Rabeprazole Sodium DR (Page 5 of 7)

13. Non Clinical 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, 60, 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, 15, 30 and 60 mg/kg/day and females with 5, 15, 30, 60, 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

WeekRabeprazole sodium delayed-release tabletsPlacebo N=25
10 mg once daily N=27 20 mg once daily N=25 40 mg once daily N=26
463%*56%*54%*0%
893%*84%*85%*12%

* (p<0.001 versus placebo)

In addition, there was a statistically significant difference in favor of the rabeprazole sodium delayed-release tablets 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 delayed-release tablets 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 delayed-release tablets 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

Week20 mg Rabeprazole sodium delayed-release tablets once daily N=167 Ranitidine 150 mg four times daily N=169
459%*36%
887%*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 delayed-release tablets 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 tabletsPlacebo
10 mg once daily20 mg once daily
Study 1N=66N=67N=70
Week 483%*96%*44%
Week 1379%*93%*39%
Week 2677%*93%*31%
Week 3976%*91%*30%
Week 5273%*90%*29%
Study 2N=93N=93N=99
Week 489%*94%*40%
Week 1386%*91%*33%
Week 2685%*89%*30%
Week 3984%*88%*29%
Week 5277%*86%*29%
COMBINED STUDIESN=159N=160N=169
Week 487%*94%*42%
Week 1383%*92%*36%
Week 2682%*91%*31%
Week 3981%*89%*30%
Week 5275%*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 daily20 mg once daily
Heartburn Frequency
Study 146/55 (84%)*48/52 (92%)*17/45 (38%)
Study 250/72 (69%)*57/72 (79%)*22/79 (28%)
Daytime Heartburn Severity
Study 161/64 (95%)*60/62 (97%)*42/61 (69%)
Study 273/84 (87%) †82/87 (94%)*67/90 (74%)
Nighttime Heartburn Severity
Study 157/61 (93%)*60/61 (98%)*37/56 (66%)
Study 267/80 (84%)79/87 (91%) †64/87 (74%)

*p≤0.001 versus placebo

† 0.001<p<0.05 versus placebo

14.3 Treatment of Symptomatic GERD in Adults

Two U.S. multicenter, double-blind, placebo-controlled studies were conducted in 316 adult patients with daytime and nighttime heartburn. Patients reported 5 or more periods of moderate to very severe heartburn during the placebo treatment phase the week prior to randomization. Patients were confirmed by endoscopy to have no esophageal erosions.

The percentage of heartburn free daytime and/or nighttime periods was greater with 20 mg rabeprazole sodium delayed-release tablets compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. 28%). The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for rabeprazole sodium delayed-release tablets 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 2 to 5.

Figure 2: Mean Daytime Heartburn Scores RAB-USA-2 Figure 3: Mean Night time Heartburn Scores RAB-USA-2

Fig. 2
(click image for full-size original)

Figure 4: Mean Daytime Heartburn Scores RAB-USA-3

Fig. 4
(click image for full-size original)

Figure 5: Mean Night-time Heartburn Scores RAB-USA-3

Fig. 5
(click image for full-size original)

In addition, the combined analysis of these two studies showed 20 mg of rabeprazole sodium delayed-release tablets significantly improved other GERD-associated symptoms (regurgitation, belching and early satiety) by week 4 compared with placebo (all p values < 0.005).

A dose of 20 mg rabeprazole sodium delayed-release tablets also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).

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

14.4 Healing of Duodenal Ulcers in Adults

In a U.S. randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of rabeprazole sodium delayed-release tablets once daily versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabeprazole sodium delayed-release tablets was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below:

Table 11: Healing of Duodenal Ulcers Percentage of Patients Healed

WeekRabeprazole sodium delayed-release tabletsPlacebo N=33
20 mg once daily N=34 40 mg once daily N=33
244%42%21%
479%*91%*39%

* p≤0.001 versus placebo

At Weeks 2 and 4, significantly more patients in the rabeprazole sodium delayed-release tablets 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p≤0.018), daytime pain severity (p≤0.023), and nighttime pain severity (p≤0.035) compared with placebo patients. The only exception was the 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0.094). Significant differences in resolution of daytime and nighttime pain were noted in both rabeprazole sodium delayed-release tablets groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both rabeprazole sodium delayed-release tablets groups compared to placebo at Weeks 2 and 4 (p<0.001).

