Omeprazole 40 MG / NaHCO3 1100 MG Oral Capsule

Details

Generic Name: OMEPRAZOLE AND SODIUM BICARBONATE

Brand Name: Omeprazole and Sodium Bicarbonate

Substance Name(s):
OMEPRAZOLE
SODIUM BICARBONATE

DRUG INTERACTIONS

7 May interfere with drugs for which gastric pH can affect bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, erlotinib, digoxin, and mycophenolate mofetil) (7.1) Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines): Omeprazole and sodium bicarbonate can prolong their elimination. Monitor to determine the need for possible dose adjustments when taken with omeprazole and sodium bicarbonate capsules (7.2) Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time (7.2) Voriconazole: May increase plasma levels of omeprazole (7.2) Saquinavir: Omeprazole and sodium bicarbonate increases plasma levels of saquinavir (7.3) Omeprazole and sodium bicarbonate may reduce plasma levels of atazanavir and nelfinavir (7.3) Clopidogrel: Omeprazole and sodium bicarbonate decreases exposure to the active metabolite of clopidogrel (7.5) Tacrolimus: Omeprazole and sodium bicarbonate may increase serum levels of tacrolimus (7.6) Methotrexate: Omeprazole and sodium bicarbonate may increase serum level of methotrexate (7.8) 7.1 Drugs for which gastric pH can affect bioavailability Due to its effects on gastric acid secretion, omeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Coadministration of digoxin with omeprazole and sodium bicarbonate is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with omeprazole and sodium bicarbonate. Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and sodium bicarbonate and MMF. Use omeprazole and sodium bicarbonate with caution in transplant patients receiving MMF. [See Clinical Pharmacology (12.3)] 7.2 Drugs metabolized by cytochrome P450 (CYP) Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time. Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P-450 system (e.g., cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with omeprazole and sodium bicarbonate. Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole is not normally required. When voriconazole (400 mg every 12 hours for one day, then 200 mg for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole. Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased omeprazole serum levels. In a cross-over study in 12 healthy male subjects, St John’s wort (300 mg three times daily for 14 days), an inducer of CYP3A4, decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with omeprazole. 7.3 Antiretroviral Agents Concomitant administration of atazanavir and proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect. Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg, daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. Increased Concentration of Saquinavir For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported with an increase in AUC by 82%, in Cmax by 75% and in Cmin by 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole. 7.4 Combination Therapy with Clarithromycin Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interaction [See Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs. [See Contraindications in prescribing information for clarithromycin] 7.5 Clopidogrel Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of omeprazole80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of omeprazole and sodium bicarbonate with clopidogrel. When using omeprazole and sodium bicarbonate, consider use of alternative anti-platelet therapy. [See Pharmacokinetics (12.3)] 7.6 Tacrolimus Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus. 7.7 Interactions With Investigations of Neuroendocrine Tumors Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors. [See Clinical Pharmacology (12)]. 7.8 Methotrexate Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted. [See Warnings and Precautions (5.12)].

OVERDOSAGE

10 Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience. [See Adverse Reactions (6)] Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive. As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, a certified Regional Poison Control Center should be contacted. Telephone numbers are listed in the Physicians’ Desk Reference (PDR) or local telephone book. Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and dogs, respectively. Animals given these doses showed sedation, ptosis, tremors, convulsions, and decreased activity, body temperature, and respiratory rate and increased depth of respiration. In addition, a sodium bicarbonate overdose may cause hypocalcemia, hypokalemia, hypernatremia, and seizures.

