omeprazole/sodium bicarbonate

Omeprazole is a white to off-white crystalline powder which melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.

Omeprazole/Sodium Bicarbonate is supplied as immediate-release capsules and unit-dose packets as powder for oral suspension. Each capsule contains either 40 mg or 20 mg of omeprazole and 1100 mg of sodium bicarbonate with the following excipients: croscarmellose sodium and sodium stearyl fumarate. Packets of powder for oral suspension contain either 40 mg or 20 mg of omeprazole and 1680 mg of sodium bicarbonate with the following excipients: xylitol, sucrose, sucralose, xanthan gum, and flavorings.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic properties, but 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 acid-pump 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. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more.

Omeprazole is acid labile and thus rapidly degraded by gastric acid. Omeprazole/Sodium Bicarbonate Capsules and Powder for Oral Suspension are immediate-release formulations that contain sodium bicarbonate which raises the gastric pH and thus protects omeprazole from acid degradation.

12.2 Pharmacodynamics

Antisecretory Activity

Results from a PK/PD study of the antisecretory effect of repeated once-daily dosing of 40 mg and 20 mg of Omeprazole/Sodium Bicarbonate Oral Suspension in healthy subjects are shown in Table 5 below.

Results from a separate PK/PD study of antisecretory effect on repeated once-daily dosing of 40 mg/1100 mg and 20 mg/1100 mg of Omeprazole/Sodium Bicarbonate Capsules in healthy subjects show similar effects in general on the above three PD parameters as those for Omeprazole/Sodium Bicarbonate 40 mg/1680 mg and 20 mg/1680 mg Oral Suspension, 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

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 Nonclinical Toxicology (13.1)]. 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. 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 H2-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.

Other Effects

Systemic effects of omeprazole in the 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 I.V. 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 three days of stopping treatment.

The course of Barrett's esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of omeprazole 40 mg b.i.d. for 12 months followed by 20 mg b.i.d. for 12 months or ranitidine 300 mg b.i.d. for 24 months. No clinically significant impact on Barrett's mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett's mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett's mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter.

12.3 Pharmacokinetics

Absorption

In separate in vivo bioavailability studies, when Omeprazole/Sodium Bicarbonate Oral Suspension and Capsules are administered on an empty stomach 1 hour prior to a meal, the absorption of omeprazole is rapid, with mean peak plasma levels (% CV) of omeprazole being 1954 ng/mL (33%) and 1526 ng/mL (49%), respectively, and time to peak of approximately 30 minutes (range 10-90 min) after a single-dose or repeated-dose administration. Absolute bioavailability of Omeprazole/Sodium Bicarbonate Powder for Oral Suspension (compared to I.V. administration) is about 30-40% at doses of 20 – 40 mg, due in large part to presystemic metabolism.

When Omeprazole/Sodium Bicarbonate Oral Suspension 40 mg/1680 mg was administered in a two-dose loading regimen, the omeprazole AUC (0-inf) (ng·hr/mL) was 1665 after Dose 1 and 3356 after Dose 2, while Tmax was approximately 30 minutes for both Dose 1 and Dose 2.

Following single or repeated once daily dosing, peak plasma concentrations of omeprazole from Omeprazole/Sodium Bicarbonate are approximately proportional from 20 to 40 mg doses, but a greater than linear mean AUC (three-fold increase) is observed when doubling the dose to 40 mg. The bioavailability of omeprazole from Omeprazole/Sodium Bicarbonate increases upon repeated administration.

When Omeprazole/Sodium Bicarbonate is administered 1 hour after a meal, the omeprazole AUC is reduced by approximately 24% relative to administration 1 hour prior to a meal.

Distribution

Omeprazole is bound to plasma proteins. Protein binding is approximately 95%.

Metabolism

Following single-dose oral administration 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.

Excretion

Following single-dose oral administration of omeprazole, little if any, unchanged drug is excreted in urine. The mean plasma omeprazole half-life in healthy subjects is approximately 1 hour (range 0.4 to 3.2 hours) and the total body clearance is 500-600 mL/min.

Concomitant Use with Clopidogrel

In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together.

Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when coadministered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period.

In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction.

Special Populations

Geriatric

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.

Pediatric

The pharmacokinetics of Omeprazole/Sodium Bicarbonate has not been studied in patients < 18 years of age.

