Omeprazole (Page 8 of 11)

13.2 Animal Toxicology and/or Pharmacology

Reproduction Studies

Reproductive Toxicology Studies

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 28 times the human dose of 40 mg/day on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 28 times the human dose 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 69.1 mg/kg/day (about 2.8 to 28 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 2.8 to 28 times the human dose of 40 mg/day on a body surface area basis) [see Pregnancy, Animal Data (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 57 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 daily than with placebo (p ≤ 0.01).

Treatment of Active Duodenal Ulcer % of Patients Healed
Omeprazole Placebo
20 mg a.m.(n=99) 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 daily than with ranitidine 150 mg b.i.d. (p < 0.01).

Treatment of Active Duodenal Ulcer % of Patients Healed
Omeprazole Ranitidine
20 mg a.m. 150 mg twice daily
(n = 145) (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 b.i.d. (p < 0.01).

In a foreign multinational randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 20 mg and 40 mg of omeprazole were compared with 150 mg b.i.d. 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.

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

Week 2

*83

*83

53

Week 4

*97

*100

82

Week 8

100

100

94

H. pylori Eradication in Patients with Duodenal Ulcer Disease

Triple Therapy (omeprazole/clarithromycin/amoxicillin)

Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared omeprazole plus clarithromycin plus amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were conducted in patients with an active duodenal ulcer, and the other study (3) was conducted in patients with a history of a duodenal ulcer in the past 5 years but without an ulcer present at the time of enrollment. The dose regimen in the studies was omeprazole 20 mg twice daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days. In studies 1 and 2, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg once daily. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 1 and 2 only). H. pylori status was determined by CLOtest® , histology and culture in all three studies. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive.

The combination of omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H. pylori.

Table 5 Per-Protocol and Intent-to-Treat H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval]
Omeprazole + Clarithromycin + Amoxicillin Clarithromycin + Amoxicillin
Per-Protocol Intent-to-Treat Per-Protocol Intent-to-Treat
Study 1 * 77 [64, 86](n = 64) *69 [57, 79](n = 80) 43 [31, 56](n = 67) 37 [27, 48](n = 84)
Study 2 *78 [67, 88](n = 65) *73 [61, 82](n = 77) 41 [29, 54](n = 68) 36 [26, 47](n = 83)
Study 3 *90 [80, 96](n = 69) *83 [74, 91](n = 84) 33 [24, 44](n = 93) 32 [23, 42](n = 99)

Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer within 5 years, study 3) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest® , histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.

Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.

* (p < 0.05) versus clarithromycin plus amoxicillin.

Dual Therapy (omeprazole/clarithromycin)

Four randomized, double-blind, multi-center studies (4, 5, 6, and 7) evaluated omeprazole 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days, followed by omeprazole 20 mg once daily, (Studies 4, 5, and 7) or by omeprazole 40 mg once daily (Study 6) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies 4 and 5 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study 4 and 228 patients in Study 5. These studies compared the combination regimen to omeprazole and clarithromycin monotherapies. Studies 6 and 7 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in Study 6 and 208 patients in Study 7. These studies compared the combination regimen with omeprazole monotherapy. The results for the efficacy analyses for these studies are described below. H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated of H. pylori. In the per-protocol analysis, the following patients were excluded: dropouts, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication because they were found to have an ulcer at the end of treatment.

The combination of omeprazole and clarithromycin was effective in eradicating H. pylori.

Table 6 H. pylori Eradication Rates (Per-Protocol Analysis at 4 to 6 Weeks) % of Patients Cured [95% Confidence Interval]
Omeprazole + Clarithromycin Omeprazole Clarithromycin
U.S. Studies
Study 4 74 [60, 85] †‡ (n = 53) 0 [0, 7](n = 54) 31 [18, 47](n = 42)
Study 5 64 [51, 76] †‡ (n = 61) 0 [0, 6](n = 59) 39 [24, 55](n = 44)
Non U.S. Studies
Study 6 83 [71, 92] (n = 60) 1 [0, 7](n = 74) N/A
Study 7 74 [64, 83] (n = 86) 1 [0, 6](n = 90) N/A

Statistically significantly higher than clarithromycin monotherapy (p < 0.05)

Statistically significantly higher than omeprazole monotherapy (p < 0.05)

Ulcer healing was not significantly different when clarithromycin was added to omeprazole therapy compared with omeprazole therapy alone.

The combination of omeprazole and clarithromycin was effective in eradicating H. pylori and reduced duodenal ulcer recurrence.

Table 7 Duodenal Ulcer Recurrence Rates by H. pylori Eradication Status % of Patients with Ulcer Recurrence
H. pylori eradicated# H. pylori not eradicated#
U.S. Studies 6 months post-treatment
Study 4 *35(n=49) 60 (n=88)
Study 5 *8 (n=53) 60 (n=106)
Non U.S. Studies 6 months post-treatment
Study 6 *5 (n=43) 46 (n=78)
Study 7 *6 (n=53) 43 (n=107)
12 months post-treatment
Study 6 *5 (n=39) 68 (n=71)

# H. pylori eradication status assessed at same time point as ulcer recurrence

Combined results for omeprazole + clarithromycin, omeprazole, and clarithromycin treatment arms

Combined results for omeprazole + clarithromycin and omeprazole treatment arms

*(p ≤ 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori eradicated

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