DESCRIPTION

11 Omeprazole and sodium bicarbonate capsules is a combination of omeprazole, a proton-pump inhibitor, and sodium bicarbonate, an antacid. Omeprazole is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, a racemic mixture of two enantiomers that inhibits gastric acid secretion. Its structural formula is C17H19N3O3S, with a molecular weight of 345.42. The structural formula is: 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 and sodium bicarbonate is supplied as immediate-release capsules. Each capsule contains either 40 mg or 20 mg of omeprazole and 1100 mg of sodium bicarbonate with the following excipients: croscarmellose sodium and magnesium stearate. The capsule shell contains gelatin, titanium dioxide, sodium lauryl sulfate, NF and the colorants FD&C Blue #1 (40 mg and 20 mg), FD&C Red# 3 (20 mg) and the components of ink, Edible ink type TekPrintTM SW-9008 Black Ink (Shellac, NF; Dehydrated Alcohol, USP; Isopropyl Alcohol, USP; Butyl Alcohol, NF; Propylene Glycol, USP; Strong Ammonia Solution, NF; Black Iron Oxide, NF, E172; Potassium Hydroxide, NF) or Opacode® Monogramming ink S-1-17823 Black (Shellac, NF; Isopropyl Alcohol, USP; Iron Oxide Black, NF; N-Butyl Alcohol, NF; Propylene Glycol, USP; Ammonium Hydroxide, NF). omeprazole-str

CLINICAL STUDIES

14 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 4) Table 4: Treatment of Active Duodenal Ulcer % of Patients Healed Omeprazole 20 mg a.m. (n = 99) Placebo a.m. (n = 48) Week 2 41* 13 Week 4 75* 27 *(p < 0.01) 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 5) Table 5: Treatment of Active Duodenal Ulcer % of Patients Healed Omeprazole 20 mg a.m. (n = 145) Ranitidine 150 mg b.i.d. (n = 148) Week 2 42 34 Week 4 82* 63 *(p < 0.01) 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 6) Table 6: Treatment of Active Duodenal Ulcer % of Patients Healed Omeprazole Ranitidine 40 mg (n = 36) 20 mg (n = 34) 150 mg b.i.d. (n = 35) Week 2 83* 83* 53 Week 4 100* 97* 82 Week 8 100 100 94 *(p < 0.01) 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 7) Table 7: Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated) Omeprazole Omeprazole 40 mg q.d. (n = 214) 20 mg q.d. (n = 202) Placebo (n = 104) Week 4 55.6** 47.5** 30.8 Week 8 82.7**,+ 74.8** 48.1 **(p < 0.01) Omeprazole 40 mg or 20 mg versus placebo +(p < 0.05) Omeprazole 40 mg versus 20 mg 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 8) Table 8: Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated) Omeprazole Omeprazole Ranitidine 40 mg q.d. (n = 187) 20 mg q.d. (n = 200) 150 mg b.i.d. (n = 199) Week 4 78.1**,++ 63.5 56.3 Week 8 91.4**,++ 81.5 78.4 **(p < 0.01) Omeprazole 40 mg versus ranitidine ++(p < 0.01) Omeprazole 40 mg versus 20 mg 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 inTable 9. Table 9: % Successful Syptomatic Outcomea Omeprazole Omeprazole Placebo 20 mg a.m. 10 mg a.m. 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) a Defined as complete resolution of heartburn * (p < 0.005) versus 10 mg † (p < 0.005) versus placebo 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 10. Table 10: % Patients Healed Omeprazole Omeprazole 40 mg (n = 87) 20 mg (n = 83) Placebo (n = 43) Week 4 45* 39* 7 Week 8 75* 74* 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 occured 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 11. Table 11: Life Table Analysis Omeprazole 20 mg q.d. (n = 138) Omeprazole 20 mg 3 days per week (n = 137) Placebo (n = 131) Percent in endoscopic remission at 6 months 70* 34 11 * (p < 0.01) Omeprazole 20 mg once daily versus Omeprazole 20 mg 3 consecutive days per week or placebo. 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 12 provides the results of this study for maintenance of healing of erosive esophagitis. Table 12: Life Table Analysis Omeprazole 20 mg q.d. (n = 131) Omeprazole 10 mg q.d. (n = 133) Ranitidine 150 mg b.i.d. (n = 128) Percent in endoscopic remission at 12 months 77* 58‡ 46 * (p = 0.01) Omeprazole 20mg once daily versus Omeprazole 10 mg once daily or Ranitidine. ‡ (p = 0.03) Omeprazole 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.

