Esomeprazole Strontium (Page 7 of 10)

13.2 Animal Toxicology and/or Pharmacology

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole strontium or esomeprazole magnesium at equimolar oral doses of 70 to 280 mg esomeprazole/kg/day (about 17 to 57 times the daily MRHD of 40 mg on a body surface area basis). When administered as either the strontium or magnesium salt from postnatal day 7 through postnatal day 35, the dose of 280 mg esomeprazole/kg/day produced an increase in the number of deaths. In addition, when administered as either the strontium or magnesium salt, doses equal to or greater than 140 mg esomeprazole/kg/day (about 34 times the daily MRHD of 40 mg on a body surface area basis) produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth.

14 CLINICAL STUDIES

The safety and efficacy of esomeprazole strontium has been established based on adequate and well-controlled adult studies of esomeprazole magnesium in the healing and maintenance of erosive esophagitis, symptomatic GERD, risk reduction of NSAID-associated gastric ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence, and pathological hypersecretory conditions including Zollinger-Ellison Syndrome. Below is a display of the results of the adequate and well-controlled studies of esomeprazole magnesium in these conditions.

14.1 Healing of Erosive Esophagitis

The healing rates of 44.6 mg of esomeprazole magnesium (equivalent to 40 mg of esomeprazole), 22.3 mg of esomeprazole magnesium (equivalent to 20 mg of esomeprazole), and 20 mg of omeprazole (the approved dose for this indication) were evaluated in patients with endoscopically diagnosed erosive esophagitis in four multicenter, double-blind, randomized studies. The healing rates at Weeks 4 and 8 were evaluated and are shown in Table 6:

Table 6: Erosive Esophagitis Healing Rate (Life-Table Analysis)

Study

No. of Patients

Treatment Groups

Week 4

Week 8

Significance Level*

1

588

Esomeprazole magnesium 22.3 mg

68.7%

90.6%

N.S.

588

Omeprazole 20 mg

69.5%

88.3%

2

654

Esomeprazole magnesium 44.6 mg

75.9%

94.1%

p < 0.001

656

Esomeprazole magnesium 22.3 mg

70.5%

89.9%

p < 0.05

650

Omeprazole 20 mg

64.7%

86.9%

3

576

Esomeprazole magnesium 44.6 mg

71.5%

92.2%

N.S.

572

Omeprazole 20 mg

68.6%

89.8%

4

1216

Esomeprazole magnesium 44.6 mg

81.7%

93.7%

p < 0.001

1209

Omeprazole 20 mg

68.7%

84.2%

* log-rank test vs. omeprazole 20 mg

N.S. = not significant (p >0.05)

In these same studies of patients with erosive esophagitis, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in Table 7:

Table 7: Sustained Resolution of Heartburn (Erosive Esophagitis Patients)

Cumulative Percent# with Sustained Resolution

Study

No. of Patients

Treatment Groups

Day 14

Day 28

Significance Level*

1

573

Esomeprazole magnesium 22.3 mg

64.3%

72.7%

N.S.

555

Omeprazole 20 mg

64.1%

70.9%

2

621

Esomeprazole magnesium 44.6 mg

64.8%

74.2%

p <0.001

620

Esomeprazole magnesium 22.3 mg

62.9%

70.1%

N.S.

626

Omeprazole 20 mg

56.5%

66.6%

3

568

Esomeprazole magnesium 44.6 mg

65.4%

73.9%

N.S.

551

Omeprazole 20 mg

65.5%

73.1%

4

1187

Esomeprazole magnesium 44.6 mg

67.6%

75.1%

p <0.001

1188

Omeprazole 20 mg

62.5%

70.8%

Defined as 7 consecutive days with no heartburn reported in daily patient diary.

# Defined as the cumulative proportion of patients who have reached the start of sustained resolution

* log-rank test vs omeprazole 20 mg

N.S. = not significant (p > 0.05)

In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive days with no heartburn) was 5 days for esomeprazole magnesium 44.6 mg, 7 to 8 days for esomeprazole magnesium 22.3 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 44.6 mg of esomeprazole magnesium with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of erosive esophagitis.

Long-Term Maintenance of Healing of Erosive Esophagitis

Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients with endoscopically confirmed, healed erosive esophagitis to evaluate esomeprazole magnesium 44.6 mg (n=174), 22.3 mg (n=180), 11.15 mg (n=168) or placebo (n=171) once daily over six months of treatment.

No additional clinical benefit was seen with esomeprazole magnesium 44.6 mg over esomeprazole magnesium 22.3 mg.

The percentages of patients that maintained healing of erosive esophagitis at the various time points are shown in the Figures 2 and 3:

Figure 2: Maintenance of Healing Rates by Month (Study 177) — Esomeprazole Magnesium

figure2
(click image for full-size original)

s = scheduled visit

Figure 3: Maintenance of Healing Rates by Month (Study 178) — Esomeprazole Magnesium

figure3
(click image for full-size original)

s= scheduled visit

Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with esomeprazole magnesium compared to placebo.

In both studies, the proportion of patients on esomeprazole magnesium who remained in remission and were free of heartburn and other GERD symptoms was well differentiated from placebo.

In a third multicenter open label study of 808 patients treated for 12 months with esomeprazole magnesium 44.6 mg, the percentage of patients that maintained healing of erosive esophagitis was 93.7% for six months and 89.4% for one year.

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