OMEPRAZOLE: 87,111 Adverse Event Reports & Safety Profile

The active ingredient in omeprazole delayed-release capsule, USP is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1 H -benzimidazole, a compound that inhibits gastric acid secretion. Its molecular formula is C 17 H 19 N 3 O 3 S, with a molecular weight of 345.42. The structural formula is: Omeprazole is a white to off-white crystalline powder that melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.

The

Dissolution test to be performed according to USP Test 2. Omeprazole is supplied as delayed-release capsules for oral administration. Each delayed-release capsule contains either 10 mg, 20 mg or 40 mg of omeprazole in the form of enteric-coated granules.

The

10 mg and 20 mg capsule contains the following inactive ingredients: anhydrous lactose, low-substituted hydroxypropyl cellulose, magnesium oxide, magnesium stearate, microcrystalline cellulose, methacrylic acid copolymer dispersion type C, polysorbate 80, povidone and talc, triethyl citrate. The capsule shells for the 10 mg have the following inactive ingredients: black iron oxide, gelatin, red iron oxide, titanium dioxide and yellow iron oxide. The capsule shells for the 20 mg have the following inactive ingredients: gelatin and titanium dioxide. The ink used for printing contains: black iron oxide, propylene glycol and shellac.

The

40 mg capsule contains the following inactive ingredients: acetone, anhydrous lactose, croscarmellose sodium, dehydrated alcohol, dibutyl sebacate, hypromellose phthalate, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, polysorbate 80, povidone and talc. The capsule shells for the 40 mg have the following inactive ingredients: hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide. In addition, the capsule shells may also contain black iron oxide, carrageenan, and potassium chloride. The ink used for printing contains black iron oxide. structure

AND USAGE Omeprazole Delayed-Release Capsules is a proton pump inhibitor (PPI) indicated for the: Treatment of active duodenal ulcer in adults (1.1) Eradication of Helicobacter pylori to reduce the risk of duodenal ulcer recurrence in adults (1.2) Treatment of active benign gastric ulcer in adults (1.3) Treatment of symptomatic gastroesophageal reflux disease (GERD) in patients 1 year of age and older (1.4) Treatment of erosive esophagitis (EE) due to acid-mediated GERD in patients 1 year of age and older (1.5) Maintenance of healing of EE due to acid-mediated GERD in patients 1 year of age and older (1.6) Pathologic hypersecretory conditions in adults (1.7) The safety and effectiveness of Omeprazole Delayed-Release Capsules in pediatric patients < 1 year of age have not been established ( 8.4 ).

1.1 Treatment of Active Duodenal Ulcer Omeprazole Delayed-Release Capsules is indicated for short-term treatment of active duodenal ulcer in adults. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy.

1.2 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

Triple Therapy Omeprazole

Delayed-Release Capsules in combination with clarithromycin and amoxicillin, is indicated for treatment of patients with H. pylori infection and duodenal ulcer disease (active or up to 1-year history) to eradicate H. pylori in adults.

Dual Therapy Omeprazole

Delayed-Release Capsules in combination with clarithromycin is indicated for treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H . pylori in adults. Among patients who fail therapy, Omeprazole Delayed-Release Capsules with clarithromycin is more likely to be associated with the development of clarithromycin resistance as compared with triple therapy. In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [see C l i nical Pharmacology (12.4) and the clarithromycin prescribing information, Microbiology section ].

1.3 Treatment of Active Benign Gastric Ulcer Omeprazole Delayed-Release Capsules is indicated for short-term treatment (4 to 8 weeks) of active benign gastric ulcer in adults.

1.4 Treatment of Symptomatic Gastroesophageal Reflux Disease (GERD)

Omeprazole

Delayed-Release Capsules is indicated for the treatment of heartburn and other symptoms associated with GERD for up to 4 weeks in patients 1 year of age and older.

1.5 Treatment of Erosive Esophagitis (EE) Due to Acid-Mediated GERD Pediatric Patients 1 Year of Age to Adults Omeprazole Delayed-Release Capsules is indicated for the short-term treatment (4 to 8 weeks) of EE due to acid-mediated GERD that has been diagnosed by endoscopy in patients 1 year of age and older. The efficacy of Omeprazole Delayed-Release 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 Delayed-Release Capsules may be considered. The safety and effectiveness of Omeprazole Delayed-Release Capsules in pediatric patients &lt; 1 year of age have not been established ( 8.4 ).