HOW SUPPLIED

16 /STORAGE AND HANDLING Omeprazole and Sodium Bicarbonate Capsules, 20 mg/1100 mg are hard gelatin capsules with a light blue opaque cap and white opaque body, imprinted in black ink with ‘U’ on the cap, ’88’ on the body and filled with white to off-white powder. Bottles of 30 NDC 13107-115-30 Bottles of 500 NDC 13107-115-05 Omeprazole and Sodium Bicarbonate Capsules, 40 mg/1100 mg are hard gelatin capsules with a dark blue opaque cap and white opaque body, imprinted in black ink with ‘U’ on the cap, ’89’ on the body and filled with white to off-white powder. Bottles of 30 NDC 13107-116-30 Bottles of 500 NDC 13107-116-05 Storage Store at 20° to 25°C (68° to 77°F); [See USP Controlled Room Temperature]. Keep this and all medications out of the reach of children. Keep container tightly closed. Protect from light and moisture.

RECENT MAJOR CHANGES

Warnings and Precautions, Acute Interstitial Nephritis (5.3) 12/2014 Warnings and Precautions, Cyanocobalamin (Vitamin B-12) Deficiency (5.4) 12/2014

GERIATRIC USE

8.5 Geriatric Use Omeprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies with buffered omeprazole have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects). The plasma half-life averaged one hour, about twice that in nonelderly, healthy subjects taking omeprazole and sodium bicarbonate. However, no dosage adjustment is necessary in the elderly. [See Clinical Pharmacology (12.3)]

DOSAGE FORMS AND STRENGTHS

3 Omeprazole and Sodium Bicarbonate Capsules, 20 mg/1100 mg: each hard gelatin capsule has a light blue opaque cap and white opaque body, imprinted in black ink with ‘U’ on the cap, ‘88’ on the body and contains 20 mg omeprazole, USP and 1100 mg sodium bicarbonate, USP. Omeprazole and Sodium Bicarbonate Capsules, 40 mg/1100 mg: each hard gelatin capsule has a dark blue opaque cap and white opaque body, imprinted in black ink with ‘U’ on the cap, ‘89’ on the body and contains 40 mg omeprazole, USP and 1100 mg sodium bicarbonate, USP. Omeprazole and sodium bicarbonate is available as a capsule in 20 mg and 40 mg strengths (3)

MECHANISM OF ACTION

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 muscosa for a day or more. Omeprazole is acid labile and thus rapidly degraded by gastric acid. Omeprazole and sodium bicarbonate capsules is an immediate-release formulation that contains sodium bicarbonate which raises the gastric pH and thus protects omeprazole from acid degradation.

INDICATIONS AND USAGE

1 Omeprazole and sodium bicarbonate is a proton pump inhibitor indicated for: Short-term treatment of active duodenal ulcer (1.1) Short-term treatment of active benign gastric ulcer (1.2) Treatment of gastroesophageal reflux disease (GERD) (1.3) Maintenance of healing of erosive esophagitis (1.4) The safety and effectiveness of omeprazole and sodium bicarbonate in pediatric patients (<18 years of age) have not been established (8.4) 1.1 Duodenal Ulcer Omeprazole and sodium bicarbonate capsules are indicated for short-term treatment of active duodenal ulcer. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. [See Clinical Studies (14.1)] 1.2 Gastric Ulcer Omeprazole and sodium bicarbonate capsules are indicated for short-term treatment (4 to 8 weeks) of active benign gastric ulcer. [See Clinical Studies (14.2)] 1.3 Treatment of Gastroesophageal Reflux Disease (GERD) Symptomatic GERD Omeprazole and sodium bicarbonate capsules are indicated for the treatment of heartburn and other symptoms associated with GERD. [See Clinical Studies (14.3)] Erosive Esophagitis Omeprazole and sodium bicarbonate capsules are indicated for the short-term treatment (4 to 8 weeks) of erosive esophagitis which has been diagnosed by endoscopy. The efficacy of omeprazole and sodium bicarbonate used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, it may be helpful to give up to an additional 4 weeks of treatment. If there is recurrence of erosive esophagitis or GERD symptoms (e.g., heartburn), additional 4 to 8 week courses of omeprazole and sodium bicarbonate may be considered. [See Clinical Studies (14.3)] 1.4 Maintenance of Healing of Erosive Esophagitis Omeprazole and sodium bicarbonate capsules are indicated to maintain healing of erosive esophagitis. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14.4)]

