PRILOSEC (Page 9 of 13)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.4 to 34 times a human dose of 40 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times a human dose of 40 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.9 times the human dose of 40 mg/day, based on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay.

Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times an oral human dose of 40 mg on a body surface area basis) was found to have no effect on fertility and reproductive performance.

In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [see Warnings and Precautions (5)]. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2 -receptor antagonists.

14 CLINICAL STUDIES

14.1 Active Duodenal Ulcer

In a multicenter, double-blind, placebo-controlled study of 147 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 2 and 4 weeks was significantly higher with PRILOSEC 20 mg once daily than with placebo (p ≤ 0.01).

Treatment of Active Duodenal Ulcer % of Patients Healed
*
(p≤0.01)

PRILOSEC

20 mg a.m.

(n=99)

Placebo

a.m.

(n=48)

Week 2

41*

13

Week 4

75*

27

Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with PRILOSEC 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received PRILOSEC had complete relief of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).

In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with PRILOSEC 20 mg once daily than with ranitidine 150 mg b.i.d. (p < 0.01).

Treatment of Active Duodenal Ulcer % of Patients Healed
*
(p < 0.01)

PRILOSEC

20 mg a.m.

(n = 145)

Ranitidine

150 mg twice daily

(n = 148)

Week 2

42

34

Week 4

82*

63

Healing occurred significantly faster in patients treated with PRILOSEC than in those treated with ranitidine 150 mg b.i.d. (p < 0.01).

In a foreign multinational randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 20 mg and 40 mg of PRILOSEC were compared with 150 mg b.i.d. of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of PRILOSEC were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of PRILOSEC, and at 8 weeks there was no significant difference between any of the active drugs.

Treatment of Active Duodenal Ulcer % of Patients Healed
*
(p ≤ 0.01)

PRILOSEC

Ranitidine

20 mg

(n = 34)

40 mg

(n = 36)

150 mg twice daily

(n = 35)

Week 2

83*

83*

53

Week 4

97*

100*

82

Week 8

100

100

94

14.2 H. pylori Eradication in Patients with Duodenal Ulcer Disease

Triple Therapy (PRILOSEC/clarithromycin/amoxicillin)

Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared PRILOSEC plus clarithromycin plus amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were conducted in patients with an active duodenal ulcer, and the other study (3) was conducted in patients with a history of a duodenal ulcer in the past 5 years but without an ulcer present at the time of enrollment. The dose regimen in the studies was PRILOSEC 20 mg twice daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days. In studies 1 and 2, patients who took the omeprazole regimen also received an additional 18 days of PRILOSEC 20 mg once daily. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 1 and 2 only). H. pylori status was determined by CLOtest®, histology and culture in all three studies. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive.

The combination of omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H. pylori.

Table 9: Per-Protocol and Intent-to-Treat H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval]
PRILOSEC +clarithromycin +amoxicillin Clarithromycin +amoxicillin
Per-Protocol * Intent-to-Treat Per-Protocol * Intent-to-Treat
*
Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer within 5 years, study 3) 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. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.
Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.
(p < 0.05) versus clarithromycin plus amoxicillin.

Study 1

77 [64, 86]

(n = 64)

69 [57, 79]

(n = 80)

43 [31, 56]

(n = 67)

37 [27, 48]

(n = 84)

Study 2

78 [67, 88]

(n = 65)

73 [61, 82]

(n = 77)

41 [29, 54]

(n = 68)

36 [26, 47]

(n = 83)

Study 3

90 [80, 96]

(n = 69)

83 [74, 91]

(n = 84)

33 [24, 44]

(n = 93)

32 [23, 42]

(n = 99)

Dual Therapy (PRILOSEC/clarithromycin)

Four randomized, double-blind, multi-center studies (4, 5, 6, and 7) evaluated PRILOSEC 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days, followed by PRILOSEC 20 mg once daily, (Studies 4, 5, and 7) or by PRILOSEC 40 mg once daily (Study 6) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies 4 and 5 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study 4 and 228 patients in Study 5. These studies compared the combination regimen to PRILOSEC and clarithromycin monotherapies. Studies 6 and 7 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in Study 6 and 208 patients in Study 7. These studies compared the combination regimen with omeprazole monotherapy. The results for the efficacy analyses for these studies are described below. H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated of H. pylori. In the per-protocol analysis, the following patients were excluded: dropouts, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication because they were found to have an ulcer at the end of treatment.

The combination of omeprazole and clarithromycin was effective in eradicating H. pylori.

Table 10: H. pylori Eradication Rates (Per-Protocol Analysis at 4 to 6 Weeks) % of Patients Cured [95% Confidence Interval]
PRILOSEC + Clarithromycin PRILOSEC Clarithromycin
*
Statistically significantly higher than clarithromycin monotherapy (p < 0.05).
Statistically significantly higher than omeprazole monotherapy (p < 0.05).

U.S. Studies

Study 4

74 [60, 85]*

(n = 53)

0 [0, 7]

(n = 54)

31 [18, 47]

(n = 42)

Study 5

64 [51, 76]*

(n = 61)

0 [0, 6]

(n = 59)

39 [24, 55]

(n = 44)

Non U.S. Studies

Study 6

83 [71, 92]

(n = 60)

1 [0, 7]

(n = 74)

N/A

Study 7

74 [64, 83]

(n = 86)

1 [0, 6]

(n = 90)

N/A

Ulcer healing was not significantly different when clarithromycin was added to omeprazole therapy compared with omeprazole therapy alone.

The combination of omeprazole and clarithromycin was effective in eradicating H. pylori and reduced duodenal ulcer recurrence.

Table 11: Duodenal Ulcer Recurrence Rates by H. pylori Eradication Status % of Patients with Ulcer Recurrence
*
H. pylori eradication status assessed at same time point as ulcer recurrence.
Combined results for PRILOSEC + clarithromycin, PRILOSEC, and clarithromycin treatment arms.
(p ≤ 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori eradicated.
§
Combined results for PRILOSEC + clarithromycin and PRILOSEC treatment arms.

H. pylori eradicated *

H. pylori not eradicated *

U.S. Studies

6 months post-treatment

Study 4

35

(n=49)

60

(n=88)

Study 5

8

(n=53)

60

(n=106)

Non U.S. Studies §

6 months post-treatment

Study 6

5

(n=43)

46

(n=78)

Study 7

6

(n=53)

43

(n=107)

12 months post-treatment

Study 6

5

(n=39)

68

(n=71)

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