OMEPRAZOLE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

NOTE: The information for omeprazole; sodium bicarbonate (Zegerid) capsules or powder packets for oral suspension is located in a separate monograph.

Route-Specific Administration

Oral Administration
-Administer on an empty stomach, 30 minutes before meals. If given once daily, administer in the morning. May be taken concurrently with antacids.
-Omeprazole tablets and omeprazole capsules are not rated as bioequivalent.
Oral Solid Formulations
-Delayed-release capsules: Capsules contain enteric-coated, delayed-release granules. Do not chew or crush the granules. The capsules can be opened and the enteric-coated granules sprinkled on applesauce or yogurt, given with fruit juices, or swallowed immediately with water. For administration via nasogastric (NG) tube, the granules remain intact when exposed to selected juices such as apple or cranberry juice for ease of administration.
-OTC tablets: Do not chew, break, or crush the tablets into food.
-OTC orally disintegrating tablets: Place tablet on the tongue; the tablet will disintegrate with or without water. Alternatively, the tablet may be swallowed whole with water. Do not chew or crush tablets.

Oral Liquid Formulations
-2.5 mg delayed-release suspension packet: When administering by mouth, empty the contents of the packet into a container with 5 mL of water. Stir gently, allowing 2 to 3 minutes for the suspension to thicken. Stir again, and then, administer. If any drug remains after drinking, add more water, stir, and administer immediately. When administering via an NG or gastric tube (French size 6 or larger), add 5 mL of water to a catheter tipped syringe; then, add the contents of a packet to the syringe. Shake immediately, allowing 2 to 3 minutes for the suspension to thicken. Shake once more and give through the NG or gastric tube. Refill the syringe with an equal amount of water. Shake and flush any remaining contents from the tube. In all cases, administer the suspension within 30 minutes of preparation.
-10 mg delayed-release suspension packet: When administering by mouth, empty the contents of the packet into a container with 15 mL of water. Stir gently, allowing 2 to 3 minutes for the suspension to thicken. Stir again, and then, administer. If any drug remains after drinking, add more water, stir, and administer immediately. When administering via an NG or gastric tube (French size 6 or larger), add 15 mL of water to a catheter tipped syringe; then, add the contents of a packet to the syringe. Shake immediately, allowing 2 to 3 minutes for the suspension to thicken. Shake once more and give through the NG or gastric tube. Refill the syringe with an equal amount of water. Shake and flush any remaining contents from the tube. In all cases, administer the suspension within 30 minutes of preparation.

Extemporaneous Compounding-Oral
Extemporaneous preparation of 2 mg/mL oral suspension ('simplified omeprazole suspension' or SOS):
-Empty the contents of one or two 20-mg omeprazole capsules into an empty 10- or 20-mL syringe with needle in place (plunger removed).
-Replace the plunger and uncap the needle.
-Withdraw 10 or 20 mL of sodium bicarbonate 8.4% (1 mEq/mL) solution (for omeprazole 20 or 40 mg, respectively) from the bicarbonate vial.
-Allow preparation to stand for at least 30 minutes, with intermittent agitation, to allow the granules to suspend.
-The preparation forms a milky white suspension with a final concentration of 2 mg/mL.
-Storage: The suspension is stable for 14 days at 24 degrees C and for 30 days at 5 degrees C and -20 degrees C; at room temperature, greater than 90% potency is maintained for 7 days.

Animal and human data have demonstrated a proliferation of enterochromaffin-like cells due to hypergastrinemia, which may be associated with the development of malignant gastric carcinoma during long-term administration of omeprazole. Data suggest that omeprazole may be given for as long as 5 years without concern for the development of gastric neoplasia. Twenty-five patients with H2-receptor antagonist-resistant gastroesophageal reflux disease (GERD) were treated and then followed on long-term (at least 4 years) omeprazole therapy. Persistent increases in median gastrin concentrations were noted during treatment; concentrations did not significantly increase during maintenance therapy. A subgroup of patients with very high gastrin concentrations (more than 500 ng/L) had a higher incidence of enterochromaffin-like cell hyperplasia than did other patients. Neoplasia or dysplasia were not seen in biopsies, however. Gastro-duodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome receiving long-term omeprazole; however, this finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. The overall risk of carcinoid tumors during therapy with proton pump inhibitors (PPIs) is low based on cumulative safety experience; monitoring of serum gastrin levels during PPI therapy is generally not necessary.