Gender

There are no known differences in the absorption or excretion of omeprazole between males and females.

Hepatic Insufficiency

In patients with chronic hepatic disease, the bioavailability of omeprazole from a buffered solution increased to approximately 100% compared to an I.V. dose, reflecting decreased first-pass effect, and the mean plasma half-life of the drug increased to nearly 3 hours compared to the mean half-life of 1 hour in normal subjects. Plasma clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired should be considered.

Renal Insufficiency

In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m², the disposition of omeprazole from a buffered solution was very similar to that in healthy subjects, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. No dose reduction is necessary in patients with renal impairment.

Asian Population

In pharmacokinetic studies of single 20-mg omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared to Caucasians. Dose adjustment, particularly where maintenance of healing of erosive esophagitis is indicated, for Asian subjects should be considered.

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 (approximately 0.35 to 28.5 times the human dose of 40 mg/day, based on body surface area) 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 2.8 times the human dose of 40 mg/day, based on body surface area) 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 3.3 times the human dose of 40 mg/day, based on body surface area). 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 28.5 times the human dose of 40 mg/day, based on body surface area). 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 [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.

Omeprazole at oral doses up to 138 mg/kg/day (about 28 times the human dose of 40 mg/day, based on body surface area) was found to have no effect on the fertility and general reproductive performance in rats.

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproduction studies conducted in pregnant rats at omeprazole doses up to 138 mg/kg/day (about 28 times the human dose of 40 mg/day, based on body surface area) and in pregnant rabbits at doses up to 69 mg/kg/day (about 28 times the human dose of 40 mg/day, based on body surface area) 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 2.8 to 28 times the human dose of 40 mg/day, based on body surface area) 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, based on body surface area).

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)

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 b.i.d. (p < 0.01). (See Table 7)

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, 40 mg and 20 mg of omeprazole were compared to 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. (See Table 8)

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)

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)

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 in Table 11.

Erosive Esophagitis - In a U.S. multicenter double-blind placebo controlled study of 40 mg or 20 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 shown in Table 12.

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%).

14.4 Long Term Maintenance Treatment 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 in Table 13.

In an international multicenter double-blind study, omeprazole 20 mg daily and 10 mg daily were compared to ranitidine 150 mg twice daily in patients with endoscopically confirmed healed esophagitis. Table 14 provides the results of this study for maintenance of healing of erosive esophagitis.

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 Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients

A double-blind, multicenter, randomized, non-inferiority clinical trial was conducted to compare Omeprazole/Sodium Bicarbonate Oral Suspension 40 mg/1680 mg and I.V. cimetidine for the reduction of risk of upper gastrointestinal (GI) bleeding in critically ill patients (mean APACHE II score = 23.7). The primary endpoint was significant upper GI bleeding defined as bright red blood which did not clear after adjustment of the nasogastric tube and a 5 to 10 minute lavage, or persistent Gastroccult® positive coffee grounds for 8 consecutive hours which did not clear with 100 cc lavage. Omeprazole/Sodium Bicarbonate Oral Suspension 40 mg/1680 mg (two doses administered 6 to 8 hours apart on the first day via orogastric or nasogastric tube, followed by 40 mg q.d. thereafter) was compared to continuous I.V. cimetidine (300 mg bolus, and 50 to 100 mg/hr continuously thereafter) for up to 14 days (mean = 6.8 days). A total of 359 patients were studied, age range 16 to 91 (mean = 56 yrs), 58.5% were males, and 64% were Caucasians. The results of the study showed that Omeprazole/Sodium Bicarbonate was non-inferior to I.V. cimetidine, 10/181(5.5%) patients in the cimetidine group vs. 7/178 (3.9%) patients in the Omeprazole/Sodium Bicarbonate group experienced clinically significant upper GI bleeding.

15 REFERENCES

• Friedman JM and Polifka JE. Omeprazole. In: Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). 2nd ed. Baltimore, MD: The Johns Hopkins University Press 2000; p. 516.
• Kallen BAJ. Use of omeprazole during pregnancy – no hazard demonstrated in 955 infants exposed during pregnancy. Eur Obstet Gynecol Reprod Biol 2001; 96(1):63-8.
• Ruigómez A, Rodriquez LUG, Cattaruzzi C, et al. Use of cimetidine, omeprazole, and ranitidine in pregnant women and pregnancy outcomes. Am J Epidemiol 1999; 150: 476-81.
• Lalkin A, Loebstein, Addis A, et al. The safety of omeprazole during pregnancy: a multicenter prospective controlled study. Am J Obstet Gynecol 1998: 179:727-30.

