NEXIUM (Page 10 of 12)

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 EE in Adults

The healing rates of NEXIUM delayed-release capsules 40 mg, NEXIUM delayed-release capsules 20 mg, and omeprazole delayed-release capsules 20 mg (the approved dose for this indication) once daily were evaluated in adult patients with endoscopically diagnosed EE in four multicenter, double-blind, randomized studies. The healing rates at Weeks 4 and 8 were evaluated and are shown in Table 11:

Table 11: EE Healing Rate (Life-Table Analysis) in Adults with EE Treated with NEXIUM Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies
*
log-rank test vs. omeprazole 20 mg.

Study

No. of Patients

Treatment Group

EE Healing Rates

Significance Level *

Week 4

Week 8

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 EE, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in Table 12:

Table 12: Sustained Resolution * of Heartburn in Adults with EE Treated with NEXIUM Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies
*
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 Group

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 EE.

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