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of omeprazole and sodium bicarbonate have not been established in pediatric patients less than 18 years of age. Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg on a body surface area basis. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth. [See Nonclinical Toxicology (13.2)]

PREGNANCY

8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies on the use of omeprazole and sodium bicarbonate in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about68 times and 42 times, respectively, an oral human dose of 40 mg (based on a body surface area basis for a 60 kg person). However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 33.6 times an oral human dose of 40 mg (see Animal Data). Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, omeprazole and sodium bicarbonate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Reproductive studies conducted with omeprazole in rats at oral 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 rabbits at doses up to 69 mg/kg/day (about 33.6times 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 69.1 mg/kg/day (about 3.36 to 33.6 times an oral human dose of 40 mg 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 3.36 to 33.6 times an oral human dose of 40 mg on a body surface area basis). Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development were performed with the S- enantiomer, esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg of esomeprazole on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 16.8 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses of esomeprazole magnesium equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses of esomeprazole magnesium equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). A pre- and post natal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.

NUSRING MOTHERS

8.3 Nursing Mothers Omeprazole concentrations have been measured in breast milk of a woman following oral administration of 20 mg. The peak concentration of omeprazole in breast milk was less than 7% of the peak serum concentration. The concentration will correspond to 0.004 mg of omeprazole in 200 mL of milk. Because omeprazole is excreted in human milk, because of the potential for serious adverse reactions in nursing infants from omeprazole, and because of the potential for tumorigenicity shown for omeprazole in rat carcinogenicity studies, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In addition, sodium bicarbonate should be used with caution in nursing mothers.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Concomitant Gastric Malignancy: Symptomatic response to therapy with omeprazole and sodium bicarbonate capsules does not preclude the presence of gastric malignancy (5.1) Atrophic Gastritis: Has been observed in gastric corpus biopsies from patients treated long-term with omeprazole (5.2) Acute interstitial nephritis has been observed in patients taking PPIs. (5.3) Cyanocobalamin (vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. (5.4) Buffer Content: contains sodium bicarbonate (5.5) PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.6) Avoid concomitant use of omeprazole and sodium bicarbonate with clopidogrel (5.7) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine (5.8) Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.9) Avoid concomitant use of omeprazole and sodium bicarbonate with St John’s Wort or rifampin due to the potential reduction in omeprazole concentrations (5.10, 7.2) Interactions with diagnostic investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased Choromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. (5.11, 12.2) 5.1 Concomitant Gastric Malignancy Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. 5.2 Atrophic gastritis Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole. 5.3 Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including omeprazole and sodium bicarbonate. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue omeprazole and sodium bicarbonate if acute interstitial nephritis develops. [See Contraindications (4)]. 5.4 Cyanocobalamin (vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed. 5.5 Buffer Content Each omeprazole and sodium bicarbonate capsule contains 1100 mg (13 mEq) of sodium bicarbonate. The total content of sodium in each capsule is 304 mg. The sodium content of omeprazole and sodium bicarbonate capsules should be taken into consideration when administering to patients on a sodium restricted diet. Because omeprazole and sodium bicarbonate capsules contain sodium bicarbonate, they should be used with caution in patients with Bartter’s syndrome, hypokalemia, hypocalcemia, and problems with acid-base balance. Long-term administration of bicarbonate with calcium or milk can cause milk-alkali syndrome. Chronic use of sodium bicarbonate may lead to systemic alkalosis and increased sodium intake can produce edema and weight increase. 5.6 Clostridium difficile Associated Diarrhea Published observational studies suggest that PPI therapy like omeprazole and sodium bicarbonate may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve. [See Adverse Reactions (6.2)] Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 5.7 Interaction with Clopidogrel Avoid concomitant use of omeprazole and sodium bicarbonate with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that interfere with CYP2C19 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using omeprazole and sodium bicarbonate, consider alternative anti-platelet therapy. [See Drug Interactions (7.5) and Pharmacokinetics (12.3)] 5.8 Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis- related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long- term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. [See Dosage and Administration (2) and Adverse Reactions (6.2)] 5.9 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.[See Adverse Reactions (6.2)] 5.10 Concomitant Use of Omeprazole and Sodium Bicarbonate with St John’s Drugs which induce CYP2C19 OR CYP34A (such as St John’s Wort or rifampin) can substantially decrease omeprazole concentrations [See Drug Interactions (7.2)]. Avoid concomitant use of omeprazole and sodium bicarbonate with St John’s Wort or rifampin. 5.11 Interactions with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop omeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. [See Pharmacodynamics (12.2)]. 5.12 Concomitant use of Omeprazole and Sodium Bicarbonate with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients. [See Drug Interactions (7.8)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide. Instruct patients that omeprazole and sodium bicarbonate capsules 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. Omeprazole and sodium bicarbonate is available either as 40 mg or 20 mg capsules with 1100 mg sodium bicarbonate. Patients should be instructed not to substitute omeprazole and sodium bicarbonate capsules for other omeprazole and sodium bicarbonate dosage forms because different dosage forms contain different amounts of sodium bicarbonate. [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 and sodium bicarbonate 40 mg; therefore, two 20 mg capsules of omeprazole and sodium bicarbonate should not be substituted for one capsule of omeprazole and 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 and sodium bicarbonate capsules (304 mg per capsule). 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 (5.5)] Patients should be informed that the most frequent adverse reactions associated with omeprazole and sodium bicarbonate capsules include headache, abdominal pain, nausea, diarrhea, vomiting and flatulence. [See Adverse Reactions (6)] Pregnant women should be advised that a harmful effect of omeprazole and 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 any cardiovascular or neurological symptoms including palpitations, dizziness, seizures and tetany as these may be signs of hypomagnesemia. [See Warnings and Precautions (5.6)] 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 (5.9)] Manufactured by: Aurolife Pharma LLC Dayton, NJ 08810 Manufactured for: Aurobindo Pharma USA, Inc. Dayton, NJ 08810 Revised: 03/2016