The safety profile of omeprazole is similar in adults, and in children and adolescents 1 to 17 years old. Common gastrointestinal (GI) related adverse events reported during double-blind and open-label studies include, abdominal pain (5.2%), nausea (4%), diarrhea (3.7%), vomiting (3.2%), flatulence (2.7%), acid regurgitation (1.9%) and constipation (1.5%). During postmarketing surveillance, the following GI adverse events were also reported: gastric polyps/fundic gland polyps, abdominal swelling, anorexia, dysgeusia, esophageal candidiasis, irritable colon, mucosal atrophy of the tongue, pancreatitis (some fatal), stomatitis, stool discoloration, and xerostomia. 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.

Hypersensitivity reactions including rash have been reported in 2% of patients receiving omeprazole during double-blind and open-label studies. In addition, postmarketing surveillance of omeprazole use has identified the following hypersensitivity and dermatological adverse reactions: alopecia, anaphylactic shock, anaphylactoid reactions, angioedema, bronchospasm, erythema multiforme, hyperhidrosis, petechiae, photosensitivity, purpura, pruritus, skin inflammation, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), urticaria, and xerosis.

During postmarketing surveillance, the following adverse events have been reported in association with omeprazole use: cholestasis, elevated hepatic enzymes (ALT, AST, GGT, alkaline phosphatase), hyperbilirubinemia, hepatic encephalopathy, hepatic failure (some fatal), hepatic necrosis (some fatal), hepatocellular disease, jaundice, and mixed hepatitis.

During postmarketing surveillance, hematologic adverse reactions have been reported with omeprazole use and include agranulocytosis (some fatal), anemia, hemolytic anemia, leukocytosis, leukopenia, neutropenia, pancytopenia, and thrombocytopenia. Generally, long-term (e.g., at least 2 to 3 years) treatment with acid-suppressing agents can lead to malabsorption of vitamin B12 (cyanocobalamin). In a study of healthy adult volunteers, it was shown that omeprazole caused a significant reduction in cyanocobalamin absorption. In a large case-controlled study, adult patients with and without an incident diagnosis of vitamin B12 deficiency (n = 25,956 and 184,199, respectively) were compared, and a correlation between vitamin B12 deficiency and gastric acid-suppression therapy was found. Receipt of at least 2 years of a proton pump inhibitor (PPI) or H2-receptor antagonist was associated with an increased risk for vitamin B12 deficiency. A dose-dependent relationship was evident, as daily doses more than 1.5 PPI pills/day were more strongly associated with vitamin B12 deficiency compared to daily doses less than 0.75 pills/day. The precise risk in pediatric patients has not been defined. It may be prudent to monitor patients for signs of pernicious anemia. Neurological manifestations of pernicious anemia can occur in the absence of hematologic changes.

In double-blind and open-label studies of omeprazole, headache was among the most common adverse reactions reported (2.9% to 6.9%). Dizziness (1.5%) was also reported with omeprazole therapy at a greater frequency than placebo. Other nervous system and psychiatric adverse events identified during postmarketing surveillance of omeprazole therapy include aggression, agitation, anxiety, apathy, confusion, depression, dream abnormalities (abnormal dreams), drowsiness (somnolence), hallucinations, hemifacial dysesthesia, insomnia, nervousness, paresthesias, tremor, and vertigo.

