1995; 6:984-90.

115. van der Hulst RWM, Keller JJ, Rauws EAJ et al. Treatment of Helicobacter pylori infection: a review of the world literature. Helicobacter . 1996; 1:6-19. [PubMed 9398908]

116. Lind T, Veldhuyzen van Zanten S, Unge P et al. Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I study. Helicobacter . 1996; 1:138-44. [PubMed 9398894]

117. Anon. The choice of antibacterial drugs. Med Lett Drugs Ther . 1996; 38:25-34. [PubMed 8598824]

118. Graham DY, Lew GM, Klein PD et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med . 1992; 116:705-8. [PubMed 1558340]

119. Cutler AF, Schubert TT. Patient factors affecting Helicobacter pylori eradication with triple therapy. Am J Gastroenterol . 1993; 88:505-9. [PubMed 8470629]

120. Logan RP, Gummett PA, Hegarty BT et al. Clarithromycin and omeprazole for Helicobacter pylori . Lancet . 1992; 25:340:239.

121. Graham DY. Treatment of peptic ulcers caused by Helicobacter pylori . N Engl J Med . 1993; 328:349-50. [PubMed 8419823]

122. Hosking SW, Ling TK, Yung MY et al. Randomised controlled trial of short term treatment to eradicate Helicobacter pylori in patients with duodenal ulcer. BMJ . 1992; 305:502-4. [PubMed 1392995]

123. Bell GD, Powell K, Burridge SM et al. Experience with 'triple' anti- Helicobacter pylori eradication therapy: side effects and the importance of testing the pre-treatment bacterial isolate for metronidazole resistance. Aliment Pharmacol Ther . 1992; 6:427-35. [PubMed 1420735]

124. Fennerty MB. Practice guidelines for treatment of peptic ulcer disease. JAMA . 1996; 276:1135. [PubMed 8827957]

125. Lindberg P, Brandstrom A, Wallmark B et al. Omeprazole: the first proton pump inhibitor. Medicinal Res Rev . 1990; 10:1-54.

126. Langtry HD, Wilde IW. Lansoprazole: an update of its pharmacological properties and clinical efficacy in the management of acid-related disorders. Drugs . 1997; 54:1473-500.

127. Chun AHC, Shi HH, Achari R et al. Lansoprazole: adminstration of the contents of a capsule dosage formulation through a nasogastric tube. Clin Ther . 1996; 18:833-42. [PubMed 8930427]

128. Greco S, Mazzaglia G. Glossitis, stomatitis, and black tongue with lansoprazole plus clarithromycin. Ann Pharmacother . 1995; 31:1548.

129. Garnett RG. Lansoprazole: a proton pump inhibitor. Ann Pharmacother . 1996; 30:1425. [PubMed 8968456]

130. Unge P, Anderson T. Drug interactions with proton pump inhibitors. Drugs . 1997; 3:171-9.

131. Zimmerman AE, Katona BG. Lansoprazole: a comprehensive review. Pharmacother . 1997; 17:308-26.

132. Hatlebakk JG, Nesje LB, Hausken T et al. Lansoprazole capsules and amoxicillin oral suspension in the treatment of peptic ulcer disease. Scand J Gastroenterol . 1995; 11:1053-7.

133. Leufkens H, Claessens A, Heerdink E et al. A prospective follow-up study of 5669 users of lansoprazole in daily practice. Aliment Pharmacol Ther . 1997; 11:887-97. [PubMed 9354197]

134. Takeda Pharmaceuticals America, Inc. PrevPac^® (lansoprazole 30-mg capsules, amoxicillin 500-mg capsules, and clarithromycin 500-mg tablets) prescribing information. Deerfield, IL; 2009 Oct

135. Salcedo JA, Al-Kawas F. Treatment of Helicobacter pylori infection. Arch Intern Med . 1998; 158:842-51. [PubMed 9570169]

136. Roth S, Agrawal N, Mahowald M et al. Misoprostol heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin. Arch Intern Med . 1989; 149:775-9. [PubMed 2495779]

137. Nightingale S. Warning changes on NSAIA labeling. JAMA . 1989; 261:1396.

138. Graham DY. Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinflammatory drug therapy. Gastroenterology . 1989; 96:675-81. [PubMed 2642452]

139. Knodel LC. Preventing NSAID-induced gastric ulcers: the role of misoprostol. Hosp Formul . 1989; 24(Suppl A):27-30.

140. Stern WR. Summary of the 33rd meeting of the Food and Drug Administration's Gastrointestinal Drugs Advisory Committee, September 15-16, 1988. Am J Gastroenterol . 1989; 84:351-3. [PubMed 2494882]

141. Miller SR, Fries JF, Spitz P et al. Patients at high risk for developing upper gastrointestinal complications associated with non-steroidal antiinflammatory drugs. Am J Gastroenterol . 1988; 83:1055.

