Omeprazole/Bicarbonate

Warnings and Precautions, Fundic Gland Polyps ( 5.13 ) 06/2018

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 Indication Recommended Adult Dosage Omeprazole and sodium bicarbonate capsules 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 an additional 4 weeks of treatment may be given if no response; if recurrence, additional 4 to 8-week courses may be considered. Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily studied for 12 months. 2.1 Important Administration Instructions Omeprazole and sodium bicarbonate is available as a capsule 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 capsules should be taken into consideration when prescribing this product [see Warnings and Precautions (5.3) ]: Omeprazole and sodium bicarbonate capsule: each 20 mg and 40 mg capsule contains 1,100 mg (13 mEq) of sodium bicarbonate. The total content of sodium in each capsule is 304 mg. Due to the sodium bicarbonate content of omeprazole and sodium bicarbonate capsules: Do not substitute two 20 mg omeprazole and sodium bicarbonate capsules with one 40 mg omeprazole and sodium bicarbonate capsule. 2.2 Dosage Regimen The recommended dosage regimen by indication in adults of omeprazole and sodium bicarbonate capsules is summarized in Table 1. All recommended dosages are based upon omeprazole content. Table 1: Recommended Dosage Regimen of Omeprazole and Sodium Bicarbonate Capsules in Adults by Indication Indication Dosage of Omeprazole and Sodium Bicarbonate Capsules Treatment Duration Treatment of Active Duodenal Ulcer 20 mg once daily 4 weeks Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy [See Clinical Studies (14.1) ]. , The efficacy of omeprazole and sodium bicarbonate capsules 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 capsules may be considered. 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 Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily Controlled studies do not extend beyond 12 months. 2.3 Preparation and Administration Omeprazole and Sodium Bicarbonate Capsules Swallow capsules intact with water. Do not open the capsule and do not administer with liquids other than water. Take on an empty stomach at least one hour before a meal [see Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS Omeprazole and Sodium Bicarbonate Capsules, 20mg/1,100 mg: White to off white powder filled in size "00" hard gelatin capsules with opaque white colored cap and opaque white colored body imprinted "SG" on cap and "363" on body with black ink. Omeprazole and Sodium Bicarbonate Capsules, 40 mg/1,100 mg: White to off white powder filled in size "00" hard gelatin capsules with opaque light blue colored cap and opaque white colored body imprinted "SG" on cap and "364" on body with black ink. Capsules ( 3 ) : 20 mg omeprazole and 1,100 mg sodium bicarbonate 40 mg omeprazole and 1,100 mg sodium bicarbonate

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 )

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 …

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 USE IN SPECIFIC POPULATIONS Hepatic Impairment and Asian Patients : Avoid use for maintenance of healing of erosive esophagitis. ( 8.6 , 8.7 ) 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 capsules 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 …

12.1 Mechanism of Action Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H 2 histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more. Omeprazole is acid labile and thus rapidly degraded by gastric acid. Omeprazole and sodium bicarbonate capsules are immediate-release formulations that contain sodium bicarbonate which raises the gastric pH and thus protects omeprazole from acid degradation.

11 DESCRIPTION Omeprazole and sodium bicarbonate is a combination of omeprazole, a proton-pump inhibitor, and sodium bicarbonate, an antacid. Omeprazole is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3,5dimethyl-2- pyridinyl)methyl]sulfinyl]-1 H -benzimidazole, a racemic mixture of two enantiomers that inhibits gastric acid secretion. Its empirical formula is C 17 H 19 N 3 O 3 S, with a molecular weight of 345.42. The structural formula is: Omeprazole, USP is a white or almost white powder which melts with decomposition at about 155°C. Soluble in dichloromethane, practically insoluble 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 1,100 mg of sodium bicarbonate with the following excipients: croscarmellose sodium and sodium stearyl fumarate. The capsules consist of gelatin and titanium dioxide. In addition the 20 mg/1,100 mg capsule shell contains sodium lauryl sulfate and the 40 mg/1,100 mg capsule shell contains FD&C Blue 1. The capsules are printed with edible ink containing black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, propylene glycol, potassium hydroxide, shellac and strong ammonia solution. Omeprazole and sodium bicarbonate capsules are immediate-release formulations that contain sodium bicarbonate which raises the gastric pH and thus protects omeprazole from acid degradation. Chemical Structure

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Omeprazole and Sodium Bicarbonate Capsules, 20mg/1100 mg: White to off white powder filled in size "00" hard gelatin capsules with opaque white colored cap and opaque white colored body imprinted "SG" on cap and "363" on body with black ink. They are supplied as: NDC: 71205-984-30 Bottles of 30s NDC: 71205-984-60 Bottles of 60s NDC: 71205-984-90 Bottles of 90s Omeprazole and Sodium Bicarbonate Capsules, 40 mg/1100 mg: White to off white powder filled in size "00" hard gelatin capsules with opaque light blue colored cap and opaque white colored body imprinted "SG" on cap and "364" on body with black ink. They are supplied as: NDC: 71205-985-30 Bottles of 30s NDC: 71205-985-60 Bottles of 60s NDC: 71205-985-90 Bottles of 90s Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light and moisture.