In double-blind and open-label studies, upper respiratory tract infection (1.9%) and cough (1.1%) were reported among omeprazole treated patients. In pediatric studies, adverse reactions of the respiratory system (not specified) were reported in 75% of patients aged 1 to up to 2 years and in 18.5% of patients 2 to 16 years of age. Fever was reported in postmarketing reports of omeprazole use, and in 33% of patients 1 to 2 year of age. Epistaxis and pharyngeal pain have also been noted postmarketing. Gastric acid suppression with proton pump inhibitors (PPIs) has been associated with an increased risk of infection in pediatric patients. A prospective, multi-center study in previously healthy infants and young children found an increased risk of pneumonia (OR: 6.39; 95% CI = 1.38 to 29.7) and acute gastroenteritis (OR: 3.58; 95% CI = 1.87 to 6.86) in patients receiving gastric acid inhibitors (n = 91) compared to controls (n = 95). Another study in critically ill pediatric patients (n = 60) did not find an increased incidence of ventilator-associated pneumonia in patients receiving acid-suppression therapy compared to those not receiving treatment. Until more is known about the relationship between acid-suppression and pneumonia, clinicians are encouraged to carefully select patients before empirically initiating acid-suppressive therapy with H2-blockers or PPIs. A causal relationship between the use of omeprazole and pneumonia has not been established. Increasing evidence in adults suggests a link between acid-suppression therapy and pneumonia (community- and hospital-acquired). Several mechanisms have been proposed to account for this association. One such mechanism states that gastric pH serves as a barrier against pathogenic colonization of the gastrointestinal tract. An increase in gastric pH allows for bacterial and viral invasion which, in theory, can precipitate respiratory infections. Another proposed mechanism accounts for the role that gastric acid may have on stimulating the cough reflex that allows for the clearing of infectious agents from the respiratory tract. Finally, the fact that acid-suppressive therapy may impair white blood cell function, which in turn may lead to a depressed immune response to an infection, is listed among possible mechanisms.

In double blind and open-label studies, asthenia (1.3%) and back pain (1.1%) were reported in omeprazole treated patients. During postmarketing surveillance, arthralgia (joint pain), leg pain, muscle cramps, myalgia, and myasthenia (muscle weakness) were also reported. Proton pump inhibitors (PPIs) have been associated with a possible increased risk of bone fractures of the hip, wrist, and spine. There have been 6 epidemiological studies that have reported an increased risk of fractures with the use of PPIs; the studies compared claims data of patients treated with PPIs versus individuals who were not using PPIs. Depending on the study, exposure to PPIs ranged between 1 to 12 years. The emergence of fractures varied among studies; one study reported an increase in fractures with use of PPIs in the previous year and another study found an increase after 5 to 7 years of PPI use. Increased risk was primarily observed in adult patients, patients taking prescription PPIs for at least 1 year, and patients who had been taking high doses (doses greater than those recommended with OTC use). Alternatively, in another epidemiological study with similar study design, a relationship between PPI use and fractures was not established; the study population did not have major risk factors for fracture at study entry. It should be noted that randomized clinical trials (RCTs) of PPIs have not found an increased risk of fractures of the hip, wrist, or spine; some limitations of these RCTs were study duration (generally 6 months) and insufficient information on effects of higher than recommended doses. Until more data are available, when prescribing PPIs, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. In patients at risk for or with osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.

Cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), and lupus-like symptoms have occurred in patients taking proton pump inhibitors (PPIs), including omeprazole. Both exacerbation and new onset of existing autoimmune disease have be reported, with the majority of PPI-induced lupus erythematosus cases being CLE. Subacute CLE (SCLE) is the most common form of CLE reported in patients treated with PPIs, occurring within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Histological findings were usually observed without organ involvement. SLE is less commonly reported; PPI associated SLE is generally milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from infants to the elderly. Most patients presented with rash; however, arthralgia and cytopenia were also reported. Do not administer PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE occur, 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 (ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

Omeprazole administration to pediatric patients is generally well tolerated, with an adverse reaction profile similar to that of adults. Adverse reactions unique to the pediatric population, however, have been reported. For example, accidental injury occurs with a 3.8% frequency in the 2 to 16 year old age group; however, a causal relationship of these adverse reactions to omeprazole has not been determined. Other miscellaneous adverse reactions reported during postmarketing surveillance of omeprazole in all patients include anterior ischemic optic neuropathy, blurred vision, diplopia, fatigue, malaise, ocular irritation, optic atrophy, optic neuritis, pain (unspecified), peripheral edema, tinnitus, and xerophthalmia.

Metabolic and nutritional adverse reactions reported during postmarketing surveillance of omeprazole use include hypoglycemia, hypomagnesemia with or without hypocalcemia and/or hypokalemia, hyponatremia, and weight gain. Cases of hypomagnesemia have been reported in association with prolonged (3 months to more than 1 year) proton pump inhibitor (PPI) use. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in patients at risk. Low serum magnesium may lead to serious adverse reactions such as muscle spasm (tetany), seizures, and irregular heartbeat (arrhythmias). Consider monitoring electrolyte concentrations and supplementing electrolytes when needed. Discontinuation of PPI therapy may be necessary.

