Omeprazole Sodium Bicarbonate: Package Insert and Label Information

OMEPRAZOLE SODIUM BICARBONATE- omeprazole and sodium bicarbonate capsule
Cipla USA Inc.

1 INDICATIONS AND USAGE

1.1 Duodenal Ulcer

Omeprazole and sodium bicarbonate is indicated for short-term treatment of active duodenal ulcer. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. [See Clinical Studies (14.1).]

1.2 Gastric Ulcer

Omeprazole and sodium bicarbonate is indicated for short-term treatment (4-8 weeks) of active benign gastric ulcer. [See Clinical Studies (14.2).]

1.3 Treatment of Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD

Omeprazole and sodium bicarbonate is indicated for the treatment of heartburn and other symptoms associated with GERD for up to 4 weeks. [See Clinical Studies (14.3).]

Erosive Esophagitis

Omeprazole and sodium bicarbonate is indicated for the short-term treatment (4-8 weeks) of erosive esophagitis which has been diagnosed by endoscopy.

The efficacy of omeprazole and sodium bicarbonate used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, it may be helpful to give up to an additional 4 weeks of treatment. If there is recurrence of erosive esophagitis or GERD symptoms (e.g., heartburn), an additional 4-8 week courses of omeprazole and sodium bicarbonate may be considered. [See Clinical Studies (14.3).]

1.4 Maintenance of Healing of Erosive Esophagitis

Omeprazole and sodium bicarbonate is indicated to maintain healing of erosive esophagitis. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14.4).]

2 DOSAGE AND ADMINISTRATION

Omeprazole and sodium bicarbonate is available as a capsule in 20 mg and 40 mg strengths of omeprazole for adult use. Directions for use for each indication are summarized in Table 1. All recommended doses throughout the labeling are based upon omeprazole.

Since both the 20 mg and 40 mg capsules contain the same amount of sodium bicarbonate (1,100 mg), two capsules of 20 mg are notequivalent to one capsule of omeprazole and sodium bicarbonate 40 mg; therefore, two 20 mg capsules of omeprazole and sodium bicarbonate should not be substituted for one capsule of omeprazole and sodium bicarbonate 40 mg.

Omeprazole and sodium bicarbonate capsules should be taken on an empty stomach at least one hour before a meal.

Table 1: Recommended Doses of Omeprazole and Sodium Bicarbonate by Indication for Adults 18 Years and Older

1. Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy. [See Clinical Studies (14.1).]
2. For additional information, [See Indications and Usage (1)]
3. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14).]
Indication	Recommended Dose	Frequency
Short-Term Treatment of Active Duodenal Ulcer	20 mg	Once daily for 4 weeks 1,2
Benign Gastric Ulcer	40 mg	Once daily for 4-8 weeks 2,3
Gastroesophageal Reflux Disease (GERD) Symptomatic GERD (with no esophageal erosions) Erosive Esophagitis	20 mg 20 mg	Once daily for up to 4 weeks 2 Once daily for 4-8 weeks 2
Maintenance of Healing of Erosive Esophagitis	20 mg	Once daily3

Special Populations

Hepatic Insufficiency

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3).]

Administration of Capsules

Omeprazole and sodium bicarbonate capsules should be swallowed intact with water. DO NOT USE OTHER LIQUIDS. DO NOT OPEN CAPSULE AND SPRINKLE CONTENTS INTO FOOD.

3 DOSAGE FORMS AND STRENGTHS

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.

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.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a proton pump inhibitor (PPI). In older patients, also consider an endoscopy.

5.2 Acute Interstitial Nephritis

Acute interstitial nephritis has been observed in patients taking PPIs including omeprazole and sodium bicarbonate. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue omeprazole and sodium bicarbonate if acute interstitial nephritis develops. [See Contraindications (4).]

5.3 Buffer Content

Each omeprazole and sodium bicarbonate capsule contains 1100 mg (13 mEq) of sodium bicarbonate. The total content of sodium in each capsule is 304 mg.

The sodium content of omeprazole and sodium bicarbonate products should be taken into consideration when administering to patients on a sodium restricted diet.

Because omeprazole and sodium bicarbonate products contain sodium bicarbonate, they should be used with caution in patients with Bartter’s syndrome, hypokalemia, hypocalcemia, and problems with acid-base balance. Long-term administration of bicarbonate with calcium or milk can cause milk-alkali syndrome.

Chronic use of sodium bicarbonate may lead to systemic alkalosis and increased sodium intake can produce edema and weight increase.

5.4 Clostridium difficile-Associated Diarrhea

Published observational studies suggest that PPI therapy like omeprazole and sodium bicarbonate may be associated with an increased risk of Clostridium difficile- associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve. [See Adverse Reactions (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) and Adverse Reactions (6.2).]

5.6 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 erythematous 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.

5.7 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. [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)]

5.8 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.

5.9 Hypomagnesemia

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. 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).]

5.10 Concomitant Use of Omeprazole and Sodium Bicarbonate with St. John’s Wort or Rifampin

Drugs which induce CYP2C19 or CYP34A (such as St. John’s Wort or rifampin) can substantially decrease omeprazole concentrations [see Drug Interactions (7.2)]. Avoid concomitant use of omeprazole and sodium bicarbonate with St John’s Wort or rifampin.

5.11 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 treatment 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. [See Pharmacodynamics (12.2). ]

5.12 Concomitant Use of Omeprazole and Sodium Bicarbonate with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) 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. [See Drug Interactions (7.8).]

5.13 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.

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)]

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 Asthenia	5.2 1.3	3.3 0.8
Digestive System
Constipation Diarrhea Flatulence Nausea Vomiting Acid Regurgitation	1.5 3.7 2.7 4.0 3.2 1.9	0.8 2.5 5 .8 6.7 10.0 3.3
Nervous System/Psychiatric
Headache	2.9	2.5