Lansoprazole (Page 10 of 12)

Drug-Drug Interactions

Lansoprazole may interfere with the absorption of other drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, digoxin).

Lansoprazole is metabolized through the cytochrome P 450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that lansoprazole does not have clinically significant interactions with other drugs metabolized by the cytochrome P 450 system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds are metabolized through various cytochrome P 450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

Atazanavir and Nelfinavir

Lansoprazole causes long-lasting inhibition of gastric acid secretion. Lansoprazole substantially decreases the systemic concentrations of HIV protease inhibitors, such as atazanavir and nelfinavir, which are dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir or nelfinavir and the development of HIV resistance. Therefore, lansoprazole or other proton pump inhibitors, should not be co-administered with atazanavir or nelfinavir.

Theophylline

When lansoprazole was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction is unlikely to be of clinical concern. Nonetheless, individual patients may require additional titration of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood levels.

Warfarin

In a study of healthy subjects neither the pharmacokinetics of warfarin enantiomers nor prothrombin time were affected following single or multiple 60 mg doses of lansoprazole. However, there have been reports of increased International Normalized Ratio (INR) and prothrombin time in patients receiving proton pump inhibitors, including lansoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Methotrexate and 7-hydromethotrexate

In an open-label, single-arm, eight day, pharmacokinetic study of 28 adult rheumatoid arthritis patients (who required the chronic use of 7.5 mg to 15 mg of methotrexate given weekly), administration of seven days of naproxen 500 mg twice daily and lansoprazole 30 mg daily had no effect on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate. While this study was not designed to assess the safety of this combination of drugs, no major adverse reactions were noted. However, this study was conducted with low doses of methotrexate. A drug interaction study with high doses of methotrexate has not been conducted.

Amoxicillin

Lansoprazole has also been shown to have no clinically significant interaction with amoxicillin.

Sucralfate

In a single-dose crossover study examining lansoprazole 30 mg and omeprazole 20 mg each administered alone and concomitantly with sucralfate 1 gram, absorption of the proton pump inhibitors was delayed and their bioavailability was reduced by 17% and 16%, respectively, when administered concomitantly with sucralfate. Therefore, proton pump inhibitors should be taken at least 30 minutes prior to sucralfate. In clinical trials, antacids were administered concomitantly with lansoprazole and there was no evidence of a change in the efficacy of lansoprazole.

Clopidogrel

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects who were CYP2C19 extensive metabolizers, receiving once daily administration of clopidogrel 75 mg alone or concomitantly with lansoprazole 30 mg (n = 40), for nine days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (mean AUC ratio was 86%, with 90% CI of 80 to 92%) when lansoprazole was co-administered compared to administration of clopidogrel alone.

Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In two 24 month carcinogenicity studies, Sprague-Dawley rats were treated with oral lansoprazole doses of 5 mg/kg/day to 150 mg/kg/day, about one to 40 times the exposure on a body surface (mg/m 2) basis of a 50 kg person of average height [1.46 m 2 body surface area (BSA)] given the recommended human dose of 30 mg/day. Lansoprazole produced dose-related gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats. It also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 mg/kg/day to 150 mg/kg/day (four to 40 times the recommended human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.

In a 24 month carcinogenicity study, CD-1 mice were treated with oral lansoprazole doses of 15 mg/kg/day to 600 mg/kg/day, two to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg/kg/day and 600 mg/kg/day (40 to 80 times the recommended human dose based on BSA) and female mice treated with 150 mg/kg/day to 600 mg/kg/day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 mg/kg/day to 600 mg/kg/day (10 to 80 times the recommended human dose based on BSA).

A 26 week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test, or the rat bone marrow cell chromosomal aberration test.

Lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproduction studies have been performed in pregnant rats at oral lansoprazole doses up to 150 mg/kg/day [40 times the recommended human dose (30 mg/day) based on body surface area (BSA)] and pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day (16 times the recommended human dose based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.

14 CLINICAL STUDIES

Duodenal Ulcer: In a U.S. multicenter, double-blind, placebo-controlled, dose-response (15 mg, 30 mg, and 60 mg of lansoprazole once daily) study of 284 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after two and four weeks was significantly higher with all doses of lansoprazole than with placebo. There was no evidence of a greater or earlier response with the two higher doses compared with lansoprazole 15 mg. Based on this study and the second study described below, the recommended dose of lansoprazole in duodenal ulcer is 15 mg per day ( Table 7).