16 HOW SUPPLIED/STORAGE AND HANDLING

Omeprazole/Sodium Bicarbonate 20-mg Capsules: Each opaque, hard gelatin, white capsule, imprinted with the Santarus logo and “20”, contains 20 mg omeprazole and 1100 mg sodium bicarbonate.

NDC 66993-412-30 Bottles of 30 capsules

Omeprazole/Sodium Bicarbonate 40-mg Capsules: Each opaque, hard gelatin, colored dark blue and white capsule, imprinted with the Santarus logo and “40”, contains 40 mg omeprazole and 1100 mg sodium bicarbonate.

NDC 66993-413-30 Bottles of 30 capsules

Omeprazole/Sodium Bicarbonate Powder for Oral Suspension is a white, flavored powder packaged in unit-dose packets. Each packet contains either 20 mg or 40 mg omeprazole and 1680 mg sodium bicarbonate.

NDC 66993-414-30 Cartons of 30: 20-mg unit-dose packets
NDC 66993-415-30 Cartons of 30: 40-mg unit-dose packets

Storage

Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F). [See USP Controlled Room Temperature].

Keep this medication out of the hands of children. Keep container tightly closed. Protect from light and moisture.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide.

Instruct patients that Omeprazole/Sodium Bicarbonate should be taken on an empty stomach at least one hour prior to a meal. [See Dosage and Administration (2)]

Instruct patients in Directions for Use as follows:

Capsules: Swallow intact capsule with water. DO NOT USE OTHER LIQUIDS. DO NOT OPEN CAPSULE AND SPRINKLE CONTENTS INTO FOOD.

Powder for Oral Suspension: Empty packet contents into a small cup containing 1-2 tablespoons of water. DO NOT USE OTHER LIQUIDS OR FOODS. Stir well and drink immediately. Refill cup with water and drink.

Omeprazole/Sodium Bicarbonate is available either as 40 mg or 20 mg capsules with 1100 mg sodium bicarbonate. Omeprazole/Sodium Bicarbonate is also available either as 40 mg or 20 mg single-dose packets of powder for oral suspension with 1680 mg sodium bicarbonate.

Patients should be instructed not to substitute Omeprazole/Sodium Bicarbonate Capsules or Suspension for other Omeprazole/Sodium Bicarbonate dosage forms because different dosage forms contain different amounts of sodium bicarbonate and magnesium hydroxide. [See Dosage and Administration (2)]

Patients should be advised that since both the 20 mg and 40 mg oral suspension packets contain the same amount of sodium bicarbonate (1680 mg), two packets of 20 mg are not equivalent to one packet of Omeprazole/Sodium Bicarbonate 40 mg; therefore, two 20 mg packets of Omeprazole/Sodium Bicarbonate should not be substituted for one packet of Omeprazole/Sodium Bicarbonate 40 mg. Conversely ½ of a 40mg packet should not be substituted for one 20mg packet. [See Dosage and Administration (2)]

Patients should be advised that since both the 20 mg and 40 mg capsules contain the same amount of sodium bicarbonate (1100 mg), two capsules of 20 mg are not equivalent to one capsule of Omeprazole/Sodium Bicarbonate 40 mg; therefore, two 20 mg capsules of Omeprazole/Sodium Bicarbonate should not be substituted for one capsule of Omeprazole/Sodium Bicarbonate 40 mg. [See Dosage and Administration (2)]

Patients should be advised that this drug is not approved for use in patients less than 18 years of age. [See Pediatric Use (8.4)]

Patients on a sodium-restricted diet or patients at risk of developing congestive heart failure (CHF) should be informed of the sodium content of Omeprazole/Sodium Bicarbonate Capsules (304 mg per capsule) and Omeprazole/Sodium Bicarbonate Powder (460 mg per packet). Patients should be informed that chronic use of sodium bicarbonate may cause problems and increased sodium intake can cause swelling and weight gain. If this occurs, they should contact their healthcare provider. [See Warnings and Precautions (5.3)]

