13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57 times a human dose of 20 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 6 times a human dose of 20 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.2 to 6.5 times the human dose on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 57 times the human dose on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay.

Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance.

In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [See Warnings and Precautions (5) ] Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.

13.2. Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 56 times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 56 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 5.5 to 56 times the human dose 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 5.6 to 56 times the human doses on a body surface area basis).

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 20 mg a.m.	Placebo a.m.
	(n=99)	(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)
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 6

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 †**	Intnet-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 teh 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 teh study. Additionally, if patients dropped out of the study due to an adverse event related to teh study drug, they were in cluded 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 7

H. pylori Eradication Rates (Per-Protocol Analyssi 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]†‡	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 omeprazoel 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 8

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

14.2 Gastric Ulcer

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

Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)

	Omeprazole 20mg once daily (n=202)	Omeprazole 40mg once daily (n=214)	Placebo (n=104)
Week 4	47.5**	55.6**	30.8
Week 8	74.8**	82.7**,+	48.1

**(p<0.01) omeprazole 40mg or 20mg versus placebo
+(p<0.05) omeprazole 40mg versus 20mg

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 daily, 20 mg once daily, and ranitidine 150 mg twice a day were evaluated.

Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)

	Omeprazole 20mg once daily (n=200)	Omeprazole 40mg once daily (n=187)	Ranitidine 150 twice daily (n=199)
Week 4	63.5	78.1**,++	56.3
Week 8	81.5	91.4**,++	78.4

**(p<0.01) omeprazole 40mg versus ranitidine
++(p<0.01) omeprazole 40mg versus 20mg

14.3 Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD

A placebo-controlled study was conducted in Scandinavia to compare the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD patients without erosive esophagitis. Results are shown below.

% Successful Symptomatic Outcomea

	Omeprazole 20 mg a.m.	Omeprazole 10 mg a.m.	Placebo a.m.
All patients	46*† (n=205)	31† (n=199)	13 (n=105)
Patients with confirmed GERD	56*,† (n=115)	36† (n=109)	14 (n=59)

aDefined as complete resolution of heartburn *(p<0.005) versus 10mg †(p<0.005) versus placebo

14.4 Erosive Esophagitis

In a U.S. multicenter double-blind placebo controlled study of 20 mg or 40 mg of omeprazole delayed-release capsules in patients with symptoms of GERD and endoscopically diagnosed erosive esophagitis of grade 2 or above, the percentage healing rates (per protocol) were as follows:

Week	20mg Omeprazole (n=83)	40mg Omeprazole (n=87)	Placebo (n=43)
4	39**	45**	7
8	74**	75**	14

**(p<0.01) omeprazole versus placebo

In this study, the 40 mg dose was not superior to the 20 mg dose of omeprazole in the percentage healing rate. Other controlled clinical trials have also shown that omeprazole is effective in severe GERD. In comparisons with histamine H2-receptor antagonists in patients with erosive esophagitis, grade 2 or above, omeprazole in a dose of 20 mg was significantly more effective than the active controls. Complete daytime and nighttime heartburn relief occurred significantly faster (p < 0.01) in patients treated with omeprazole than in those taking placebo or histamine H2- receptor antagonists.

In this and five other controlled GERD studies, significantly more patients taking 20 mg omeprazole (84%) reported complete relief of GERD symptoms than patients receiving placebo (12%).

Long Term Maintenance Of Healing of Erosive Esophagitis

In a U.S. double-blind, randomized, multicenter, placebo controlled study, two dose regimens of omeprazole were studied in patients with endoscopically confirmed healed esophagitis. Results to determine maintenance of healing of erosive esophagitis are shown below.

Life Table Analysis
Omeprazole

	Omeprazole 20mg once daily (n=138)	Omeprazole 20mg 3 days per week (n=137)	Placebo (n=131)
Percent in endoscopic remission at 6 months	*70	34	11

*(p<0.01) omeprazole 20mg once daily versus omeprazole 20mg 3 consecutive days per week or placebo

In an international multicenter double-blind study, omeprazole 20 mg daily and 10 mg daily were compared with ranitidine 150 mg twice daily in patients with endoscopically confirmed healed esophagitis. The table below provides the results of this study for maintenance of healing of erosive esophagitis.

Life Table Analysis

	Omeprazole 20mg once daily (n=131)	Omeprazole 10 mg once daily (n=133)	Ranitidine 150 mg twice daily (n=128)
Percent in endoscopic remission at 12 months	*77	**‡**58	46

*(p=0.01) omeprazole 20 mg once daily, versus omeprazole 10 mg once daily or Ranitidine
‡(p=0.03) ompeprazole 10 mg once daily, versus Ranitidine

In patients who initially had grades 3 or 4 erosive esophagitis, for maintenance after healing, 20 mg daily of omeprazole was effective, while 10 mg did not demonstrate effectiveness.

14.5 Pathological Hypersecretory Conditions

In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple endocrine adenomas, omeprazole delayed-release capsules significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg every other day to 360 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery, and below 5 mEq/hr in patients with prior gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients [see Dosage and Administration (2) ] omeprazole was well tolerated at these high dose levels for prolonged periods (> 5 years in some patients). In most ZE patients, serum gastrin levels were not modified by omeprazole. However, in some patients serum gastrin increased to levels greater than those present prior to initiation of omeprazole therapy. At least 11 patients with ZE syndrome on long-term treatment with omeprazole developed gastric carcinoids. These findings are believed to be a manifestation of the underlying condition, which is known to be associated with such tumors, rather than the result of the administration of omeprazole. [See Adverse Reactions (6) ]

14.6 Pediatric GERD

Symptomatic GERD

The effectiveness of omeprazole for the treatment of nonerosive GERD in pediatric patients 2 to 16 years of age is based in part on data obtained from pediatric patients in an uncontrolled phase III study. [See Use in Specific Populations (8.4)]

The study enrolled 113 pediatric patients 2 to 16 years of age with a history of symptoms suggestive of nonerosive GERD. Patients were administered a single dose of omeprazole (10 mg or 20 mg, based on body weight) for 4 weeks either as an intact capsule or as an open capsule in applesauce. Successful response was defined as no moderate or severe episodes of either pain-related symptoms or vomiting/regurgitation during the last 4 days of treatment. Results showed success rates of 60% (9/15; 10 mg omeprazole) and 59% (58/98; 20 mg omeprazole), respectively.

Healing of Erosive Esophagitis

In an uncontrolled, open-label dose-titration study, healing of erosive esophagitis in pediatric patients 1 to 16 years of age required doses that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7 mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than 6% of a 24-hour study). After titration, patients remained on treatment for 3 months. Forty-four percent of the patients were healed on a dose of 0.7 mg/kg body weight; most of the remaining patients were healed with 1.4 mg/kg after an additional 3 months’ treatment. Erosive esophagitis was healed in 51 of 57 (90%) children who completed the first course of treatment in the healing phase of the study. In addition, after 3 months of treatment, 33% of the children had no overall symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation/vomiting.

Maintenance of Healing of Erosive Esophagitis

In an uncontrolled, open-label study of maintenance of healing of erosive esophagitis in 46 pediatric patients, 54% of patients required half the healing dose. The remaining patients increased the healing dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire maintenance period, or returned to half the dose before completion. Of the 46 patients who entered the maintenance phase, 19 (41%) had no relapse. In addition, maintenance therapy in erosive esophagitis patients resulted in 63% of patients having no overall symptoms.