1.6 Maintenance of Healing of EE Due to Acid-Mediated GERD Omeprazole Delayed-Release Capsules is indicated for the maintenance healing of EE due to acid-mediated GERD in patients 1 year of age and older. Controlled studies do not extend beyond 12 months.

1.7 Pathological Hypersecretory Conditions Omeprazole Delayed-Release Capsules is indicated for the long-term treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) in adults.

AND ADMINISTRATION Indications Recommended Adult ( Error! Hyperlink reference not valid.) and Pediatric Dosage ( Error! Hyperlink reference not valid.) Treatment of Active Duodenal Ulcer 20 mg once daily for 4 weeks; some patients may require an additional 4 weeks ( Error! Hyperlink reference not valid. ) H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: Omeprazole Delayed-Release Capsules 20 mg Each drug twice daily for 10 days ( Error! Hyperlink reference not valid. )* Amoxicillin 1000 mg Clarithromycin 500 mg Dual Therapy: Omeprazole Delayed-Release Capsules 40 mg once daily for 14 days** Clarithromycin 500 mg three times daily for 14 days ( Error! Hyperlink reference not valid. )

Active Benign Gastric Ulcer

40 mg once daily for 4 to 8 weeks ( Error! Hyperlink reference not valid. ) Symptomatic GERD 20 mg once daily for up to 4 weeks ( Error! Hyperlink reference not valid. ) See full prescribing information for weight based dosing in pediatric patients 1 year of age and older ( Error! Hyperlink reference not valid. ) EE due to Acid-Mediated GERD 20 mg once daily for 4 to 8 weeks ( Error! Hyperlink reference not valid. )*** See full prescribing information for weight based dosing in pediatric patients 1 year of age and older ( Error! Hyperlink reference not valid. ) Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily ( Error! Hyperlink reference not valid. )**** See full prescribing information for weight based dosing in pediatric patients 1 year of age and older ( Error! Hyperlink reference not valid. )

Pathological Hypersecretory Conditions

Starting dose is 60 mg once daily (varies with individual patient, see full prescribing information) as long as clinically indicated ( Error! Hyperlink reference not valid. ) * if ulcer present, continue Omeprazole Delayed-Release Capsules 20 mg once daily for an additional 18 days. ** if ulcer present, continue Omeprazole Delayed-Release Capsules 20 mg once daily for an additional 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. Reduce the dosage to 10 mg once daily for patients with hepatic impairment (Child Pugh Class A, B, or C) and Asian patients ( Error! Hyperlink reference not valid. )

2.1 Recommended Adult Dosage Regimen by Indication Table 1 shows the recommended dosage of Omeprazole Delayed-Release Capsules in adult patients by indication.

Table

1: Recommended Dosage Regimen of Omeprazole Delayed-Release Capsules in Adults by Indication Indication Dosage of Omeprazole Delayed-Release Capsules Treatment Duration Treatment of Active Duodenal Ulcer 20 mg once daily 4 weeks 1 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy Omeprazole Delayed-Release Capsules 20 mg Amoxicillin 1000 mg Clarithromycin 500 mg Take all three drugs twice daily 10 days In patients with an ulcer present at the time of initiation of therapy, continue Omeprazole Delayed-Release Capsules 20 mg once daily for an additional 18 days for ulcer healing and symptom relief.

Dual Therapy Omeprazole

Delayed-Release Capsules 40 mg once daily Clarithromycin 500 mg three times daily 14 days In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of Omeprazole Delayed-Release Capsules 20 mg once daily is recommended for ulcer healing and symptom relief.

Active Benign Gastric Ulcer

40 mg once daily 4 to 8 weeks Treatment of Symptomatic GERD 20 mg once daily Up to 4 weeks Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily 4 to 8 weeks 2 Pathological Hypersecretory Conditions 20 mg once daily 3 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 to achieve healing. 2. The efficacy of Omeprazole Delayed-Release 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 Delayed-Release Capsules may be considered. 3. Dosage reduction to 10 mg once daily is recommended for patients with hepatic impairment (Child-Pugh Class A, B or C) and Asian patients when used for the maintenance of healing of EE [see Use in Specific Populations ( 8 .6 , 8 .7 ) and Clinical Pharmacology ( 1 2 .3 , 12 .5 )].

