Sodium Bicarbonate

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) .]

DOSAGE & ADMINISTRATION Indication Recommended Adult Dosage Omeprazole and Sodium Bicarbonate for oral suspension Active Duodenal Ulcer 20 mg once daily for 4 weeks; some patients may require an additional 4 weeks Active Benign Gastric Ulcer 40 mg once daily for 4 to 8 weeks Treatment of Symptomatic GERD 20 mg once daily for up to 4 weeks Treatment of EE due to Acid-Mediated GERD 20 mg once daily for 4 to 8 weeks* Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily** 40 mg Omeprazole and Sodium Bicarbonate for oral suspension Reduction of Risk of Upper GI Bleeding in Critically Ill Patients 40 mg initially followed by 40 mg 6 to 8 hours later and 40 mg once daily thereafter for 14 days *an additional 4 weeks of treatment may be given if no response; if recurrence, additional 4 to 8-week courses may be considered. **studied for 12 months. 2.1 Important Administration Instructions Omeprazole and sodium bicarbonate is available as a powder for oral suspension in 20 mg and 40 mg strengths of omeprazole for adult use. All recommended doses throughout the labeling are based upon omeprazole. The sodium content of omeprazole and sodium bicarbonate for oral suspension should be taken into consideration when prescribing this product [see Warnings and Precautions (5.3)] : Omeprazole and sodium bicarbonate for oral suspension: each 20 mg and 40 mg packet of contains 1,680 mg (20 mEq) of sodium bicarbonate. The total content of sodium in each packet is 460 mg. Due to the sodium bicarbonate content of omeprazole and sodium bicarbonate for oral suspension: Do not substitute two packets of 20 mg omeprazole and sodium bicarbonate for oral suspension with one packet of 40 mg omeprazole and sodium bicarbonate for oral suspension. 2.2 Dosage Regimen The recommended dosage regimen by indication in adults of omeprazole and sodium bicarbonate for oral suspension is summarized in Table 1 . Only 40 mg omeprazole and sodium bicarbonate for oral suspension is indicated for the reduction of risk of upper GI bleeding in critically ill adult patients and the dosage regimen is summarized in Table 2 . All recommended dosages are based upon omeprazole content. Table 1: Recommended Dosage Regimen of Omeprazole and Sodium Bicarbonate for Oral Suspension in Adults by Indication Indication Dosage of omeprazole and sodium bicarbonate for oral suspension Treatment Duration Treatment of Active Duodenal Ulcer 20 mg once daily 4 weeks 1,2 Treatment of Active Benign Gastric Ulcer 40 mg once daily 4 to 8 weeks Treatment of Symptomatic GERD 20 mg once daily Up to 4 weeks Treatment of EE due to Acid-Mediated GERD 20 mg once daily 4 to 8 weeks 2 Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily Controlled studies do not extend beyond 12 months. 1 Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy [see Clinical Studies (14.1)]. 2 The efficacy of omeprazole and sodium bicarbonate used for longer than 8 weeks in patients with EE has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of EE or GERD symptoms (e.g., heartburn), additional 4 to 8-week courses of omeprazole and sodium bicarbonate may be considered . Table 2: Recommended Dosage Regimen of 40 mg Omeprazole and Sodium Bicarbonate for Oral Suspension in Adults by Indication Indication Dosage of 40 mg omeprazole and sodium bicarbonate for oral suspension Treatment Duration Reduction of Risk of Upper GI Bleeding in Critically Ill Patients 40 mg initially; followed by 40 mg 6 to 8 hours later; and 40 mg once daily thereafter 14 days 2.3 Preparation and Administration Omeprazole and Sodium Bicarbonate for Oral Suspension Omeprazole and sodium bicarbonate for oral suspension is intended to be mixed with water and administered orally or via a nasogastric (NG) or orogastric (OG) tube. If administered orally, take on an empty stomach at least one hour before a meal. If administered via NG or OG tube, suspend enteral feeding approximately 3 hours before and 1 hour after administration of omeprazole and sodium bicarbonate for oral suspension. Oral Administration Empty the contents of a packet into a small cup containing 5 to 10 mL of water. Do not mix with liquids or foods other than water. Stir well and drink immediately. Refill cup with water and drink immediately. Nasogastric (NG) or Orogastric (OG) Tube Administration Add 20 mL of water to a catheter tipped syringe and then add the contents of a packet. Use an appropriately-sized catheter tipped syringe. Do not mix with liquids or foods other than water. Shake the syringe to dissolve the powder. Administer 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.