Miscellaneous adverse events reported during postmarketing surveillance of omeprazole include angina, bradycardia, chest pain (unspecified), hypertension, palpitations, and sinus tachycardia. After completion of a comprehensive review, the FDA believes that the long-term use of omeprazole (or esomeprazole) is not likely to be associated with an increased risk of heart problems. Preliminary analysis of 2 small, long-term clinical studies raised concerns about a possible link between the long-term use of these drugs and cardiovascular events. In both studies, patients with severe gastroesophageal reflux disease (GERD) were randomized to receive drug therapy, with omeprazole or esomeprazole, or surgery to control GERD. Results from the studies appeared to show an increased risk of myocardial infarction, heart failure, and heart-related sudden death in patients who received drug therapy compared to those who received surgery. However, the results of these 2 studies along with results from other comparative studies of omeprazole, which did not show an increased risk of heart-related adverse events, were analyzed by the FDA. The FDA did not find a correlation between the reported cardiovascular events and the use of either drug; thus, the FDA recommends that health care professionals and their patients continue to prescribe and use these products in accordance with their labeled uses.

During postmarketing surveillance of omeprazole, microscopic colitis has been reported. A link between the onset of microscopic colitis and proton pump inhibitor (PPI) therapy has been suggested in case reports and case series. Reports and subsequent histological confirmation of both collagenous colitis and lymphocytic colitis, 2 distinct forms of microscopic colitis, have been observed in patients treated with lansoprazole, another PPI. One case series included 6 patients who developed microscopic colitis after a formulary switch to lansoprazole from omeprazole; upon lansoprazole discontinuation, associated symptoms resolved. The mechanism of this rare adverse reaction is not clear; however, an idiosyncratic immune reaction is suspected. Because small changes in the structures of PPIs may elicit different immunological responses, it is difficult to predict if this adverse reaction can be expected with other PPIs. Until more is known about the association between PPIs and microscopic colitis, clinicians should advise patients to report prolonged watery loose stools and PPI discontinuation or substitution should be considered in these patients.

C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with omeprazole. PPI therapy, such as omeprazole, may be associated with an increased risk of CDAD, especially in hospitalized patients. The use of gastric acid suppressive therapy, such as PPIs, may increase the risk of enteric infection or superinfection by encouraging the growth of gut microflora. If pseudomembranous colitis is suspected or confirmed, institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate.

Acute tubulo-interstitial nephritis (AIN or TIN) has been observed in patients taking PPIs, including omeprazole, 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, 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 evaluate patients with suspected acute AIN. Other urogenital adverse reactions reported during the use of omeprazole include hematuria, albuminuria (proteinuria), elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, increased urinary frequency, testicular pain, and gynecomastia. A few cases of renal failure have been described with omeprazole therapy in published literature case reports.

Omeprazole is contraindicated in patients with known hypersensitivity to omeprazole or other substituted benzimidazoles such as esomeprazole or lansoprazole (i.e., known proton pump inhibitors (PPIs) hypersensitivity). There has been evidence of PPI cross-sensitivity in some sensitive individuals in literature reports, and some cases have been serious (e.g., angioedema or anaphylaxis). Serious rash and severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS), erythema multiforme, 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. Discontinue the PPI at the first signs or symptoms of severe cutaneous adverse reactions or other hypersensitivity and consider further evaluation. Acute tubulo-interstitial nephritis (TIN or AIN) 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, anorexia). There have been reports of patients who were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue omeprazole and evaluate patients with suspected acute TIN.

Omeprazole should be administered with caution to patients with hepatic disease since clearance of the drug can be prolonged. Dosage reduction should be considered in patients with severe hepatic impairment (e.g., cirrhotic liver disease) and/or in those patients receiving long-term therapy. In addition, omeprazole has been associated with hepatitis and, in rare instances, hepatic failure.

Poor metabolizers of CYP2C19 are expected to have higher exposure to omeprazole than normal (extensive) metabolizers. Approximately 3% of White patients and 15% to 20% of Asian patients are CYP2C19 poor metabolizers. Asian patients exhibit a 4-fold increase in AUC of omeprazole compared to White patients. For adult patients, a dosage reduction of omeprazole to 10 mg once daily is recommended for Asian patients for maintenance of healing of erosive esophagitis (EE).