2.2 Recommended Pediatric Dosage Regimen by Indication Table 2 shows the recommended dosage of Omeprazole Delayed-Release Capsules in pediatric patients by indication.

Table

2: Recommended Dosage Regimen of Omeprazole Delayed-Release Capsules in Pediatric Patients by Indication Indication Omeprazole Delayed-Release Capsules Dosage Regimen and Duration Patient Age Weight-Based Dose (mg) Regimen and Duration Treatment of Symptomatic GERD 1 to 16 years 5 to less than 10 kg: 5 mg Once daily for up to 4 weeks 10 to less than 20 kg: 10 mg 20 kg and greater: 20 mg Treatment of EE due to Acid-Mediated GERD 1 to 16 years 5 to less than 10 kg: 5 mg Once daily for 4 to 8 weeks 1 10 to less than 20 kg: 10 mg 20 kg and greater: 20 mg Maintenance of Healing of EE due to Acid-Mediated GERD 1 to 16 years 5 to less than 10 kg: 5 mg Once daily. Controlled studies do not extend beyond 12 months 10 to less than 20 kg: 10 mg 20 kg and greater: 20 mg 1. The efficacy of Omeprazole Delayed-Release 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 Delayed-Release Capsules may be considered.

2.3 Administration Instructions Take Omeprazole Delayed-Release Capsules before meals. Antacids may be used concomitantly with Omeprazole Delayed-Release Capsules. Missed doses: If a dose is missed, administer as soon as possible. However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose.

Omeprazole

Delayed-Release Capsules Swallow Omeprazole Delayed-Release Capsules whole; do not chew. For patients unable to swallow an intact capsule, Omeprazole Delayed-Release Capsules can be opened and administered as follows: Place one tablespoon of applesauce into a clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. Open the capsule. Carefully empty all of the microtablets inside the capsule on the applesauce. Mix the microtablets with the applesauce. Swallow applesauce and microtablets immediately with a glass of cool water to ensure complete swallowing of the microtablets. Do not chew or crush the microtablets. Do not save the applesauce and microtablets for future use.

Omeprazole Delayed-Release Capsules is contraindicated in patients with known hypersensitivity reactions including anaphylaxis to the formulation or any substituted benzimidazole.

Omeprazole

Delayed-Release Capsules is contraindicated in patients with known hypersensitivity reactions including anaphylaxis to the formulation [see Warnings and Precautions ( 5.2 )] or any substituted benzimidazole. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6 )] . Proton pump inhibitors (PPIs), including Omeprazole Delayed-Release Capsules, are contraindicated in patients receiving rilpivirine-containing products Proton pump inhibitors (PPIs), including Omeprazole Delayed-Release Capsules, are contraindicated in patients receiving rilpivirine-containing products [see D rug Interactions ( 7 )]. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with Omeprazole Delayed-Release Capsules, refer to the CONTRAINDICATIONS section of their package inserts.For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with Omeprazole Delayed-Release Capsules, refer to the CONTRAINDICATIONS section of their package inserts. Patients with known hypersensitivity to substituted benzimidazoles or any component of the formulation. ( 4 ) Patients receiving rilpivirine-containing products. ( 4 , 7 ) Refer to the Contraindications section of the prescribing information for clarithromycin and amoxicillin, when administered in combination with Omeprazole Delayed-Release Capsules. ( 4 )

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

0.6 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.

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) and Adverse Reactions (6.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span>.

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 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using Omeprazole and Sodium Bicarbonate, consider alternative antiplatelet therapy <span class="opacity-50 text-xs">[see Drug Interactions (7) and Clinical Pharmacology (12.3 )]</span>.

5.9 Cyanocobalamin (Vitamin B-12)

Deficiency

Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with Omeprazole and Sodium Bicarbonate.

5.10 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [ see Adverse Reactions (6.2) ]. Consider monitoring magnesium and calcium levels prior to initiation of Omeprazole and Sodium Bicarbonate and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.11 Interaction with St. John’s wort or Rifampin Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s wort or rifampin) can substantially decrease omeprazole concentrations <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Avoid concomitant use of Omeprazole and Sodium Bicarbonate with St. John’s wort or rifampin.

