NEXIUM (Page 9 of 11)

13.2 Animal Toxicology and/or Pharmacology

Reproduction Studies

Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole [see Use in Specific Populations (8.1)].

Juvenile Animal Study

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg /kg/day (about 17 to 68 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose 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. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

14 CLINICAL STUDIES

14.1 Healing of Erosive Esophagitis

The healing rates of NEXIUM 40 mg, NEXIUM 20 mg, and omeprazole 20 mg (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 the Table 9:

Table 9: Erosive Esophagitis Healing Rate (Life-Table Analysis)
*
log-rank test vs. omeprazole 20 mg.

Study

No. of Patients

Treatment Groups

Week 4

Week 8

Significance Level *

1

588

NEXIUM 20 mg

68.7%

90.6%

N.S.

588

Omeprazole 20 mg

69.5%

88.3%

2

654

NEXIUM 40 mg

75.9%

94.1%

p < 0.001

656

NEXIUM 20 mg

70.5%

89.9%

p < 0.05

650

Omeprazole 20 mg

64.7%

86.9%

3

576

NEXIUM 40 mg

71.5%

92.2%

N.S.

572

Omeprazole 20 mg

68.6%

89.8%

4

1216

NEXIUM 40 mg

81.7%

93.7%

p < 0.001

1209

Omeprazole 20 mg

68.7%

84.2%

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 the Table 10:

Table 10: Sustained Resolution * of Heartburn (Erosive Esophagitis Patients)
*
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.

Cumulative Percent with Sustained Resolution

Study

No. of Patients

Treatment Groups

Day 14

Day 28

Significance Level

1

573

NEXIUM 20 mg

64.3%

72.7%

N.S.

555

Omeprazole 20 mg

64.1%

70.9%

2

621

NEXIUM 40 mg

64.8%

74.2%

p <0.001

620

NEXIUM 20 mg

62.9%

70.1%

N.S.

626

Omeprazole 20 mg

56.5%

66.6%

3

568

NEXIUM 40 mg

65.4%

73.9%

N.S.

551

Omeprazole 20 mg

65.5%

73.1%

4

1187

NEXIUM 40 mg

67.6%

75.1%

p <0.001

1188

Omeprazole 20 mg

62.5%

70.8%

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 NEXIUM 40 mg, 7 to 8 days for NEXIUM 20 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 40 mg of NEXIUM 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 NEXIUM 40 mg (n=174), 20 mg (n=180), 10 mg (n=168) or placebo (n=171) once daily over six months of treatment.

No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 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)

Figure 2 Maintenance of Healing Rates by Month (Study 117)
(click image for full-size original)

s= scheduled visit

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

Figure 3 Maintenance of Healing Rates by Month (Study 178)
(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 NEXIUM compared to placebo.

In both studies, the proportion of patients on NEXIUM 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 NEXIUM 40 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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