Gastric polyps/fundic gland polyps have been reported during postmarketing surveillance. Patients are usually asymptomatic and fundic gland polyps are identified incidentally on endoscopy. The risk of fundic gland polyps increases with long term proton pump inhibitor (PPI) use, especially beyond one year. Use the shortest duration of PPI therapy appropriate to treat specific condition. Symptomatic response to therapy with omeprazole does not preclude the presence of gastric cancer or other malignancy. Omeprazole decreases intragastric acidity. Subsequently, the number of bacteria in gastric secretions and, correspondingly, the amount of carcinogenic N-nitroso compounds produced by these bacteria increase. Gastro-duodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome receiving long-term omeprazole; however, this finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. The overall risk of carcinoid tumors during therapy with proton pump inhibitors (PPI) is low based on cumulative safety experience; monitoring of serum gastrin levels during PPI therapy is generally not necessary. One trial studied 25 adult patients with H2-receptor antagonist-resistant gastroesophageal reflux disease (GERD) who were treated and then followed on long-term (4 years or more) omeprazole therapy; neoplasia or dysplasia were not seen in biopsies. In a retrospective review of pediatric patients, 7 of 31 children had gastric polyps and/or nodules noted between 10 and 48 months of omeprazole therapy. Nodules in 4 of the 6 children disappeared spontaneously with continuation of therapy; the polyps persisted. The gastric changes in these patients were benign during the 31 month observation period.

The package labeling for non-prescription (OTC) omeprazole states that patients should not self-medicate with omeprazole if they have trouble swallowing (dysphagia), vomiting with blood, or bloody or black stools (GI bleeding). Also, a patient should speak with a health care provider prior to using omeprazole OTC if there is a history of any of the following: chest pain, heartburn for more than 3 months, heartburn with dizziness, lightheadedness or sweating, abdominal pain, unexplained weight loss, or wheezing. Such symptoms need medical evaluation and perhaps prescription therapy.

Consider pseudomembranous colitis in patients presenting with diarrhea after PPI use. PPI therapy, such as omeprazole, may be associated with an increased risk of C. difficile-associated diarrhea (CDAD), especially in hospitalized patients. CDAD may range in severity from mild to life-threatening. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Chronic use of gastric acid-suppressing agents should be used cautiously and with monitoring in patients who are prone to vitamin B12 deficiency. Daily treatment with a gastric acid-suppressing medication, such as omeprazole, over a long period of time (e.g., generally >= 2-3 years) has been associated with malabsorption of cyanocobalamin in adults. Consider the possibility of cyanocobalamin deficiency if clinical symptoms are observed.

Use omeprazole with caution in patients with a pre-existing risk of hypocalcemia (e.g., hypoparathyroidism), hypokalemia, or hypomagnesemia; consider monitoring magnesium and calcium concentrations prior to initiating therapy and periodically while on treatment in these patients. Supplement with magnesium and/or calcium as needed and consider discontinuing proton pump inhibitor (PPI) therapy if hypomagnesemia or hypocalcemia is refractory to treatment. For patients expected to be on PPI therapy for a prolonged period of time or who take concomitant medications such as digoxin or those that may cause hypomagnesemia (e.g., diuretics), consider monitoring of serum magnesium prior to initiation and periodically during treatment. Daily treatment with a PPI over a long period of time (e.g., 3 months to more than 1 year) may lead to hypomagnesemia; cases have been reported in patients taking omeprazole. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in patients at risk. In most patients, the treatment of hypomagnesemia required magnesium replacement and PPI discontinuation. Low serum magnesium may lead to serious adverse reactions such as muscle spasm (tetany), seizures, and irregular heartbeat (arrhythmias). Use PPIs with caution and, if possible, avoid long term (greater than 14 days) use in patients with congenital long QT syndrome, as they may be at higher risk for arrhythmias.

Use omeprazole with caution in pediatric patients with low bone density. Observational studies have suggested that proton pump inhibitors (PPIs) may be associated with an increased risk for osteoporosis related fractures of the hip, wrist, or spine. In studies, patients at highest risk of fracture were those who received high-dose (defined as multiple daily doses) and long-term PPI therapy (a year or longer). Until more data are available, when prescribing PPIs, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. In patients with or at risk for osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.