5.12 Interactions with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop Omeprazole and Sodium Bicarbonate treatment for 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> .

5.13 Interaction with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

5.14 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPIs users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

INTERACTIONS 1. Atazanavir and nelfinavir: omeprazole reduces plasma levels of atazanavir and nelfinavir. Concomitant use is not recommended (7.1) 2. Saquinavir: omeprazole increases plasma levels of saquinavir. Monitor for toxicity and consider dose reduction of saquinavir (7.1) 3. May interfere with drugs for which gastric pH affects bioavailability (e.g., ketoconazole, iron salts, erlotinib, ampicillin esters, digoxin and mycophenolate mofetil). Patients treated with omeprazole and digoxin may need to be monitored for increases in digoxin toxicity. (7.2 ) 4. Clopidogrel: omeprazole decreases exposure to the active metabolite of clopidogrel. (7.3 , 12.3 ) 5. Clopidogrel: Omeprazole decreases exposure to the active metabolite of clopidogrel. (7.3 , 12.3 ) 6. Cilostazol: omeprazole increases systemic exposure of cilostazol and one of its active metabolites. Consider dose reduction of cilostazol. (7.3 ) 7. Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines): omeprazole can prolong their elimination. Monitor and determine need for dose adjustments (7.3) 8. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time (7.3) 9. Combined inhibitor of CYP2C19 and 3A4 (e.g. voriconazole) may raise omeprazole levels (7.3) 10. Tacrolimus: omeprazole may increase serum levels of tacrolimus (7.4) 11. Methotrexate: Omeprazole may increase serum levels of methotrexate ( 7.7 )

7.1 Interference with Antiretroviral Therapy Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction. Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19. Reduced concentrations of atazanavir and nelfinavir For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C max by 37% and 89% and C min by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, C max by 96%, and C min by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. Increased concentrations of saquinavir For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in C max by 75%, and in C min by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with omeprazole. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.

7.2 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 theirbioavailability. 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). Co-administration of digoxin with omeprazole is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with omeprazole. 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 MMF. Use omeprazole with caution in transplant patients receiving MMF <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

7.3 Effects on Hepatic Metabolism/Cytochrome P-450 Pathways Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time. Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome 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. 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. However, in patients with Zollinger-Ellison syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered. When voriconazole (400 mg Q12h x 1 day, then 200 mg x 6 days) was given with omeprazole (40 mg once daily x 7 days) to healthy subjects, it significantly increased the steady-state C max and AUC 0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole. Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in crossover study, increased C max and AUC of cilostazol by 18% and 26% respectively. C max and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered. Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased omeprazole serum levels. In a cross-over study in 12 healthy male subjects, St John’s wort (300 mg three times daily for 14 days), an inducer of CYP3A4, decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (C max and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (C max and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with omeprazole.

Clopidogrel

Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of omeprazole with clopidogrel. When using omeprazole, consider use of alternative anti-platelet therapy [see Pharmacokinetics (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.

7.4 Tacrolimus Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus.

7.5 Interactions with Investigations of Neuroendocrine Tumors Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors. <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.10 ) and Clinical Pharmacology (12) ]</span>.

7.6 Combination Therapy with Clarithromycin Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions <span class="opacity-50 text-xs">[see Warnings and Precautions in prescribing information for clarithromycin ]</span>. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs <span class="opacity-50 text-xs">[see Contraindications in prescribing information for clarithromycin ]</span>.

7.7 Methotrexate Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted <span class="opacity-50 text-xs">[see Warnings and Precautions (5.11) ]</span>.

Active ingredient(s) Active ingredients (in each powder packet) Omeprazole, USP 20 mg....................................Acid Reducer Sodium Bicarbonate, USP 1,680 mg..................Allows absorption of this omeprazole product

Inactive ingredients anhydrous lactose, hypromellose, hypromellose acetate succinate, iron oxide red, iron oxide yellow, lactose monohydrate, methyl cellulose, monoethanolamine, propylene glycol, sodium lauryl sulfate, sodium starch glycolate, sodium stearate, sodium stearyl fumarate, talc, triethyl citrate and titanium dioxide. The imprinting ink contains ammonium hydroxide, black iron oxide, n-butyl alcohol, propylene glycol and shellac. Questions or Comments? Call toll free 1-800-818-4555 weekdays.

Safety

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