Omeprazole and Sodium Bicarbonate 20 mg; 1100 mg Capsule, 15-count — NDC 85509-1031-1 (Billing 85509-1031-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acidpump inhibitor, in that it blocks the final step of acid production. This effect is dose related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.

12.2Pharmacodynamics Antisecretory Activity Results from a pharmacokinetic/pharmacodynamic (PK/PD) study of the antisecretory effect of repeated once-daily dosing of 40 mg and 20 mg of ZEGERID for oral suspension in healthy subjects are shown in Table 8 below. Table 8: Effect of ZEGERID for Oral Suspension on Intragastric pH, Day 7 1. P < 0.05 20 mg vs.

40 mg Once-Daily Dosage of ZEGERID for Oral Suspension Parameter 40 mg omeprazole and 1,680 mg sodium bicarbonate (n = 24) 20 mg omeprazole and 1,680 mg sodium bicarbonate (n = 28) % Decrease from Baseline for Integrated Gastric Acidity (mmol•hr/L) 84% 82% Coefficient of Variation 20% 24% % Time Gastric pH >4 1 (Hours) 1 77% (18.6 h) 51% (12.2 h) Coefficient of Variation 27% 43% Median pH 5.2

4.2Coefficient of Variation 17% 37% Note: Values represent medians. All parameters were measured over a 24-hour period. Results from a separate PK/PD study of antisecretory effect on repeated once-daily dosing of 40 mg/1,100 mg and 20 mg/1,100 mg of Omeprazole and Sodium Bicarbonate capsules in healthy subjects show similar effects in general on the above three PD parameters as those for ZEGERID for oral suspension 40 mg/1,680 mg and 20 mg/1,680 mg, respectively.

The antisecretory effect lasts longer than would be expected from the very short (1 hour) plasma half-life, apparently due to irreversible binding to the parietal H+/K+ ATPase enzyme. Enterochromaffin-like (ECL) Cell Effects Human gastric biopsy specimens have been obtained from more than 3000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients.

These studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions. Serum Gastrin Effects In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment.

In comparison with histamine H 2 -receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6-fold vs. 1.1- to 1.8-fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.11 )] . Other Effects Systemic effects of omeprazole in the central nervous system (CNS), cardiovascular and respiratory systems have not been found to date.

Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a sin… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acidpump inhibitor, in that it blocks the final step of acid production. This effect is dose related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.

12.3Pharmacokinetics Absorption Table 9 show the systemic exposures and the time reach peak concentration (T max ) of omeprazole in healthy subjects following administration of Omeprazole and Sodium Bicarbonate capsules, on an empty stomach one hour prior to a meal. Table 9: Arithmetic Mean (CV%) of the Systemic Exposures (C max , AUC) and T max of Omeprazole after a Single Oral Dose and Multiple Once-Daily Doses of Omeprazole and Sodium Bicarbonate Capsules n.a.: not applicable *AUC 0-24h was used on Day 7 20 mg Omeprazole and Sodium Bicarbonate capsules 40 mg Omeprazole and Sodium Bicarbonate capsules Day 1 Day 7 % Change (Day 7/ Day 1) Day 1 Day 7 % Change (Day 7/ Day 1) Cmax (ng/mL) 498.1 (50.9) 679.8 (44.0) 36 1154 (53.0) 1526 (48.7) 32 Tmax (hr) [min – max] 0.61 [0.25-1.5] 0.82 [0.25-1.5] n.a.

0.56[0.25-1.5] 0.97 [0.25-3.5] n.a. AUC 0-inf * (ng•hr/mL) 509.7 (60.5) 1029 (67.9) 102 1882 (120) 3866 (83.3) 105 Following single or repeated once-daily dosing, peak plasma concentrations (C max ) of omeprazole from Omeprazole and Sodium Bicarbonate capsules were approximately proportional from 20 to 40 mg doses. A greater than dose proportional increase in mean steady-state AUC (more than three-fold increase on Day 7) was observed when doubling the dose to 40 mg.

The bioavailability of omeprazole from Omeprazole and Sodium Bicarbonate capsules increases upon repeated administration. The percent changes in C max and AUC between steady-state (Day 7) and single dose (Day 1) indicate omeprazole is a time-dependent autoinhibitor of CYP2C19. When Omeprazole and Sodium Bicarbonate capsule 40 mg is administered one hour after a meal, the omeprazole AUC is reduced by approximately 27% and 22%, respectively, relative to administration one hour prior to a meal [see Dosage and Administration ( 2.3 )] .

Distribution Omeprazole is bound to plasma proteins. Protein binding is approximately 95%. Elimination Metabolism Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system.

The major part of its metabolism is dependent on the polymorphically expressed CYP2C19 [see Clinical Pharmacology ( 12.5 )] , responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. The mean plasma omeprazole half-life following administration of Omeprazole and Sodium Bicarbonate capsule in healthy subjects is approximately 1 hour (range 0.4 to 4.2 hours), and the total body clearance is 500 to 600 mL/min.

Excretion Following single-dose oral administration of a buffered solution of omeprazole, the majority of the dose (about 77%) is eliminated in urine as at least six metabolites. Two metabolites have been identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces.

This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma – the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity.

Specific Populations Geriatric Patients The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly subjects versus 58% in young subjects given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole, and no unchanged drug was detected.