Patients should be informed that the most frequent adverse reactions associated with Omeprazole/Sodium Bicarbonate include headache, abdominal pain, nausea, diarrhea, vomiting and flatulence. [See Adverse Reactions (6)]

Pregnant women should be advised that a harmful effect of Omeprazole/Sodium Bicarbonate on the fetus can not be ruled out and that the drug should be used with caution during pregnancy. [See Pregnancy (8.1)]

Patients should be advised to use this drug with caution if they are regularly taking calcium supplements. [See Warnings and Precautions (5.3)]

Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea [see Warnings and Precautions (5.4)].

Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures and tetany as these may be signs of hypomagnesemia. [See Warnings and Precautions (5.7)]

PRASCO

Omeprazole/Sodium Bicarbonate Capsules are:
Distributed by: Prasco Laboratories, Mason, OH 45040 USA
Manufactured by: Norwich Pharmaceuticals, Inc., North Norwich, NY 13814

Omeprazole/Sodium Bicarbonate Powder for Oral Suspension is:
Distributed by: Prasco Laboratories, Mason, OH 45040 USA
Manufactured by: Patheon Inc., Whitby, Ontario L1N 5Z5, Canada

For more information call 1-877-817-2973

Revised: 11/2012

S0045E

MEDICATION GUIDE

Omeprazole / Sodium Bicarbonate
Powder for Oral Suspension and Capsules

Read this Medication Guide before you start taking Omeprazole/Sodium Bicarbonate and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about Omeprazole/Sodium Bicarbonate?

Omeprazole/Sodium Bicarbonate may help with your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

Omeprazole/Sodium Bicarbonate can cause serious side effects, including:

• Omeprazole/Sodium Bicarbonate contains sodium bicarbonate. Tell your doctor if you are on a sodium restricted diet or if you have Bartter's Syndrome (a rare kidney disorder).
  Tell your doctor right away if you have confusion, shaking hands, dizziness, muscle twitching, nausea, vomiting, and numbness or tingling in the face, arms, or legs.
• Diarrhea. Omeprazole/Sodium Bicarbonate may increase your risk of getting severe diarrhea. This diarrhea may be caused by an infection (Clostridium difficile) in your intestines.
  Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away.
• Bone fractures. People who take multiple daily doses of Proton pump inhibitor medicines for a long period of time (a year or longer) may have an increased risk of fractures of the hip, wrist or spine. You should take Omeprazole/Sodium Bicarbonate exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Talk to your doctor about your risk of bone fracture if you take Omeprazole/Sodium Bicarbonate.

Omeprazole/Sodium Bicarbonate can have other serious side effects. See “What are the possible side effects of Omeprazole/Sodium Bicarbonate?”

What is Omeprazole/Sodium Bicarbonate?

Omeprazole/Sodium Bicarbonate is a prescription medicine called a proton pump inhibitor (PPI). Omeprazole/Sodium Bicarbonate reduces the amount of acid in your stomach.

Omeprazole/Sodium Bicarbonate is used in adults for:

• for 4 weeks to heal ulcers in the first part of the small bowel (duodenal ulcers). Your doctor may prescribe another 4 weeks of Omeprazole/Sodium Bicarbonate.
• for up to 8 weeks for healing stomach ulcers
• for up to 4 weeks to treat heartburn and other symptoms that happen with gastroesophageal reflux disease (GERD).
  GERD happens when acid from the stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping.
• for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE)
• to maintain healing of the esophagus. It is not known if Omeprazole/Sodium Bicarbonate is safe and effective if used longer than 12 months (1 year).
• to lower the risk of stomach bleeding in critically ill people(40 mg Oral Suspension only)

It is not known if Omeprazole/Sodium Bicarbonate is safe and effective in children less than 18 years of age.

Who should not take Omeprazole/Sodium Bicarbonate?

Do not take Omeprazole/Sodium Bicarbonate if you:

• are allergic to omeprazole or any of the other ingredients in Omeprazole/Sodium Bicarbonate. See the end of this Medication Guide for a complete list of ingredients in Omeprazole/Sodium Bicarbonate.
• are allergic to any other proton pump inhibitor (PPI) medicine.

What should I tell my doctor before I take Omeprazole/Sodium Bicarbonate?

