Omeprazole/Bicarbonate (Page 2 of 10)

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	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