Rabeprazole Sodium (Page 7 of 10)

12.5 Pharmacogenomics

In a clinical study in evaluating rabeprazole sodium delayed-release tablets in Japanese adult patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher rabeprazole plasma levels in poor metabolizers. The clinical relevance of this is not known. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In an 88/104-week carcinogenicity study in CD-1 mice, rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased tumor occurrence. The highest tested dose produced a systemic exposure to rabeprazole (AUC) of 1.40 µg•hr/mL which is 1.6 times the human exposure (plasma AUC0-∞ = 0.88 µg•hr/mL) at the recommended dose for GERD (20 mg/day). In a 28-week carcinogenicity study in p53+/- transgenic mice, rabeprazole at oral doses of 20 mg/kg/day, 60 mg/kg/day, and 200 mg/kg/day did not cause an increase in the incidence rates of tumors but produced gastric mucosal hyperplasia at all doses. The systemic exposure to rabeprazole at 200 mg/kg/day is about 17 to 24 times the human exposure at the recommended dose for GERD. In a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated with oral doses of 5 mg/kg/day, 15 mg/kg/day, 30 mg/kg/day and 60 mg/kg/day and females with 5 mg/kg/day, 15 mg/kg/day, 30 mg/kg/day, 60 mg/kg/day, and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumors in female rats at all doses including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1 µg•hr/mL which is about 0.1 times the human exposure at the recommended dose for GERD. In male rats, no treatment related tumors were observed at doses up to 60 mg/kg/day producing a rabeprazole plasma exposure (AUC) of about 0.2 µg•hr/mL (0.2 times the human exposure at the recommended dose for GERD).

Rabeprazole was positive in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward gene mutation test, and the mouse lymphoma cell (L5178Y/TK+/–) forward gene mutation test. Its demethylated-metabolite was also positive in the Ames test. Rabeprazole was negative in the in vitro Chinese hamster lung cell chromosome aberration test, the in vivo mouse micronucleus test, and the in vivo and ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) tests.

Rabeprazole at intravenous doses up to 30 mg/kg/day (plasma AUC of 8.8 µg•hr/mL, about 10 times the human exposure at the recommended dose for GERD) was found to have no effect on fertility and reproductive performance of male and female rats.

14 CLINICAL STUDIES

14.1 Healing of Erosive or Ulcerative GERD in Adults

In a U.S., multicenter, randomized, double-blind, placebo-controlled study, 103 patients were treated for up to eight weeks with placebo, 10 mg, 20 mg, or 40 mg rabeprazole sodium delayed-release tablets once daily. For this and all studies of GERD healing, only patients with GERD symptoms and at least grade 2 esophagitis (modified Hetzel-Dent grading scale) were eligible for entry. Endoscopic healing was defined as grade 0 or 1. Each rabeprazole dose was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment.

The percentage of patients demonstrating endoscopic healing was as follows:

Table 7: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed

Week

Rabeprazole sodium delayed-release tablets

Placebo

N=25

10 mg once daily

N=27

20 mg once daily

N=25

40 mg once daily

N=26

4

63%*

56%*

54%*

0%

8

93%*

84%*

85%*

12%

* (p < 0.001 versus placebo)

In addition, there was a statistically significant difference in favor of the rabeprazole sodium 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p ≤ 0.026). All rabeprazole sodium groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p ≤ 0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all rabeprazole sodium groups when compared to placebo at both Weeks 4 and 8 (p ≤ 0.007).

In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, the percentage of patients healed at endoscopy after four and eight weeks of treatment was statistically superior in the patients treated with rabeprazole sodium delayed-release tablets compared to ranitidine:

Table 8: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed

Week

20 mg rabeprazole sodium delayed-

release tablets once daily

N=167

Ranitidine 150 mg

four times daily

N=169

4

59%*

36%

8

87%*

66%

* (p < 0.001 versus ranitidine)

A dose of 20 mg once daily of rabeprazole sodium delayed-release tablets was significantly more effective than ranitidine 150 mg four times daily in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p < 0.001). Rabeprazole sodium was also more effective in complete resolution of daytime heartburn (p ≤ 0.025), and nighttime heartburn (p ≤ 0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study.

The recommended dosage of rabeprazole sodium delayed-release tablets is 20 mg once daily for 4 to 8 weeks.

14.2 Long-Term Maintenance of Healing of Erosive or Ulcerative GERD in Adults

The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric antisecretory therapy was assessed in two U.S., multicenter, randomized, double-blind, placebo-controlled studies of identical design of 52 weeks duration. The two studies randomized 209 and 285 patients, respectively, to receive either 10 mg or 20 mg of rabeprazole sodium delayed-release tablets once daily or placebo. As demonstrated in Tables 10 and 11 below, patients treated with rabeprazole sodium delayed-release tablets were significantly superior to placebo in both studies with respect to the maintenance of healing of GERD and the proportions of patients remaining free of heartburn symptoms at 52 weeks. The recommended dosage of rabeprazole sodium delayed-release tablets is 20 mg once daily.

Table 9: Percent of Patients in Endoscopic Remission

Rabeprazole sodium delayed-release tablets

Placebo

10 mg once

daily

20 mg once

daily

Study 1

N=66

N=67

N=70

Week 4

83%*

96%*

44%

Week 13

79%*

93%*

39%

Week 26

77%*

93%*

31%

Week 39

76%*

91%*

30%

Week 52

73%*

90%*

29%

Study 2

N=93

N=93

N=99

Week 4

89%*

94%*

40%

Week 13

86%*

91%*

33%

Week 26

85%*

89%*

30%

Week 39

84%*

88%*

29%

Week 52

77%*

86%*

29%

COMBINED

STUDIES

N=159

N=160

N=169

Week 4

87%*

94%*

42%

Week 13

83%*

92%*

36%

Week 26

82%*

91%*

31%

Week 39

81%*

89%*

30%

Week 52

75%*

87%*

29%

* (p < 0.001 versus placebo)

Table 10: Percent of Patients Without Relapse in Heartburn Frequency and Daytime and Nighttime Heartburn Severity at Week 52

Rabeprazole sodium delayed-release tablets

Placebo

10 mg once daily

20 mg once daily

Heartburn Frequency

Study 1

46/55 (84%)*

48/52 (92%)*

17/45 (38%)

Study 2

50/72 (69%)*

57/72 (79%)*

22/79 (28%)

Daytime Heartburn

Severity

Study 1

61/64 (95%)*

60/62 (97%)*

42/61 (69%)

Study 2

73/84 (87%)

82/87 (94%)*

67/90 (74%)

Nighttime Heartburn

Severity

Study 1

57/61 (93%)*

60/61 (98%)*

37/56 (66%)

Study 2

67/80 (84%)

79/87 (91%)

64/87 (74%)

* p ≤ 0.001 versus placebo

0.001 < p < 0.05 versus placebo

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