Before you take Omeprazole/Sodium Bicarbonate, tell your doctor if you:

• have been told that you have low magnesium, calcium, or potassium levels in your blood.
• have liver problems
• have heart failure
• have Bartter's syndrome (a rare kidney disorder)
• have any allergies
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if Omeprazole/Sodium Bicarbonate can harm your unborn baby.
• are breastfeeding or plan to breastfeed. Omeprazole/Sodium Bicarbonate can pass into your breast milk and may harm your baby. You and your doctor should decide if you will take Omeprazole/Sodium Bicarbonate or breastfeed. You should not do both. Talk with your doctor about the best way to feed your baby if you take Omeprazole/Sodium Bicarbonate.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Omeprazole/Sodium Bicarbonate may affect how other medicines work, and other medicines may affect how Omeprazole/Sodium Bicarbonate works.

Especially tell your doctor if you take:

• diazepam (Valium®)
• warfarin (Coumadin® Jantoven)
• phenytoin (Dilantin®)
• cyclosporine (Gengraf, Neoral, Sandimmune)
• disulfiram (Antabuse®)
• a benzodiazepine medicine
• ketoconazole (Nizoral®)
• an antibiotic that contains ampicillin
• products that contain iron
• digoxin (Lanoxin®)
• voriconazole (Vfend®)
• atazanavir (Reyataz®)
• nelfinavir (Viracept®)
• tacrolimus (Prograf®)
• saquinavir (Fortovase®)
• clarithromycin (Biaxin®, Biaxin XL)
• clopidogrel (Plavix®)
• St. John's Wort (Hypericum perforatum)
• rifampin (Rifater, Rifamate, Rimactane, Rifadin)
• methotrexate

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Omeprazole/Sodium Bicarbonate?

• Take Omeprazole/Sodium Bicarbonate exactly as prescribed by your doctor.
• Do not change your dose or stop taking Omeprazole/Sodium Bicarbonate without talking to your doctor. Take Omeprazole/Sodium Bicarbonate on an empty stomach at least one hour before a meal.
• Empty the contents of a packet of Omeprazole/Sodium Bicarbonate Powder for Oral Suspension into a small cup containing 1 to 2 tablespoons of water. Do not use other liquids or foods. Stir well and drink immediately. Refill cup with water and drink.
• Swallow Omeprazole/Sodium Bicarbonate Capsules whole with water. Do not use other liquids. Do not crush or chew the capsule. Do not open the capsule and sprinkle contents into food.
• If you miss a dose of Omeprazole/Sodium Bicarbonate, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not take two doses to make up for a missed dose.
• Do not substitute two 20 mg packets for one 40 mg packet of Omeprazole/Sodium Bicarbonate Powder for Oral Suspension because you will receive twice the amount of sodium bicarbonate. Talk to your doctor if you have questions.
• Do not substitute two 20 mg capsules for one 40 mg capsule of Omeprazole/Sodium Bicarbonate because you will receive twice the amount of sodium bicarbonate. Talk to your doctor if you have questions.
• If you take too much Omeprazole/Sodium Bicarbonate, call your doctor or Poison Control Center right away, or go to the nearest hospital emergency room.
• Your doctor may prescribe antibiotic medicines with Omeprazole/Sodium Bicarbonate to help treat a stomach infection and heal stomach-area (duodenal) ulcers that are caused by bacteria called H. pylori. Make sure you read the patient information that comes with an antibiotic before you start taking it.
• See the “Instructions for Use” at the end of this Medication Guide for instructions on how to mix and give Omeprazole/Sodium Bicarbonate Powder for Oral Suspension through a nasogastric tube or orogastric tube.

What are the possible side effects of Omeprazole/Sodium Bicarbonate?

Omeprazole/Sodium Bicarbonate may cause serious side effects, including:

• See “What is the most important information I should know about Omeprazole/Sodium Bicarbonate?”
• Chronic (lasting a long time) inflammation of the stomach lining (Atrophic Gastritis). Taking Omeprazole/Sodium Bicarbonate for a long period of time may increase the risk of inflammation to your stomach lining. You may or may not have symptoms. Tell your doctor if you have stomach pain, nausea, vomiting, or weight loss.
• Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in some people who take a proton pump inhibitor medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium.
  