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 Tubulointerstitial Nephritis: Discontinue treatment and evaluate patients. ( 5.2 ) Sodium Bicarbonate Buffer Content : Take sodium content into consideration in patients on a sodium-restricted diet. Avoid in patients with Bartter’s syndrome, hypokalemia, hypocalcemia, and problems with acid-base balance. ( 5.3 ) Clostridium difficile -Associated Diarrhea : PPI therapy may be associated with increased risk. ( 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 ) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.6 ) 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. ( 5.7 ) Interaction with Clopidogrel : Avoid concomitant use of Omeprazole and Sodium Bicarbonate. ( 5.8 ) Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.9 ) Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.10 ) Interaction with St. John’s wort or Rifampin : Avoid concomitant use of Omeprazole and Sodium Bicarbonate. ( 5.11 , 7 ) Interactions with Diagnostic Investigations for Neuroendocrine Tumors : Increased Chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors; temporarily stop Omeprazole and Sodium Bicarbonate at least 14 days before assessing CgA levels. ( 5.12 ) 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. ( 5.13 , 7 ) Fundic Gland Polyps : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.14 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with Omeprazole and Sodium Bicarbonate 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 Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea and anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue Omeprazole and Sodium Bicarbonate and evaluate patients with suspected acute TIN [ see Contraindications (4) ]. 5.3 Sodium Bicarbonate Buffer Content Each 20 mg and 40 mg Omeprazole and Sodium Bicarbonate capsule contains 1,100 mg (13 mEq) of sodium bicarbonate. The total content of sodium in each capsule is 304 mg. Each 20 mg and 40 mg packet of Omeprazole and Sodium Bicarbonate for oral suspension contains 1,680 mg (20 mEq) of sodium bicarbonate. The total content of sodium in each packet is 460 mg. Chronic 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 gain. The sodium content of Omeprazole and Sodium Bicarbonate products should be taken into consideration when administering to patients on a sodium-restricted diet or those at risk for developing congestive heart failure. Avoid Omeprazole and Sodium Bicarbonate in patients with Bartter’s syndrome, hypokalemia, hypocalcemia, and problems with acid-base balance. 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 [ Adverse Reactions (6.2) ] . Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 5.5 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 (2.2) and Adverse Reactions (6.2) ] . 5.6 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2)]. Discontinue Omeprazole and Sodium Bicarbonate at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.7 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving Omeprazole and Sodium Bicarbonate, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.8 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

CONTRAINDICATIONS Omeprazole and Sodium Bicarbonate is contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.2) Error! Hyperlink reference not valid. Adverse Reactions (6.2)] . Proton pump inhibitors (PPIs), including Omeprazole and Sodium Bicarbonate, are contraindicated in patients receiving rilpivirine containing products [see Drug Interactions (7) ] . Known hypersensitivity to any components of the formulation ( 4 ) Patients receiving rilpivirine-containing products ( 4 , 7 )

DRUG INTERACTIONS Tables 6 and 7 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with omeprazole and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 6: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3) ] . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3) ] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. Intervention: Rilpivirine-containing products: Concomitant use with Omeprazole and Sodium Bicarbonate is contraindicated [see Contraindications (4) ]. Atazanavir: Avoid concomitant use with Omeprazole and Sodium Bicarbonate. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with Omeprazole and Sodium Bicarbonate. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs. Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. Methotrexate Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.13) ]. Intervention: A temporary withdrawal of Omeprazole and Sodium Bicarbonate may be considered in some patients receiving high-dose methotrexate. CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clopidogrel Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3) ]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel . Intervention: Avoid concomitant use with Omeprazole and Sodium Bicarbonate. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.8) ]. Citalopram Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3) ] . Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. Cilostazol Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3) ]. Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. Phenytoin Clinical Impact: Potential for increased exposure of phenytoin. Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. Diazepam Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3) ] . Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed. Digoxin Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3) ]. Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): 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) ] . See the prescribing information for other drugs dependent on gastric pH for absorption. Tacrolimus Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 . Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.12 ) and Clinical Pharmacology (12.2) ] . Intervention: Temporarily stop PRILOSEC treatment at least 14 days 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. Interaction with Secretin Stimulation Test Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. Intervention: Temporarily stop Omeprazole and Sodium Bicarbonate treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2) ] . False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. Intervention: An alternative confirmatory method should be considered to verify positive results. Other Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with Omeprazole and Sodium Bicarbonate. Table 7: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3) ]. Intervention: St. John’s wort, rifampin: Avoid concomitant use with Omeprazole and Sodium Bicarbonate [see Warnings and Precautions (5.11) ]. Ritonavir-containing products: See prescribing information for specific drugs. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of ome

ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial 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 )] . Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.6 )] . Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions ( 5.7 )] . Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions ( 5.9 )] . Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions ( 5.10 )] . Fundic Gland Polyps [see Warnings and Precautions ( 5.14 )] . Most common adverse reactions (≥2%) are: headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 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 practice. The safety of KONVOMEP has been established, in part, based on oral studies of an oral delayed-release omeprazole product and another oral omeprazole and sodium bicarbonate product. Clinical Trials with Omeprazole In the U.S. clinical trial population of 465 adult patients, the adverse reactions summarized in Table 2 were reported to occur in 1% or more of patients on therapy with omeprazole. Table 2: Adverse Reactions Occurring in 1% or More of Adult Patients in US Clinical Trials of Omeprazole Therapy Omeprazole % (n = 465) Placebo % (n = 64) Ranitidine % (n = 195) Headache 7 6 8 Diarrhea 3 3 2 Abdominal Pain 2 3 3 Nausea 2 3 4 Upper Respiratory Infection (URI) 2 2 3 Dizziness 2 0 3 Vomiting 2 5 2 Rash 2 0 0 Constipation 1 0 0 Cough 1 0 2 Asthenia 1 2 2 Back Pain 1 0 1 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 2631 patients and subjects received omeprazole. Table 3: Adverse Reactions Occurring in 1% or More of Adult Patients in International Clinical Trials of Omeprazole Therapy Omeprazole % (n = 2631) Placebo % (n = 120) Abdominal Pain 5.2 3.3 Nausea 4.0 6.7 Diarrhea 3.7 2.5 Vomiting 3.2 10.0 Headache 2.9 2.5 Flatulence 2.7 5.8 Acid Regurgitation 1.9 3.3 Constipation 1.5 0.8 Asthenia 1.3 0.8 Clinical Trial of Another Omeprazole and Sodium Bicarbonate Product, 40 mg Adverse reactions reported in at least 3% of critically ill adult patients in a clinical trial of 40 mg omeprazole and sodium bicarbonate for oral suspension compared to intravenous cimetidine for up to 14 days are presented in Table 4 . Table 4: Common Adverse Reactions Reported in at least 3% of patients in either treatment group. by Body System and Preferred Term in a Randomized Controlled Trial of Critically Ill Adult Patients Treated up to 14 Days Body System Preferred Term Omeprazole and Sodium Bicarbonate for Oral Suspension, 40 mg (%) (n = 178) Intravenous Cimetidine 1,200 mg per day (%) (n = 181) NOS = Not otherwise specified. Blood and Lymphatic System Disorders Anemia NOS 7.9 7.7 Anemia NOS Aggravated 2.2 3.9 Thrombocytopenia 10.1 6.1 Cardiac Disorders Atrial Fibrillation 6.2 3.9 Bradycardia NOS 3.9 2.8 Supraventricular Tachycardia 3.4 1.1 Tachycardia NOS 3.4 3.3 Ventricular Tachycardia 4.5 3.3 Gastrointestinal Disorders In this trial, clinically significant upper gastrointestinal bleeding was considered a serious adverse reaction, but it is not included in this table. Constipation 4.5 4.4 Diarrhea NOS 3.9 8.3 Gastric Hypomotility 1.7 3.3 General Disorders and Administration Site Conditions Hyperpyrexia 4.5 1.7 Edema NOS 2.8 6.1 Pyrexia 20.2 16.0 Infections and Infestations Candidal Infection NOS 1.7 3.9 Oral Candidiasis 3.9 0.6 Sepsis NOS 5.1 5.0 Urinary Tract Infection 2.2 3.3 Investigations Liver Function Tests NOS Abnormal 1.7 3.3 Metabolism and Nutrition Disorders Fluid Overload 5.1 7.7 Hyperglycemia NOS 10.7 11.6 Hyperkalemia 2.2 3.3 Hypernatremia 1.7 5.0 Hypocalcemia 6.2 5.5 Hypoglycemia NOS 3.4 4.4 Hypokalemia 12.4 13.3 Hypomagnesemia 10.1 9.9 Hyponatremia 3.9 2.8 Hypophosphatemia 6.2 3.9 Psychiatric Disorders Agitation 3.4 8.8 Respiratory, Thoracic, and Mediastinal Disorders Acute Respiratory Distress Syndrome 3.4 3.9 Nosocomial Pneumonia 11.2 9.4 Pneumothorax NOS 0.6 4.4 Respiratory Failure 1.7 3.3 Skin and Subcutaneous Tissue Disorders Decubitus Ulcer 3.4 2.8 Rash NOS 5.6 6.1 Vascular Disorders Hypertension NOS 7.9 3.3 Hypotension NOS 9.6 6.6 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of omeprazole and sodium bicarbonate. 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. Omeprazole Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, urticaria (see also Skin 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-glutamyl transpeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred, including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic failure (some fatal), and hepatic encephalopathy. Infections and Infestations: Clostridium difficile -associated diarrhea. Metabolism and Nutritional Disorders: Hypomagnesemia, hypocalcemia, hypokalemia, [see Warnings and Precautions ( 5.10 )] , hyponatremia, hypoglycemia and weight gain. Musculoskeletal: Muscle cramps, myalgia, muscle weakness, joint pain, bone fracture, and leg pain. Nervous System/Psychiatric: Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia. Respiratory: Epistaxis, pharyngeal pain. Skin: Severe generalized skin reactions including TEN (some fatal), SJS, DRESS, AGEP, cutaneous lupus erythematosus and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis. Special Senses: Tinnitus, taste perversion. Ocular: Blurred vision, ocular irritation, dry eye syndrome, optic atrophy, anterior ischemic optic neuropathy, optic neuritis, and double vision. Urogenital: Tubulointerstitial nephritis, urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, gynecomastia, and erectile dysfunction. Hematologic: Rare instances of pancytopenia, agranulocytosis (some fatal), thrombocytopenia, neutropenia, leukopenia, anemia, leukocytosis, and hemolytic anemia have been reported. Sodium Bicarbonate Metabolic alkalosis, seizures, and tetany.