The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects), and its plasma half-life averaged one hour, similar to that of young healthy subjects. Male and Female Patients There are no known differences in the absorption or excretion of omeprazole between males and females. Racial or Ethnic Groups [see Clinical Pharmacology ( 12.5 )] Patients… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Antisecretory Activity Results from a pharmacokinetic/pharmacodynamic (PK/PD) study of the antisecretory effect of repeated once-daily dosing of 40 mg and 20 mg of ZEGERID for oral suspension in healthy subjects are shown in Table 8 below. Table 8: Effect of ZEGERID for Oral Suspension on Intragastric pH, Day 7 1. P < 0.05 20 mg vs.

40 mg Once-Daily Dosage of ZEGERID for Oral Suspension Parameter 40 mg omeprazole and 1,680 mg sodium bicarbonate (n = 24) 20 mg omeprazole and 1,680 mg sodium bicarbonate (n = 28) % Decrease from Baseline for Integrated Gastric Acidity (mmol•hr/L) 84% 82% Coefficient of Variation 20% 24% % Time Gastric pH >4 1 (Hours) 1 77% (18.6 h) 51% (12.2 h) Coefficient of Variation 27% 43% Median pH 5.2

4.2Coefficient of Variation 17% 37% Note: Values represent medians. All parameters were measured over a 24-hour period. Results from a separate PK/PD study of antisecretory effect on repeated once-daily dosing of 40 mg/1,100 mg and 20 mg/1,100 mg of Omeprazole and Sodium Bicarbonate capsules in healthy subjects show similar effects in general on the above three PD parameters as those for ZEGERID for oral suspension 40 mg/1,680 mg and 20 mg/1,680 mg, respectively.

The antisecretory effect lasts longer than would be expected from the very short (1 hour) plasma half-life, apparently due to irreversible binding to the parietal H+/K+ ATPase enzyme. Enterochromaffin-like (ECL) Cell Effects Human gastric biopsy specimens have been obtained from more than 3000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients.

These studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions. Serum Gastrin Effects In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment.

In comparison with histamine H 2 -receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6-fold vs. 1.1- to 1.8-fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.11 )] . Other Effects Systemic effects of omeprazole in the central nervous system (CNS), cardiovascular and respiratory systems have not been found to date.

Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single intravenous dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion.

No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased. As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria.

The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within th… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES The effectiveness of Omeprazole and Sodium Bicarbonate capsules has been established, in part, based on studies of an oral delayed-release omeprazole product for the treatment of active duodenal ulcer, active benign gastric ulcer, symptomatic GERD, EE due to acid-mediated GERD, and maintenance of healing of EE due to acid-mediated GERD [see Clinical Studies ( 14.1 , 14.2 , 14.3 , 14.4 , 14.5 )].

14.1Active 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 delayed-release capsules 20 mg once a day than with placebo (p ≤ 0.01) (See Table 11 ). Table 11: Treatment of Active Duodenal Ulcer 1. (p ≤ 0.01) % of Patients Healed Omeprazole 20 mg a.m.

(n = 99) Placebo a.m. (n = 48) Week 2 41 1 13 Week 4 75 1 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 12). Table 12: Treatment of Active Duodenal Ulcer % of Patients Healed 1. (p < 0.01) Omeprazole 20 mg a.m.

(n = 145) Ranitidine 150 mg twice daily (n = 148) Week 2 42 34 Week 4 82 1 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 13.) Table 13: Treatment of Active Duodenal Ulcer % of Patients Healed 1. (p ≤ 0.01) Omeprazole Ranitidine 150 mg twice daily (n = 35) 40 mg (n = 36) 20 mg (n = 34) Week 2 83 1 83 1 53 Week 4 100 1 97 1 82 Week 8 100 100 94

14.2Active Benign 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 14.) Table 14: Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated) 1. (p < 0.01) omeprazole 40 mg or 20 mg versus placebo 2.

(p < 0.05) omeprazole 40 mg versus 20 mg Omeprazole 40 mg once daily (n = 214) Omeprazole 20 mg once daily (n = 202) Placebo (n = 104) Week 4 55.6 1 47.5 1

30.8Week 8 82.7 1,2 74.8 1

48.1For 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 15. ) Table 15: Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated) 1. (p < 0.01) omeprazole 40 mg versus ranitidine 2. (p < 0.01) omeprazole 40 mg versus 20 mg Omeprazole 40 mg once daily (n = 187) Omeprazole 20 mg once daily (n = 200) Ranitidine 150 mg twice daily (n = 199) Week 4 78.1 1,2 63.5

56.3Week 8 91.4 1,2 81.5 78.4

14.3Symptomatic GERD A p… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44 and 140.8 mg/kg/day (approximately 0.4 to 34.2 times the human dose of 40 mg/day 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 (approximately 3.36 times the human dose of 40 mg/day on a body surface area basis) for one year, 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 versus 10% controls). By the second year the difference between treated and control rats was much smaller (46% versus 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 0.1 to 3.9 times the human dose of 40 mg/day 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 and females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day 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.

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. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other PPIs or high doses of H 2 -receptor antagonists. Omeprazole at oral doses up to 138 mg/kg/day (about 33.6 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on the fertility and general reproductive performance in rats.