Omeprazole/Bicarbonate

1 INDICATIONS AND USAGE Omeprazole and sodium bicarbonate is a proton pump inhibitor (PPI) 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 capsules in pediatric patients (<18 years of age) have not been established. ( 8.4 ) 1.1 Duodenal Ulcer Omeprazole and sodium bicarbonate is 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 is indicated for short-term treatment (4-8 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 is indicated for the treatment of heartburn and other symptoms associated with GERD for up to 4 weeks. [See Clinical Studies (14.3) .] Erosive Esophagitis Omeprazole and sodium bicarbonate is indicated for the short-term treatment (4-8 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), an additional 4-8 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 is indicated to maintain healing of erosive esophagitis. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14.4) .]

2 DOSAGE AND ADMINISTRATION 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 (1,100 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 Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy. [See Clinical Studies (14.1) .] , For additional information, [See Indications and Usage (1) ] Benign Gastric Ulcer 40 mg Once daily for 4-8 weeks , Controlled studies do not extend beyond 12 months. [See Clinical Studies (14) .] 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 4-8 weeks Maintenance of Healing of Erosive Esophagitis 20 mg Once daily • 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 4-8 weeks ( 2 ) • Gastroesophageal Reflux Disease (GERD) ( 2 ) o Symptomatic GERD (with no esophageal erosions): 20 mg once daily for up to 4 weeks o Erosive Esophagitis: 20 mg once daily for 4-8 weeks • Maintenance of Healing of Erosive Esophagitis: 20 mg once daily* ( 2 ) *Studied for 12 months 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.

5 WARNINGS AND PRECAUTIONS • Gastric Malignancy: In adults, symptomatic response does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 ) • Acute interstitial nephritis has been observed in patients taking PPIs. ( 5.2 ) • Buffer Content: contains sodium bicarbonate ( 5.3 ) • PPI therapy may be associated with increased risk of Clostridium difficile- associated diarrhea. ( 5.4 ) • 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. ( 5.5 ) • Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue omeprazole and sodium bicarbonate and refer to specialist for evaluation. ( 5.6 ) • Avoid concomitant use of omeprazole and sodium bicarbonate with clopidogrel. ( 5.7 ) • Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.8 ) • 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 Chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. ( 5.11 , 12.2 ) • Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider a temporary withdrawal of omeprazole and sodium bicarbonate. ( 5.12 , 7.8 ) • Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.13 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a proton pump inhibitor PPI. In older patients, also consider an endoscopy. 5.2 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) .] 5.3 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 products should be taken into consideration when administering to patients on a sodium restricted diet. Because omeprazole and sodium bicarbonate products 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. 5.4 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 …

4 CONTRAINDICATIONS Omeprazole and sodium bicarbonate is contraindicated in patients with known hypersensitivity to any components of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria. [See Adverse Reactions (6) .] • Known hypersensitivity to any components of the formulation ( 4 )

7 DRUG INTERACTIONS • 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. ( 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 ) 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 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 international normalized ratio (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 P450 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 C max and AUC 0-24 of omeprazol…

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 about 68 times and 42 times, respectively, an oral human dose of 40 mg (based on 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 Error! Hyperlink reference not valid. ) . 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 H 2 -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 H 2 -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 H 2 -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 33.6 times an oral human dose of 40 mg on a body …

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.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: • Acute Interstitial Nephritis [see Warnings and Precautions (5.2) ] • Clostridium difficile -Associated Diarrhea [see Warnings and Precautions (5.4) ] • Bone Fracture [see Warnings and Precautions (5.5) ] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6) ] • Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.8) ] • Hypomagnesemia [see Warnings and Precautions (5.9) ] • Fundic Gland Polyps [see Warnings and Precautions (5.13) ] Most common adverse reactions (incidence ≥ 2%) are: headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Westminster Pharmaceuticals, LLC at 1-844-221-7294 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the U.S. clinical trial population of 465 patients, the adverse reactions summarized in Table 2 were reported to occur in 1% or more of patients on therapy with omeprazole. Numbers in parentheses indicate percentages of the adverse reactions considered by investigators as possibly, probably or definitely related to the drug. Table 2: Adverse Reactions Occurring in 1% or More of Patients on Omeprazole Therapy Omeprazole (n = 465) Placebo (n = 64) Ranitidine (n = 195) Headache 6.9 (2.4) 6.3 7.7 (2.6) Diarrhea 3.0 (1.9) 3.1 (1.6) 2.1 (0.5) Abdominal Pain 2.4 (0.4) 3.1 2.1 Nausea 2.2 (0.9) 3.1 4.1 (0.5) URI 1.9 1.6 2.6 Dizziness 1.5 (0.6) 0.0 2.6 (1.0) Vomiting 1.5 (0.4) 4.7 1.5 (0.5) Rash 1.5 (1.1) 0.0 0.0 Constipation 1.1 (0.9) 0.0 0.0 Cough 1.1 0.0 1.5 Asthenia 1.1 (0.2) 1.6 (1.6) 1.5 (1.0) Back Pain 1.1 0.0 0.5 Table 3 summarizes the adverse reactions that occurred in 1% or more of omeprazole-treated patients from international double-blind and open-label clinical trials in which 2,631 patients and subjects received omeprazole. Table 3: Incidence of Adverse Reactions ≥ 1% Causal Relationship not Assessed Omeprazole (n = 2631) Placebo (n = 120) Body as a Whole, Site Unspecified Abdominal Pain 5.2 3.3 Asthenia 1.3 0.8 Digestive System Constipation 1.5 0.8 Diarrhea 3.7 2.5 Flatulence 2.7 5 .8 Nausea 4.0 6.7 Vomiting 3.2 10.0 Acid Regurgitation 1.9 3.3 Nervous System/Psychiatric Headache 2.9 2.5 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of omeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria (see also Error! Hyperlink reference not valid. below), fever, pain, fatigue, malaise, and systemic lupus erythematosus. Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema. Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis, abdominal swelling and fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. Hepatic: Mild and, rarely, marked elevations of liver function tests [ALT (SGPT), AST (SGOT), γ-glutamyltranspeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has…