Use with caution in patients with a history of systemic lupus erythematosus (SLE) as omeprazole has been reported to activate or exacerbate SLE.

Administration of omeprazole may result in laboratory test interference, specifically serum chromogranin A (CgA) tests for neuroendocrine tumors, urine tests for tetrahydrocannabinol (THC), secretin stimulation tests, and diagnostic tests for Helicobacter pylori. Gastric acid suppression may increase serum CgA. Increased CgA concentrations may cause false positive results in diagnostic investigations for neuroendocrine tumors. To prevent this interference, temporarily stop omeprazole at least 14 days before assessing CgA concentrations and consider repeating the test if initial concentrations are high. If serial tests are performed, ensure the same commercial laboratory is used as reference ranges may vary. Reports have suggested use of proton pump inhibitors (PPIs) may cause false positive urine screening tests for THC. If a PPI-induced false positive urine screen is suspected, confirm the positive results using an alternative testing method. Omeprazole may cause a hyper-response in gastrin secretion to the secretin stimulation test, falsely suggesting gastrinoma. Health care providers are advised to temporarily stop omeprazole at least 14 days prior to performing a secretin stimulation test to allow gastrin concentrations to return to baseline. Preparations that combine PPIs with antimicrobials and bismuth are known to suppress H. pylori; thus, ingestion of these preparations within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of omeprazole in the 1 to 2 weeks prior to the test and the use of antimicrobials and bismuth preparations in the 4 weeks prior to the test.

Description: Omeprazole is a proton pump inhibitor (PPI) that has a long duration of action, allowing for once-daily administration. Because omeprazole is acid labile, the oral formulations consist of enteric-coated granules. In pediatrics, omeprazole is indicated for short term therapy of gastroesophageal reflux disease (GERD) and for maintenance therapy of erosive esophagitis. Although many studies have demonstrated some level of benefit from the use of PPIs in the treatment of GERD or erosive esophagitis when compared to placebo, conflicting evidence on the safety and efficacy of PPIs warrants cautious use of these drugs in pediatric patients, particularly infants. PPIs are not recommended as first-line therapy for symptomatic GERD in otherwise healthy infants (1 to 11 months); nonpharmacologic measures such as diet modification and positioning strategies are recommended first-line and treatment with PPIs should be reserved for use in infants with acid reflux disease diagnosed by endoscopy (e.g., erosive esophagitis). On the basis of available research, no clear advantage has been demonstrated for the use of one PPI over another in the treatment of GERD. Instead, a key to optimizing effectiveness is tailoring dosage timing; administer traditional delayed release PPIs 30 to 60 min before a meal for maximal pH control. A one-time switch to a different PPI in a refractory patient may be useful. Omeprazole is used for gastric and duodenal ulcers, gastric hypersecretory conditions including Zollinger-Ellison syndrome, systemic mastocytosis, and multiple endocrine adenoma. It is also used in combination with antibiotics in the eradication of Helicobacter pylori (H. pylori) infection for the reduction of the risk of duodenal ulcer recurrence. Due to concern regarding long-term use, omeprazole was originally approved by the FDA in September 1989 for acute treatment only; although precautions exist with the long-term use of PPIs, omeprazole has been approved for the maintenance of healing of erosive esophagitis. Of particular concern, PPIs have been associated with an increased risk of Clostridium difficile-associated diarrhea. In a retrospective case-controlled trial in 136 pediatric patients, the use of a PPI was significantly higher in the Clostridium difficile positive group compared with the Clostridium difficile negative group (OR = 4.5; 95% CI = 1.4 to 14.4). Omeprazole is FDA-approved in pediatric patients as young as 1 month of age.

General Dosing Information
-Omeprazole magnesium 20.6 mg tablets and capsules contain 20 mg of omeprazole.

-For Asian patients, the manufacturer of omeprazole states that dosage reduction should be considered; however, no specific dosage guidelines are available.

