Lansoprazole (Page 7 of 9)

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 1 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 (4 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, 2 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.

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, 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 7).

Table 7: Duodenal Ulcer Healing Rates

* (p ≤ 0.001) versus placebo.
Week	Lansoprazole
	15 mg daily	30 mg daily	60 mg daily	Placebo
	(N = 68)	(N = 74)	(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 4 weeks, the lack of significant difference at 2 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.
Week	Lansoprazole		Ranitidine
	15 mg daily	30 mg daily	300 mg h.s.	Placebo
	(N = 80)	(N = 77)	(N = 82)	(N = 41)
2	35%	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 capsules and clarithromycin tablets as triple 14 day therapy or in combination with amoxicillin capsules 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 4 to 6 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

* 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.
(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‡	86‡
		[80 to 97.7]	[73.3 to 93.5]
		(N = 48)	(N = 55)
M95-392	14 days	86§	83§
		[75.7 to 93.6]	[72 to 90.8]
		(N = 66)	(N = 70)
M95-399¶	14 days	85	82
		[77 to 91]	[73.9 to 88.1]
		(N = 113)	(N = 126)
	10 days	84	81
		[76 to 89.8]	[73.9 to 87.6]
		(N = 123)	(N = 135)

Table 10: 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) versus lansoprazole alone. § (p < 0.05) versus 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‡	70‡
	[62.5 to 87.2]	[56.8 to 81.2]
	(N = 51)	(N = 60)
M93-125	66§	61§
	[51.9 to 77.5]	[48.5 to 72.9]
	(N = 58)	(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

* (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%

% = Life Table Estimate

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
	15 mg daily	30 mg daily	60 mg daily	Placebo
Week	(N = 65)	(N = 63)	(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 8 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 4, 8, and 12 weeks was significantly higher with 15 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 *

* % = Life Table Estimate
Week	Lansoprazole 15 mg daily	Lansoprazole 30 mg daily	Misoprostol 200 mcg four times daily	Placebo
	(N = 121)	(N = 116)	(N = 106)	(N = 112)
4	90%	92%	96%	66%
8	86%	88%	95%	60%
12	80%	82%	93%	51%

(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.

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 8 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 8 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		Lansoprazole	Lansoprazole
	Placebo	15 mg	30 mg
	(n = 43)	(n = 80)	(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: Mean Severity of Day Heartburn by Study Day for Evaluable Patients (3 = Severe, 2 = Moderate, 1 = Mild, 0 = None)

Figure 1: Mean Severity of Day Heartburn by Study Day for Evaluable Patients (3 = Severe, 2 = Moderate, 1 = Mild, 0 = None)

Figure 2: Mean Severity of Night Heartburn by Study Day for Evaluable Patients (3 = Severe, 2 = Moderate, 1 = Mild, 0 = None)

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 8 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 2 or more and grades 3 and 4 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.
Week	Lansoprazole
	15 mg daily	30 mg daily	60 mg daily	Placebo
	(N = 69)	(N = 65)	(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.
	Lansoprazole	Ranitidine
	30 mg daily	150 mg twice daily
Week	(N = 115)	(N = 127)
2	66.7%*	38.7%
4	82.5%*	52%
6	93%*	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 H₂ -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 H₂ -receptor antagonists with lansoprazole, as all patients had demonstrated unresponsiveness to the histamine H₂ -receptor antagonist mode of treatment. It does indicate, however, that lansoprazole may be useful in patients failing on a histamine H₂ -receptor antagonist (Table 18) [see Indications and Usage (1.7) ].

Table 18: Reflux Esophagitis Healing Rates in Patients Poorly Responsive to Histamine H₂ -Receptor Antagonist Therapy

* (p ≤ 0.001) versus ranitidine.
	Lansoprazole	Ranitidine
	30 mg daily	150 mg twice daily
Week	(N = 100)	(N = 51)
4	74.7%*	42.6%
8	83.7%*	32%

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

* (p ≤ 0.001) versus placebo.
			Percent in Endoscopic Remission
Trial	Drug	No. of Pts.	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%

% = Life Table Estimate

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) ].