Table 7. Duodenal Ulcer Healing Rates
*
(p ≤ 0.001) versus placebo.

Lansoprazole

Placebo

Week

15 mg daily (N = 68)

30 mg daily (N = 74)

60 mg daily (N = 70)

(N = 72)

2

42.4% *

35.6% *

39.1% *

11.3%

4

89.4% *

91.7% *

89.9% *

46.1%

Lansoprazole 15 mg was significantly more effective than placebo in relieving day and nighttime abdominal pain and in decreasing the amount of antacid taken per day.

In a second U.S. multicenter study, also double-blind, placebo-controlled, dose-comparison (15 mg and 30 mg of lansoprazole once daily), and including a comparison with ranitidine, in 280 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after four weeks was significantly higher with both doses of lansoprazole than with placebo. There was no evidence of a greater or earlier response with the higher dose of lansoprazole. Although the 15 mg dose of lansoprazole was superior to ranitidine at four weeks, the lack of significant difference at two weeks and the absence of a difference between 30 mg of lansoprazole and ranitidine leaves the comparative effectiveness of the two agents undetermined ( Table 8) [see Indications and Usage (1.1)] .

Table 8. Duodenal Ulcer Healing Rates
*
(p ≤ 0.05) versus placebo and ranitidine.
(p ≤ 0.05) versus placebo.

Lansoprazole

Ranitidine

Placebo

Week

15 mg daily (N = 80)

30 mg daily (N = 77)

300 mg h.s. (N = 82)

(N = 41)

2

35.0%

44.2%

30.5%

34.2%

4

92.3% *

80.3%

70.5%

47.5%

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence: Randomized, double-blind clinical studies performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of lansoprazole in combination with amoxicillin and clarithromycin as triple 14 day therapy or in combination with amoxicillin as dual 14 day therapy for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of two different eradication regimens were established:

Triple Therapy: Lansoprazole 30 mg twice daily/Amoxicillin 1 gram twice daily/Clarithromycin 500 mg twice daily

Dual Therapy: Lansoprazole 30 mg three times daily/Amoxicillin 1 gram three times daily

All treatments were for 14 days. H. pylori eradication was defined as two negative tests (culture and histology) at four to six weeks following the end of treatment.

Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

A randomized, double-blind clinical study performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of lansoprazole triple therapy for 10 and 14 days. This study established that the 10 day triple therapy was equivalent to the 14 day triple therapy in eradicating H. pylori ( Tables 9 and 10) [see Indications and Usage (1.2)] .

Table 9. H. pylori Eradication Rates — Triple Therapy (Lansoprazole/Amoxicillin/Clarithromycin) Percent of Patients Cured [95% Confidence Interval] (Number of Patients)
*
Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy.
Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.
(p < 0.05) versus lansoprazole/amoxicillin and lansoprazole/clarithromycin dual therapy.
§
(p < 0.05) versus clarithromycin/amoxicillin dual therapy.
The 95% confidence interval for the difference in eradication rates, 10 day minus 14 day is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.

Study

Duration

Triple Therapy Evaluable Analysis *

Triple Therapy Intent-to-Treat Analysis

M93-131

14 days

92 [80.0 to 97.7] (N = 48)

86 [73.3 to 93.5] (N = 55)

M95-392

14 days

86 §[75.7 to 93.6] (N = 66)

83 §[72.0 to 90.8] (N = 70)

M95-399

14 days

85 [77.0 to 91.0] (N = 113)

82 [73.9 to 88.1] (N = 126)

10 days

84 [76.0 to 89.8] (N = 123)

81 [73.9 to 87.6] (N = 135)

Table 10. H. pylori Eradication Rates – 14 Day Dual Therapy (Lansoprazole/Amoxicillin) Percent of Patients Cured [95% Confidence Interval] (Number of Patients)
*
Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.
Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.
(p < 0.05) versus lansoprazole alone.
§
(p < 0.05) versus lansoprazole alone or amoxicillin alone.

