Lansoprazole: Package Insert and Label Information (Page 7 of 11)

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of greater than 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg three times daily/amoxicillin 1 g three times daily dual therapy and a total of 12.8% (22/172) of the patients failed the 10 and 14 day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.

Susceptibility Test for Helicobacter pylori

For susceptibility testing information about Helicobacter pylori , see Microbiology section in prescribing information for clarithromycin and amoxicillin.

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 to 150 mg/kg/day, about one to 40 times the exposure on a body surface (mg/m²) basis of a 50 kg person of average height [1.46 m² 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 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 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 and 600 mg/kg/day (40 to 80 times the recommended human dose based on BSA) and female mice treated with 150 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 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.

14 CLINICAL STUDIES

14.1 Duodenal Ulcer

In a U.S. multicenter, double-blind, placebo-controlled, dose-response (15, 30, 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 9).

Table 9. Duodenal Ulcer Healing Rates

* (p ≤ 0.001) vs 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 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 10) [see Indications and Usage (1.1)].

Table 10. Duodenal Ulcer Healing Rates

* (p ≤ 0.05) vs placebo and ranitidine. † (p ≤ 0.05) vs 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%

14.2 Eradication of H. pylori 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 g twice daily/clarithromycin 500 mg twice daily

Dual therapy: lansoprazole 30 mg three times daily/amoxicillin 1 g 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 11 and 12) [see Indications and Usage (1.2)].

Table 11. H. pylori Eradication Rates – Triple Therapy

* 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) vs lansoprazole/amoxicillin and lansoprazole/clarithromycin dual therapy. § (p < 0.05) vs 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.
(Lansoprazole/Amoxicillin/Clarithromycin)Percent of Patients Cured[95% Confidence Interval](Number of Patients)
Study	Duration	Triple Therapy Evaluable Analysis *	Triple Therapy Intent-to-Treat Analysis †
M93-131	14 days	92‡ [80.0-97.7] (N = 48)	86‡ [73.3-93.5] (N = 55)
M95-392	14 days	86§ [75.7-93.6] (N = 66)	83§ [72.0-90.8] (N = 70)
M95-399¶	14 days	85 [77.0-91.0] (N = 113)	82 [73.9-88.1] (N = 126)
	10 days	84 [76.0-89.8] (N = 123)	81 [73.9-87.6] (N = 135)

Table 12. H. pylori Eradication Rates – 14 Day Dual Therapy

* 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) vs lansoprazole alone. § (p < 0.05) vs lansoprazole alone or amoxicillin alone.
(Lansoprazole/Amoxicillin)Percent of Patients Cured[95% Confidence Interval](Number of Patients)
Study	Dual Therapy Evaluable Analysis *	Dual Therapy Intent-to-Treat Analysis †
M93-131	77‡ [62.5-87.2] (N = 51)	70‡ [56.8-81.2] (N = 60)
M93-125	66§ [51.9-77.5] (N = 58)	61§ [48.5-72.9] (N = 67)