An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg rabeprazole sodium delayed-release tablets once daily with 20 mg omeprazole once daily. The study was designed to provide at least 80% power to exclude a difference of at least 10% between rabeprazole sodium delayed-release tablets and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, rabeprazole sodium delayed-release tablets was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:

Table 12: Healing of Duodenal Ulcers Percentage of Patients Healed

WeekRabeprazole sodium delayed-release tablets 20 mg once daily N=102 Omeprazole 20 mg once daily N=103 95% Confidence Interval for the Treatment Difference (Rabeprazole sodium delayed-release tablets — Omeprazole)
269%61%(–6%, 22%)
498%93%(–3%, 15%)

Rabeprazole sodium delayed-release tablets and omeprazole were comparable in providing complete resolution of symptoms.

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

14.5 Helicobacter pylori Eradication in Patients with Peptic Ulcer Disease or Symptomatic Non-Ulcer Disease in Adults

The U.S. multicenter study was a double-blind, parallel-group comparison of rabeprazole sodium delayed-release tablets, amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin, and clarithromycin for 10 days. Therapy consisted of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1:1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) [PUD] and those who were symptomatic but without peptic ulcer disease [NPUD], as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative 13C-UBT for H. pylori ≥6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7-day and 10-day RAC regimens were found to be similar to 10-day OAC regimen using either the Intent-to-Treat (ITT) or Per-Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens.

Table 13: Helicobacter Pylori Eradication at ≥6 Weeks After the End of Treatment

Treatment Group Percent (%) of Patients Cured (Number of Patients)Difference (RAC – OAC) [95% Confidence Interval]
7-day RAC*10-day OAC
Per Protocola84.3% (N=166)81.6% (N=179)2.8 [-5.2, 10.7]
Intent-to-Treatb77.3% (N=194)73.3% (N=206)4.0 [-4.4,12.5]
10-day RAC*10-day OAC
Per Protocola86.0% (N=171)81.6% (N=179)4.4 [-3.3, 12.1]
Intent-to-Treatb78.1% (N=196) 73.3% (N=206) 4.8 [-3.6, 13.2]
3-day RAC10-day OAC
Per Protocola29.9% (N=167)81.6% (N=179)-51.6 [-60.6, -42.6]
Intent-to-Treatb27.3% (N=187) 73.3% (N=206) -46.0 [-54.8, -37.2]

a Patients were included in the analysis if they had H. pylori infection documented at baseline, defined as a positive 13C-UBT plus rapid urease test or culture, and were not protocol violators. Patients who dropped out of the study due to an adverse event related to the study drug were included in the evaluable analysis as failures of therapy.
bPatients were included in the analysis if they had documented H. pylori infection at baseline as defined above and took at least one dose of study medication. All dropouts were included as failures of therapy.

*The 95% confidence intervals for the difference in eradication rates for 7-day RAC minus 10-day RAC are (-9.3, 6.0) in the PP population and (-9.0, 7.5) in the ITT population.

The recommended dosage of rabeprazole sodium delayed-release tablets is 20 mg twice daily with amoxicillin and clarithromycin for 7 days.

14.6 Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults

Twelve patients with idiopathic gastric hypersecretion or Zollinger-Ellison syndrome have been treated successfully with rabeprazole sodium delayed-release tablets at doses from 20 to 120 mg for up to 12 months. Rabeprazole sodium delayed-release tablets produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. Rabeprazole sodium delayed-release tablets also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of rabeprazole sodium delayed-release tablets used to treat this small cohort of patients with gastric hypersecretion were well tolerated.
The recommended starting dosage of rabeprazole sodium delayed-release tablets is 60 mg once daily.

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