Study

Dual Therapy Evaluable Analysis *

Dual Therapy Intent-to-Treat Analysis

M93-131

77 [62.5 to 87.2] (N = 51)

70 [56.8 to 81.2] (N = 60)

M93-125

66 §[51.9 to 77.5] (N = 58)

61 §[48.5 to 72.9] (N = 67)

Long-Term Maintenance Treatment of Duodenal Ulcers: Lansoprazole has been shown to prevent the recurrence of duodenal ulcers. Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed duodenal ulcers. Patients remained healed significantly longer and the number of recurrences of duodenal ulcers was significantly less in patients treated with lansoprazole than in patients treated with placebo over a 12 month period ( Table 11) [see Indications and Usage (1.3)] .

Table 11. Endoscopic Remission Rates
% = Life Table Estimate.
*
(p ≤ 0.001) versus placebo.

Trial

Drug

No. of Pts.

Percent in Endoscopic Remission

0 to 3 mo.

0 to 6 mo.

0 to 12 mo.

#1

Lansoprazole 15 mg daily

86

90% *

87% *

84% *

Placebo

83

49%

41%

39%

#2

Lansoprazole 30 mg daily

18

94% *

94% *

85% *

Lansoprazole 15 mg daily

15

87% *

79% *

70% *

Placebo

15

33%

0%

0%

In trial #2, no significant difference was noted between lansoprazole 15 mg and 30 mg in maintaining remission.

Gastric Ulcer: In a U.S. multicenter, double-blind, placebo-controlled study of 253 patients with endoscopically documented gastric ulcer, the percentage of patients healed at four and eight weeks was significantly higher with lansoprazole 15 mg and 30 mg once a day than with placebo ( Table 12) [see Indications and Usage (1.4)] .

Table 12. Gastric Ulcer Healing Rates
*
(p ≤ 0.05) versus placebo.

Lansoprazole

Placebo

Week

15 mg daily (N = 65)

30 mg daily (N = 63)

60 mg daily (N = 61)

(N = 64)

4

64.6% *

58.1% *

53.3% *

37.5%

8

92.2% *

96.8% *

93.2% *

76.7%

Patients treated with any lansoprazole dose reported significantly less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets used per day than the placebo group.

Independent substantiation of the effectiveness of lansoprazole 30 mg was provided by a meta-analysis of published and unpublished data.

Healing of NSAID-Associated Gastric Ulcer: In two U.S. and Canadian multicenter, double-blind, active-controlled studies in patients with endoscopically confirmed NSAID-associated gastric ulcer who continued their NSAID use, the percentage of patients healed after eight weeks was statistically significantly higher with 30 mg of lansoprazole than with the active control. A total of 711 patients were enrolled in the study, and 701 patients were treated. Patients ranged in age from 18 to 88 years (median age 59 years), with 67% female patients and 33% male patients. Race was distributed as follows: 87% Caucasian, 8% Black, 5% Other. There was no statistically significant difference between lansoprazole 30 mg daily and the active control on symptom relief (i.e., abdominal pain) ( Table 13) [see Indications and Usage (1.5)] .

Table 13. NSAID-Associated Gastric Ulcer Healing Rates *
*
Actual observed ulcer(s) healed at time points ± 2 days.
Dose for healing of gastric ulcer.
(p ≤ 0.05) versus the active control.

Study #1

Lansoprazole 30 mg daily

Active Control

Week 4

60% (53/88)

28% (23/83)

Week 8

79% (62/79)

55% (41/74)

Study #2

Lansoprazole 30 mg daily

Active Control

Week 4

53% (40/75)

38% (31/82)

Week 8

77% (47/61)

50% (33/66)

Risk Reduction of NSAID-Associated Gastric Ulcer: In one large U.S., multicenter, double-blind, placebo- and misoprostol-controlled (misoprostol blinded only to the endoscopist) study in patients who required chronic use of an NSAID and who had a history of an endoscopically documented gastric ulcer, the proportion of patients remaining free from gastric ulcer at four, eight, and 12 weeks was significantly higher with 15 mg or 30 mg of lansoprazole than placebo. A total of 537 patients were enrolled in the study, and 535 patients were treated. Patients ranged in age from 23 to 89 years (median age 60 years), with 65% female patients and 35% male patients. Race was distributed as follows: 90% Caucasian, 6% Black, 4% other. The 30 mg dose of lansoprazole demonstrated no additional benefit in risk reduction of the NSAID-associated gastric ulcer than the 15 mg dose ( Table 14) [see Indications and Usage (1.6)] .