For the treatment and maintenance of gastroesophageal reflux disease (GERD):
Oral dosage:
Neonates*: Limited data are available; 0.7 mg/kg/day PO once daily for 7 days has been studied. Single doses up to 1.5 mg/kg/day PO have been studied in a pharmacokinetic trial. In 10 preterm neonates (34 to 40 weeks postmenstrual age) with GERD, 0.7 mg/kg/day PO once daily was administered in a randomized, double blind, placebo-controlled trial. Compared to placebo, omeprazole significantly reduced gastric acidity (% time pH less than 4, 54% vs. 14%, p less than 0.0005) and number of acid GER episodes (119 vs. 60 episodes, p less than 0.05). In a pharmacokinetic trial of 24 neonates and infants (aged 0 to 24 months), single doses of 1 to 1.5 mg/kg/dose were studied; increased omeprazole exposure was observed in a few patients younger than 5 months. Multiple doses of 1.5 mg/kg/day have not been studied in neonates.
Infants*: Limited data are available; 0.5 mg/kg/day PO once daily for 6 weeks has been studied; however, doses up to 1.5 mg/kg/day PO have been reported. In 12 infants (aged 2.9 +/- 0.9 months) with peptic esophagitis (grade 2) who did not respond to cimetidine, 0.5 mg/kg/day resulted in a marked decrease in symptoms, endoscopic and histologic signs of esophagitis, and intragastric acidity. In an 8-week trial of 115 patients (aged 0.7 to 21.8 months) receiving omeprazole 0.5 to 1.5 mg/kg/day, symptoms were reduced in all groups. A more rapid onset of symptomatic improvement was noted in patients receiving larger doses. PPIs are not recommended as first line therapy for symptomatic GERD in otherwise healthy infants (1 to 11 months); nonpharmacologic measures such as diet modification and positioning strategies are recommended. Reserve pharmacologic treatment for use in infants with disease diagnosed by endoscopy (e.g., esophageal erosion).
Children 5 to 9 kg: 5 mg PO once daily is the FDA-approved dose. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Individualize dosage to attain clinical goals.
Children 10 to 19 kg: 10 mg PO once daily is the FDA-approved dose. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Individualize dosage to attain clinical goals; typical doses range from 10 to 20 mg/day PO, although some studies have used higher dosages.
Children 20 kg or more: 20 mg PO once daily is the FDA-approved dose. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Individualize dosage to attain clinical goals; typical doses range from 10 to 20 mg/day PO, although some studies have used higher dosages.
Adolescents: 20 mg PO once daily. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Individualize dosage to attain clinical goals.

For the treatment of duodenal ulcer or gastric ulcer:
-for short-term treatment of active benign gastric ulcer:
Oral dosage:
Adolescents older than 16 years: 40 mg PO once daily for 4 to 8 weeks. For endoscopically diagnosed gastric ulcer larger than 1 cm, 40 mg once daily was significantly more effective than 20 mg once daily at 8 weeks. For ulcer size 1 cm or less, no difference in healing rates between 40 mg and 20 mg once daily doses were observed.
-for short-term treatment of active duodenal ulcer:
Oral dosage (delayed-release capsules or delayed-release suspension):
Adolescents older than 16 years: 20 mg PO once daily for 4 to 8 weeks. Most patients heal within 4 weeks; some patients may require 8 weeks of therapy.

