Omeprazole and Sodium Bicarbonate

1 INDICATIONS AND USAGE Omeprazole and Sodium Bicarbonate for oral suspension is indicated in adults for the: short-term treatment of active duodenal ulcer. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. short-term treatment (4 to 8 weeks) of active benign gastric ulcer. treatment of heartburn and other symptoms associated with GERD for up to 4 weeks. short-term treatment (4 to 8 weeks) of EE due to acid-mediated GERD which has been diagnosed by endoscopy in adults. 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. maintenance of healing of EE due to acid-mediated GERD. Controlled studies do not extend beyond 12 months. Omeprazole and Sodium Bicarbonate for oral suspension is indicated in adults for the : reduction of risk of upper GI bleeding in critically ill adult patients. Omeprazole and Sodium Bicarbonate is a proton pump inhibitor (PPI). Omeprazole and Sodium Bicarbonate for oral suspension is indicated in adults for: Treatment of active duodenal ulcer ( 1 ) Treatment of active benign gastric ulcer ( 1 ) Treatment of erosive esophagitis (EE) due to acid-mediated gastroesophageal reflux disease (GERD) ( 1 ) Maintenance of healing of EE ( 1 ) Omeprazole and Sodium Bicarbonate for oral suspension is indicated in adults for: Reduction of risk of upper gastrointestinal (GI) bleeding in critically ill patients ( 1 )

2 DOSAGE AND ADMINISTRATION * 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. Indication ( 2 ) Recommended Adult Dosage ( 2 ) 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 2.1 Important Administration Instructions Omeprazole and Sodium Bicarbonate is available as a 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 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: 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 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. 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. 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 befo…

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 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 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 administ…

4 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 ), 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 )

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 C linical 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 ( 5.12 )]. 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 ( 5.7 )]. 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 dr…

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with Omeprazole and Sodium Bicarbonate in pregnant women. Omeprazole and Sodium Bicarbonate contains omeprazole and sodium bicarbonate. Omeprazole There are no adequate and well-controlled studies with omeprazole 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. Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person). Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg esomeprazole or 40 mg omeprazole (based on body surface area for a 60 kg person). 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 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age (see Data) . Sodium Bicarbonate Available data with sodium bicarbonate use in pregnant women are insufficient to identify a drug associated risk of major birth defects or miscarriage. Published animal studies report that sodium bicarbonate administered to rats, mice or rabbits during pregnancy did not cause adverse developmental effects in offspring. The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data There are no adequate and well-controlled studies with Omeprazole and Sodium Bicarbonate in pregnant women. 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 Register, 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 PPI. 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 PPI 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 malfor…

6 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 Ajanta Pharma USA Inc. at 855-664-7744 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 Omeprazole and Sodium Bicarbonate has been established, in part, based on oral studies of an oral delayed-release omeprazole product. Clinical Trials with Omeprazole In the U.S. clinical trial population of 465 adult patients, the adverse reactions summarized in Table 3 were reported to occur in 1% or more of patients on therapy with omeprazole. Table 3: 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 4 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 4: Adverse Reactions Occurring in 1% or More of Adult Patients in International Clinical Trials of Omeprazole Therapy Omeprazole % (N = 2,631) 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 40 mg Omeprazole and Sodium Bicarbonate for Oral Suspension 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 5 . Table 5: Common Adverse Reactions 1 by Body System and Preferred Term in a Randomized Controlled Trial of Critically Ill Adult Patients Treated up to 14 Days NOS = not otherwise specified 1 reported in at least 3% of patients in either treatment group. 2 In this trial, clinically significant upper gastrointestinal bleeding was considered a serious adverse reaction, but it is not included in this table. Body System Preferred Term Omeprazole and Sodium Bicarbonate 40 mg for oral suspension once daily % (N=178) Intravenous Cimetidine 1,200 mg per day % (N=181) 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 2 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.…