Table 14. Proportion of Patients Remaining Free of Gastric Ulcers *
(p < 0.001) Lansoprazole 15 mg daily versus placebo; lansoprazole 30 mg daily versus placebo; and misoprostol 200 mcg four times daily versus placebo. (p < 0.05) Misoprostol 200 mcg four times daily versus lansoprazole 15 mg daily; and misoprostol 200 mcg four times daily versus lansoprazole 30 mg daily.
*
% = Life Table Estimate.

Week

Lansoprazole 15 mg daily (N = 121)

Lansoprazole 30 mg daily (N = 116)

Misoprostol 200 mcg four times daily (N = 106)

Placebo (N = 112)

4

90%

92%

96%

66%

8

86%

88%

95%

60%

12

80%

82%

93%

51%

Gastroesophageal Reflux Disease (GERD): Symptomatic GERD: In a U.S. multicenter, double-blind, placebo-controlled study of 214 patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, significantly greater relief of heartburn associated with GERD was observed with the administration of lansoprazole 15 mg once daily up to eight weeks than with placebo. No significant additional benefit from lansoprazole 30 mg once daily was observed.

The intent-to-treat analyses demonstrated significant reduction in frequency and severity of day and night heartburn. Data for frequency and severity for the eight week treatment period are presented in Table 15 and in Figures 1 and 2:

Table 15. Frequency of Heartburn
*
(p < 0.01) versus placebo.

Variable

Placebo (n = 43)

Lansoprazole 15 mg (n = 80)

Lansoprazole 30 mg (n = 86)

Median

% of Days without Heartburn

Week 1

0%

71% *

46% *

Week 4

11%

81% *

76% *

Week 8

13%

84% *

82% *

% of Nights without Heartburn

Week 1

17%

86% *

57% *

Week 4

25%

89% *

73% *

Week 8

36%

92% *

80% *

Figure 1
(click image for full-size original)

Figure 2
(click image for full-size original)

In two U.S., multicenter, double-blind, ranitidine-controlled studies of 925 total patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, lansoprazole 15 mg was superior to ranitidine 150 mg (twice daily) in decreasing the frequency and severity of day and night heartburn associated with GERD for the eight week treatment period. No significant additional benefit from lansoprazole 30 mg once daily was observed [see Indications and Usage (1.7)] .

Erosive Esophagitis: In a U.S. multicenter, double-blind, placebo-controlled study of 269 patients entering with an endoscopic diagnosis of esophagitis with mucosal grading of two or more and grades three and four signifying erosive disease, the percentages of patients with healing are presented in Table 16:

Table 16. Erosive Esophagitis Healing Rates
*
(p ≤ 0.001) versus placebo.
(p ≤ 0.05) versus lansoprazole 15 mg.

Lansoprazole

Placebo

Week

15 mg daily (N = 69)

30 mg daily (N = 65)

60 mg daily (N = 72)

(N = 63)

4

67.6% *

81.3% *

80.6% *

32.8%

6

87.7% *

95.4% *

94.3% *

52.5%

8

90.9% *

95.4% *

94.4%

52.5%

In this study, all lansoprazole groups reported significantly greater relief of heartburn and less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets taken per day than the placebo group. Although all doses were effective, the earlier healing in the higher two doses suggests 30 mg daily as the recommended dose.

Lansoprazole was also compared in a U.S. multicenter, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis. Lansoprazole at a dose of 30 mg was significantly more effective than ranitidine 150 mg twice daily as shown below ( Table 17).

Table 17. Erosive Esophagitis Healing Rates
*
(p ≤ 0.001) versus ranitidine.

