Omeprazole/Bicarbonate (Page 7 of 10)

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproduction studies conducted in pregnant rats with omeprazole at doses up to 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis) and in pregnant rabbits at doses up to 69 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole.

In rabbits, omeprazole in a dose range of 6.9 to 69 mg/kg/day (about 3.3 to 33.6 times the human dose of 40 mg/day on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.3 to 33.6 times the human dose of 40 mg/day on a body surface area basis).

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 Duodenal Ulcer Disease

Active Duodenal Ulcer – In a multicenter, double-blind, placebo controlled study of 147 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 2 and 4 weeks was significantly higher with omeprazole 20 mg once a day than with placebo (p ≤ 0.01). (See Table 6)

Table 6: Treatment of Active Duodenal Ulcer
% of Patients Healed
Omeprazole 20 mg a.m. (n=99) Placebo a.m. (n=48)
*
(p ≤ 0.01)

Week 2

41*

13

Week 4

75*

27

Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with omeprazole 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received omeprazole had complete relief of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).

In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with omeprazole 20 mg once a day than with ranitidine 150 mg twice daily (p < 0.01). (See Table 7)

Table 7: Treatment of Active Duodenal Ulcer % of Patients Healed
Omeprazole 20 mg a.m. (n=145) Ranitidine 150 mg twice daily (n=148)
*
(p < 0.01)

Week 2

42

34

Week 4

82*

63

Healing occurred significantly faster in patients treated with omeprazole than in those treated with ranitidine 150 mg twice daily (p < 0.01).

In a foreign multinational randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 40 mg and 20 mg of omeprazole were compared to 150 mg twice daily of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of omeprazole were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of omeprazole, and at 8 weeks there was no significant difference between any of the active drugs. (See Table 8)

Table 8: Treatment of Active Duodenal Ulcer % of Patients Healed
Omeprazole Ranitidine 150 mg twice daily (n=35)
40 mg (n=36) 20 mg (n=34)
*
(p ≤ 0.01)

Week 2

83*

83*

53

Week 4

100*

97*

82

Week 8

100

100

94

14.2 Gastric Ulcer

In a U.S. multicenter, double-blind study of omeprazole 40 mg once a day, 20 mg once a day, and placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were obtained. (See Table 9)

Table 9: Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated)
Omeprazole 40 mg once daily (n=214) Omeprazole 20 mg once daily (n=202) Palcebo (n=104)
*
(p < 0.01) omeprazole 40 mg or 20 mg versus placebo
(p< 0.05) omeprazole 40 mg versus 20 mg

Week 4

55.6*

47.5*

30.8

Week 8

82.7*,

74.8*

48.1

For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg was significantly more effective than 20 mg at 8 weeks.

In a foreign, multinational, double-blind study of 602 patients with endoscopically diagnosed gastric ulcer, omeprazole 40 mg once a day, 20 mg once a day, and ranitidine 150 mg twice a day were evaluated. (See Table 10)

Table 10: Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated)
Omeprazole 40 mg once daily (n=187) Omeprazole 20 mg once daily (n=200) Ranitidine 150 mg twice daily (n=199)
*
(p < 0.01) omeprazole 40 versus ranitidine
(p< 0.01) omeprazole 40 mg versus 20 mg

Week 4

78.1*,

63.5

56.3

Week 8

91.4*,

81.5

78.4

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