INDICATIONS AND USAGE Sodium bicarbonate injection is indicated in the treatment of metabolic acidosis which may occur in severe renal disease, uncontrolled diabetes, circulatory insufficiency due to shock or severe dehydration, extracorporeal circulation of blood, cardiac arrest and severe primary lactic acidosis. Sodium bicarbonate is further indicated in the treatment of certain drug intoxications, including barbiturates (where dissociation of the barbiturate-protein complex is desired), in poisoning by salicylates or methyl alcohol and in hemolytic reactions requiring alkalinization of the urine to diminish nephrotoxicity of hemoglobin and its breakdown products. Sodium bicarbonate also is indicated in severe diarrhea which is often accompanied by a significant loss of bicarbonate. Treatment of metabolic acidosis should, if possible, be superimposed on measures designed to control the basic cause of the acidosis - e.g., insulin in uncomplicated diabetes, blood volume restoration in shock. But since an appreciable time interval may elapse before all of the ancillary effects are brought about, bicarbonate therapy is indicated to minimize risks inherent to the acidosis itself. Vigorous bicarbonate therapy is required in any form of metabolic acidosis where a rapid increase in plasma total CO 2 content is crucial - e.g., cardiac arrest, circulatory insufficiency due to shock or severe dehydration, and in severe primary lactic acidosis or severe diabetic acidosis.