  Tell your doctor right away if you develop any of these symptoms:
  • seizures
  • dizziness
  • abnormal or fast heartbeat
  • jitteriness
  • jerking movements or shaking (tremors)
  • muscle weakness
  • spasms of the hands and feet
  • cramps or muscle aches
  • spasm of the voice box

Your doctor may check the level of magnesium in your body before you start taking Omeprazole/Sodium Bicarbonate, or during treatment, if you will be taking Omeprazole/Sodium Bicarbonate for a long period of time.

The most common side effects with Omeprazole/Sodium Bicarbonate include:

• headache
• abdominal pain
• nausea
• diarrhea
• vomiting
• gas

Other side effects:

• Serious allergic reactions. Tell your doctor if you get any of the following symptoms with Omeprazole/Sodium Bicarbonate.
  • rash
  • face swelling
  • throat tightness
  • difficulty breathing

Your doctor may stop Omeprazole/Sodium Bicarbonate if these symptoms happen.

Using Omeprazole/Sodium Bicarbonate for a long time may cause problems such as swelling and weight gain. Tell your doctor if this happens.

If you are on a low-sodium diet or at risk of developing congestive heart failure (CHF), you and your doctor should decide if you will take Omeprazole/Sodium Bicarbonate.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Omeprazole/Sodium Bicarbonate. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Omeprazole/Sodium Bicarbonate?

• Store Omeprazole/Sodium Bicarbonate at room temperature between 59 °F to 86 °F (15 °C to 30 °C).
• Keep Omeprazole/Sodium Bicarbonate Capsules in a tightly closed container.
• Keep Omeprazole/Sodium Bicarbonate in a dry place and out of the light.

Keep Omeprazole/Sodium Bicarbonate and all medicines out of the reach of children

General information about Omeprazole/Sodium Bicarbonate.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Omeprazole/Sodium Bicarbonate for any condition for which it was not prescribed by your doctor. Do not give Omeprazole/Sodium Bicarbonate to other people, even if they have the same symptoms as you. It may harm them.

This Medication Guide summarizes the most important information about Omeprazole/Sodium Bicarbonate. If you would like more information, talk to your doctor. You can also ask your doctor or pharmacist for information about Omeprazole/Sodium Bicarbonate that is written for healthcare professionals.

For more information, go to www.santarus.com or 1-877-817-2973.

What are the ingredients in Omeprazole/Sodium Bicarbonate?

Active ingredients: omeprazole and sodium bicarbonate

Inactive ingredients of Omeprazole/Sodium Bicarbonate Powder for Oral Suspension: xylitol, sucrose, sucralose, xanthan gum, and flavorings.

Inactive ingredients of Omeprazole/Sodium Bicarbonate Capsules: croscarmellose sodium and sodium stearyl fumarate.

Instructions for Use

For instructions on taking Omeprazole/Sodium Bicarbonate Capsules and Omeprazole/Sodium Bicarbonate Powder for Oral Suspension by mouth, see “ How should I take Omeprazole/Sodium Bicarbonate? ”

Giving Omeprazole/Sodium Bicarbonate Powder for Oral Suspension through a nasogastric tube (NG tube) or gastric tube:

• Add 20 mL of water to a catheter tipped syringe and then add the contents of a packet as prescribed by your doctor. Use only a catheter tipped syringe to give Omeprazole/Sodium Bicarbonate through a NG tube or orogastric tube.
• Shake the syringe to dissolve the powder.
• Give the medicine through the NG or orogastric tube into the stomach right away.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the NG tube or orogastric tube into the stomach.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Omeprazole / Sodium Bicarbonate Capsules are distributed by Prasco Laboratories, Mason, OH 45040 and manufactured by Norwich Pharmaceuticals, Inc., North Norwich, NY 13814.

Omeprazole / Sodium Bicarbonate Powder for Oral Suspension is distributed by Prasco Laboratories, Mason, OH 45040 and manufactured by Patheon Inc., Whitby, Ontario L1N 5Z5, Canada.

For more information call 1-877-817-2973

11/2012

PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL - Omeprazole / Sodium Bicarbonate Capsules 20 mg Bottle

Prasco

NDC 66993-412-30

Omeprazole / Sodium Bicarbonate Capsules

20mg/1100mg

30 Capsules

Rx Only