Esomeprazole Magnesium (Page 9 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 esomeprazole magnesium delayed-release capsules 40 mg, esomeprazole magnesium 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 Esomeprazole Magnesium Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies

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

1 log-rank test vs. omeprazole 20 mg

Study No. of Patients Treatment Groups EE Healing Rates Significance Level 1
Week 4 Week 8
1 588 Esomeprazole magnesium 20 mg 68.7% 90.6% N.S.
588 Omeprazole 20 mg 69.5% 88.3%
2 654 Esomeprazole magnesium 40 mg 75.9% 94.1% p < 0.001
656 Esomeprazole magnesium 20 mg 70.5% 89.9% p < 0.05
650 Omeprazole 20 mg 64.7% 86.9%
3 576 Esomeprazole magnesium 40 mg 71.5% 92.2% N.S.
572 Omeprazole 20 mg 68.6% 89.8%
4 1216 Esomeprazole magnesium 40 mg 81.7% 93.7% p < 0.001
1209 Omeprazole 20 mg 68.7% 84.2%

In these same studies of patients with EE, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in the Table 12:

Table 12: Sustained Resolution1 of Heartburn in Adults with EE Treated with Esomeprazole Magnesium Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies

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

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

3. log-rank test vs. omeprazole 20 mg.

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

Cumulative Percent 2 with Sustained Resolution
Study No. of Patients Treatment Groups Day 14 Day 28 Significance Level 3
1 573 Esomeprazole magnesium 20 mg 64.3% 72.7% N.S.
555 Omeprazole 20 mg 64.1% 70.9%
2 621 Esomeprazole magnesium 40 mg 64.8% 74.2% p < 0.001
620 Esomeprazole magnesium 20 mg 62.9% 70.1% N.S.
626 Omeprazole 20 mg 56.5% 66.6%
3 568 Esomeprazole magnesium 40 mg 65.4% 73.9% N.S.
551 Omeprazole 20 mg 65.5% 73.1%
4 1187 Esomeprazole magnesium 40 mg 67.6% 75.1% p < 0.001
1188 Omeprazole 20 mg 62.5% 70.8%

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

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

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