Week

Lansoprazole 30 mg daily (N = 115)

Ranitidine 150 mg twice daily (N = 127)

2

66.7% *

38.7%

4

82.5% *

52.0%

6

93.0% *

67.8%

8

92.1% *

69.9%

In addition, patients treated with lansoprazole reported less day and nighttime heartburn and took less antacid tablets for fewer days than patients taking ranitidine 150 mg twice daily.

Although this study demonstrates effectiveness of lansoprazole in healing erosive esophagitis, it does not represent an adequate comparison with ranitidine because the recommended ranitidine dose for esophagitis is 150 mg four times daily, twice the dose used in this study.

In the two trials described and in several smaller studies involving patients with moderate to severe erosive esophagitis, lansoprazole produced healing rates similar to those shown above.

In a U.S. multicenter, double-blind, active-controlled study, 30 mg of lansoprazole was compared with ranitidine 150 mg twice daily in 151 patients with erosive reflux esophagitis that was poorly responsive to a minimum of 12 weeks of treatment with at least one H 2 -receptor antagonist given at the dose indicated for symptom relief or greater, namely, cimetidine 800 mg/day, ranitidine 300 mg/day, famotidine 40 mg/day or nizatidine 300 mg/day. Lansoprazole 30 mg was more effective than ranitidine 150 mg twice daily in healing reflux esophagitis, and the percentage of patients with healing were as follows. This study does not constitute a comparison of the effectiveness of histamine H 2 -receptor antagonists with lansoprazole, as all patients had demonstrated unresponsiveness to the histamine H 2 -receptor antagonist mode of treatment. It does indicate, however, that lansoprazole may be useful in patients failing on a histamine H 2 -receptor antagonist ( Table 18) [see Indications and Usage (1.7)] .

Table 18. Reflux Esophagitis Healing Rates in Patients Poorly Responsive to Histamine H 2 -Receptor Antagonist Therapy
*
(p ≤ 0.001) versus ranitidine.

Week

Lansoprazole 30 mg daily (N = 100)

Ranitidine 150 mg twice daily (N = 51)

4

74.7% *

42.6%

8

83.7% *

32.0%

Long-Term Maintenance Treatment of Erosive Esophagitis: Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed esophagitis. Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with lansoprazole than in patients treated with placebo over a 12 month period ( Table 19).

Table 19. Endoscopic Remission Rates
% = Life Table Estimate.
*
(p ≤ 0.001) versus placebo.

Trial

Drug

No. of Pts.

Percent in Endoscopic Remission

0 to 3 mo.

0 to 6 mo.

0 to 12 mo.

#1

Lansoprazole 15 mg daily

59

83% *

81% *

79% *

Lansoprazole 30 mg daily

56

93% *

93% *

90% *

Placebo

55

31%

27%

24%

#2

Lansoprazole 15 mg daily

50

74% *

72% *

67% *

Lansoprazole 30 mg daily

49

75% *

72% *

55% *

Placebo

47

16%

13%

13%

Regardless of initial grade of erosive esophagitis, lansoprazole 15 mg and 30 mg were similar in maintaining remission.

In a U.S., randomized, double-blind, study, lansoprazole 15 mg daily (n = 100) was compared with ranitidine 150 mg twice daily (n = 106), at the recommended dosage, in patients with endoscopically-proven healed erosive esophagitis over a 12 month period. Treatment with lansoprazole resulted in patients remaining healed (Grade 0 lesions) of erosive esophagitis for significantly longer periods of time than those treated with ranitidine (p < 0.001). In addition, lansoprazole was significantly more effective than ranitidine in providing complete relief of both daytime and nighttime heartburn. Patients treated with lansoprazole remained asymptomatic for a significantly longer period of time than patients treated with ranitidine [see Indications and Usage (1.8)] .

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome: In open studies of 57 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome (ZES) with or without multiple endocrine adenomas, lansoprazole significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia and pain. Doses ranging from 15 mg every other day to 180 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery and below 5 mEq/hr in patients with prior gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients [see Dosage and Administration (2.1)] . Lansoprazole was well tolerated at these high dose levels for prolonged periods (greater than four years in some patients). In most ZES patients, serum gastrin levels were not modified by lansoprazole. However, in some patients, serum gastrin increased to levels greater than those present prior to initiation of lansoprazole therapy [see Indications and Usage (1.9)] .

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