142. Palmer JF. Letter sent to Bathish J, of Wyeth-Ayerst Laboratories regarding labeling revisions about gastrointestinal adverse reactions to Orudis (ketoprofen). Rockville, MD: Food and Drug Administration, Division of Oncology and Radiopharmaceutical Drug Products; 1988 Sep.

143. Food and Drug Administration. Labeling revisions for NSAIDs. FDA Drug Bull . 1989; 19:3-4.

144. Roth SH. Nonsteroidal anti-inflammatory drugs: gastropathy, deaths, and medical practice. Ann Intern Med . 1988; 109:353-4. [PubMed 3044208]

145. Griffin MR, Ray WA, Schaffner W. Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med . 1988; 109:359-63. [PubMed 3261560]

146. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther . 2000; 42:57-64. [PubMed 10887424]

147. Clinch D, Banerjee AK, Ostick G et al. Non-steroidal anti-inflammatory drugs and gastrointestinal adverse effects. J R Coll Phys London . 1983; 17:228-30.

148. Levy M. Aspirin use in patients with major upper gastrointestinal bleeding and peptic-ulcer disease. N Engl J Med . 1974; 290:1158-62. [PubMed 4545100]

149. Merck. Vioxx (rofecoxib) tablets and oral suspension prescribing information. West Point, PA; 1999 Sep.

150. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med . 1999; 340:1888-99. [PubMed 10369853]

151. Lanza FL and the members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol . 1998; 93:2037-46. [PubMed 9820370]

152. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis. 2002 update. Arth Rheuma . 2002; 46:328-46.

153. Schoenfeld P, Kimmey MB, Scheiman J et al. Review article: nonsteroidal anti-inflammatory drug-associated gastrointestinal complications—guidelines for prevention and treatment. Aliment Pharmacol Ther . 1999; 13:1273-85. [PubMed 10540041]

154. Hawkins C, Hanks GW. The gastroduodenal toxicity of nonsteroidal anti-inflammatory drugs. A review of the literature. J Pain Symptom Manage . 2000; 20:140-51. [PubMed 10989252]

155. Rostom A, Wells G, Tugwell P et al. The prevention of chronic NSAID induced upper gastrointestinal toxicity: A Cochrane collaboration metaanalysis of randomized controlled trials. J Rheumatol . 2000; 27:2203-14. [PubMed 10990235]

156. 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]

157. Banks S, Greenberg R. Alternate day omeprazole in H2 receptor-antagonist resistant reflux esophagitis. Gastroenterology . 1991; 100:A29. [PubMed 2001800]

158. Dent J, Yeomans ND, Mackinnon M et al. Omeprazole v ranitidine for prevention of relapse in reflux esophagitis. A contolled double blind trial of their efficacy and safety. Gut . 1994; 35:590-8. [PubMed 8200548]

159. Sandmark S, Carlsson R, Fausa O et al. Omeprazole or ranitidine in the short-term treatment of ulcerative reflux esophagitis. Results of a double-blind randomized Scandinavian multicenter study. Scand J Gastroenterol . 1988; 23:625-32. [PubMed 3041558]

160. Chan FKL, Hung LCT, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med . 2002; 347:2104-10. [PubMed 12501222]

161. Graham DY. NSAIDs, Helicobacter pylori , and Pandora's box. N Engl J Med . 2002; 347:2162-4. [PubMed 12501230]

162. 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]

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

164. 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]

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

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

167. 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.

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

169. Graham DY, Agrawal NM, Campbell DR et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med . 2002; 162:169-75. [PubMed 11802750]

170. Takeda Pharmaceuticals America, Inc. Prevacid^® I.V. (lansoprazole) for injection prescribing information. Deerfield, IL; 2008 Jul.