DOSAGE AND ADMINISTRATION

2 Omeprazole and sodium bicarbonate is available as a capsule in 20 mg and 40 mg strengths of omeprazole for adult use. Directions for use for each indication are summarized in Table 1. All recommended doses throughout the labeling are based upon omeprazole. 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 and sodium bicarbonate 40 mg; therefore, two 20 mg capsules of omeprazole and sodium bicarbonate should not be substituted for one capsule of omeprazole and sodium bicarbonate 40 mg. Omeprazole and sodium bicarbonate capsules should be taken on an empty stomach at least one hour before a meal. Table 1: Recommended Doses of Omeprazole and Sodium Bicarbonate by Indication for Adults 18 Years and Older Indication Recommended Dose Frequency Short-Term Treatment of Active Duodenal Ulcer 20 mg Once daily for 4 weeks*,+ Benign Gastric Ulcer 40 mg Once daily for 4 to 8 weeks **,+ Gastroesophageal Reflux Disease (GERD) Symptomatic GERD (with no esophageal erosions) 20 mg Once daily for up to 4 weeks+ Erosive Esophagitis 20 mg Once daily for 4 to 8 weeks+ Maintenance of Healing of Erosive Esophagitis 20 mg Once daily** * Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy. [See Clinical Studies (14.1)] ** Controlled studies do not extend beyond 12 months. [See Clinical Studies (14)] + For additional information, [See Indications and Usage (1)] Special Populations Hepatic Insufficiency Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3)] Administration of Capsules Omeprazole and sodium bicarbonate capsules should be swallowed intact with water. DO NOT USE OTHER LIQUIDS. DO NOT OPEN CAPSULE AND SPRINKLE CONTENTS INTO FOOD. Short-Term Treatment of Active Duodenal Ulcer: 20 mg once daily for 4 weeks (some patients may require an additional 4 weeks of therapy (14.1)) (2) Gastric Ulcer: 40 mg once daily for 4 to 8 weeks (2) Gastroesophageal Reflux Disease (GERD) (2) – Symptomatic GERD (with no esophageal erosions): 20 mg once daily for up to 4 weeks – Erosive Esophagitis: 20 mg once daily for 4 to 8 weeks Maintenance of Healing of Erosive Esophagitis: 20 mg once daily * (2) *studied for 12 months