171. Takeda Pharmaceuticals America, Inc. Prevacid^® Naprapac^® 500 (lansoprazole delayed-release capsules and naproxen tablets) kit prescribing information. Deerfield, IL; 2009 Feb.

172. American Medical Association Council on Scientific Affairs. Aspartame: review of safety issues. JAMA. 1985; 254:400-2.

173. Gossel TA. A review of aspartame: characteristics, safety and uses. US Pharm. 1984; 9:26,28-30.

174. Food and Drug Administration. Aspartame as an inactive ingredient in human drug products; labeling requirements. Proposed rule. [21 CFR Part 201] Fed Regist. 1983; 48:54993-5. (lDIS 178728)

175. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist. 1983; 48:31376-82. (IDIS 172957)

176. 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]

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

178. 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]

179. 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 (HIV.gov) website. [Web]

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

181. Baxter Healthcare Corporation. 5% Dextrose injection, USP in MINI-BAG Plus container prescribing information. Deerfield, IL; 1995.

182. 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]

183. 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]

184. 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]

185. 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.

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

187. 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. [PubMed 19176635]

188. Vakily M, Zhang W, Wu J et al. Pharmacokinetics and pharmacodynamics of a known active PPI with a novel Dual Delayed Release technology, dexlansoprazole MR: a combined analysis of randomized controlled clinical trials *. Curr Med Res Opin . 2009; 25:627-38. [PubMed 19232037]

189. Miura M, Tada H, Yasui-Furukori N et al. Pharmacokinetic differences between the enantiomers of lansoprazole and its metabolite, 5-hydroxylansoprazole, in relation to CYP2C19 genotypes. Eur J Clin Pharmacol . 2004; 60:623-8. [PubMed 15448955]

190. Welage LS. Pharmacologic properties of proton pump inhibitors. Pharmacotherapy . 2003; 23:74S-80S. [PubMed 14587961]

191. Novartis. Prevacid^® 24HR (lansoprazole) drug facts. 2012. From prevacid24hr website. Accessed 2012 Jul 12. [Web]

192. Kushner PR, Snoddy AM, Gilderman L et al. Lansoprazole 15 mg once daily for 14 days is effective for treatment of frequent heartburn: results of 2 randomized, placebo-controlled, double-blind studies. Postgrad Med . 2009; 121:67-75. [PubMed 19641272]

193. Food and Drug Administration. Center for Drug Evaluation and Research: Application Number: 22-327, Summary review for lansoprazole (Prevacid 24 HR). From FDA website. Accessed 2009 Nov 4. [Web]

194. Peura DA, Riff DS, Snoddy AM et al. Clinical trial: lansoprazole 15 or 30 mg once daily vs. placebo for treatment of frequent nighttime heartburn in self-treating subjects. Aliment Pharmacol Ther . 2009; 30:459-68. [PubMed 19523177]

195. Takeda Pharmaceuticals America, Inc. Deerfield, IL: Personal communication.

224. Sanofi-Aventis/Bristol-Myers Squibb. Plavix^®, (clopidogrel bisulfate) tablets prescribing information. New Y ork, 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:S815, Abstract 3998.

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

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 at: [Web]/displayItem.do?primaryKey=967345&type=ppt. Accessed 2009 Dec 15.

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]

252. ASHP. Standardize 4 Safety: compounded oral liquid standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]

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

254. AstraZeneca. Nexium^® (esomeprazole magnesium) delayed-release capsules and packets for delayed-release oral suspension prescribing information. Wilmington, DE; 2011 Jun.

255. DiGiacinto JL, Olsen KM, Bergman KL, et al. Stability of suspension formulations of lansoprazole and omeprazole stored in amber- colored plastic oral syringes. Ann Pharmacother. 2000; 34:600-5.

256. Morrison JT, Lugo RA, Thigpen JC, et al. Stability of extemporaneously prepared lansoprazole suspension at two temperatures. J Pediatr Pharmacol Ther. 2013; 18:122-7.

257. Melkoumov A, Soukrati A, Elkin I, et al. Quality evaluation of extemporaneous delayed release liquid formulations of lansoprazole. Am J Health-Syst Pharm. 2011; 68:2069-74.

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. [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. [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. [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. [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.

312. 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]

313. 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]

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

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

316. 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]

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. [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. [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. [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]