For Helicobacter pylori (H. pylori) eradication*:
-for Helicobacter pylori (H. pylori) eradication* as part of clarithromycin-based triple therapy:
Oral dosage:
Children weighing 15 to 24 kg: 20 mg PO twice daily in combination with clarithromycin and either amoxicillin or metronidazole for 14 days.
Children and Adolescents weighing 25 to 34 kg: 30 mg PO twice daily in combination clarithromycin and either amoxicillin or metronidazole for 14 days.
Children and Adolescents weighing 35 kg or more: 40 mg PO twice daily in combination with clarithromycin and either amoxicillin or metronidazole for 14 days.
-for Helicobacter pylori (H. pylori) eradication* as part of clarithromycin-based quadruple/concomitant therapy:
Oral dosage:
Children weighing 15 to 24 kg: 20 mg PO twice daily in combination with clarithromycin, amoxicillin, and metronidazole for 14 days.
Children and Adolescents weighing 25 to 34 kg: 30 mg PO twice daily in combination with clarithromycin, amoxicillin, and metronidazole for 14 days.
Children and Adolescents weighing 35 kg or more: 40 mg PO twice daily in combination with clarithromycin, amoxicillin, and metronidazole for 14 days.
-for Helicobacter pylori (H. pylori) eradication* as part of clarithromycin-based sequential therapy:
Oral dosage:
Children weighing 15 to 24 kg: 20 mg PO twice daily in combination with amoxicillin for 5 days, followed by 20 mg PO twice daily in combination with clarithromycin and metronidazole for 5 days.
Children and Adolescents weighing 25 to 34 kg: 30 mg PO twice daily in combination with amoxicillin for 5 days, followed by 30 mg PO twice daily in combination with clarithromycin and metronidazole for 5 days.
Children and Adolescents weighing 35 kg or more: 40 mg PO twice daily in combination with amoxicillin for 5 days, followed by 40 mg PO twice daily in combination with clarithromycin and metronidazole for 5 days.
-for Helicobacter pylori (H. pylori) eradication* as part of metronidazole-based triple therapy:
Oral dosage:
Children weighing 15 to 24 kg: 20 mg PO twice daily in combination with metronidazole and amoxicillin for 14 days.
Children and Adolescents weighing 25 to 34 kg: 30 mg PO twice daily in combination with metronidazole and amoxicillin for 14 days.
Children and Adolescents weighing 35 kg or more: 40 mg PO twice daily in combination with metronidazole and amoxicillin for 14 days.
-for Helicobacter pylori (H. pylori) eradication* as part of bismuth-based quadruple therapy:
Oral dosage:
Children 1 to 8 years weighing 15 to 24 kg: 20 mg PO twice daily in combination with bismuth subsalicylate, metronidazole, and amoxicillin for 14 days.
Children 1 to 8 years weighing 25 to 34 kg: 30 mg PO twice daily in combination with bismuth subsalicylate, metronidazole, and amoxicillin for 14 days.
Children 1 to 8 years weighing 35 kg or more: 40 mg PO twice daily in combination with bismuth subsalicylate, metronidazole, and amoxicillin for 14 days.
Children 9 to 12 years weighing 15 to 24 kg: 20 mg PO twice daily in combination with bismuth subsalicylate, metronidazole, and tetracycline for 14 days.
Children and Adolescents 9 to 17 years weighing 25 to 34 kg: 30 mg PO twice daily in combination with bismuth subsalicylate, metronidazole, and tetracycline for 14 days.
Children and Adolescents 9 to 17 years weighing 35 kg or more: 40 mg PO twice daily in combination with bismuth subsalicylate, metronidazole, and tetracycline for 14 days.

For the long-term treatment of gastric hypersecretory conditions, including Zollinger-Ellison syndrome, systemic mastocytosis, and multiple endocrine adenoma syndrome:
Oral dosage:
Adolescents > 16 years: 60 mg PO once daily initially, then titrated and given in single or multiple daily doses, with dosage titration up to a maximum of 120 mg PO 3 times daily.

For NSAID-induced ulcer prophylaxis*:
Oral dosage:
Adolescents older than 16 years: 20 mg PO once daily has been studied. Patients with a history of dyspepsia or uncomplicated peptic ulcer and who were to continue receiving a NSAID were randomized to either omeprazole or placebo. At 3 months, 4.7% (4 of 85) of subjects receiving omeprazole developed peptic ulcer compared with 16.7% (15 of 90) receiving placebo.

For the treatment of erosive esophagitis (erosive GERD):
Oral dosage:
Infants 3 to 4 kg: 2.5 mg PO once daily is the FDA-approved dose. Alternatively, 0.5 mg/kg/day PO once daily for 6 weeks has been studied and doses up to 1.5 mg/kg/day PO have been reported. In 12 infants (aged 2.9 +/- 0.9 months) with peptic esophagitis (grade 2) who did not respond to cimetidine, 0.5 mg/kg/day resulted in a marked decrease in symptoms, endoscopic and histologic signs of esophagitis, and intragastric acidity. In an 8-week trial of 115 patients (aged 0.7 to 21.8 months) receiving omeprazole 0.5 to 1.5 mg/kg/day, symptoms were reduced in all groups. A more rapid onset of symptomatic improvement was noted in patients receiving larger doses.
Infants 5 to 9 kg: 5 mg PO once daily is the FDA-approved dose. Alternatively, 0.5 mg/kg/day PO once daily for 6 weeks has been studied and doses up to 1.5 mg/kg/day PO have been reported. In 12 infants (aged 2.9 +/- 0.9 months) with peptic esophagitis (grade 2) who did not respond to cimetidine, 0.5 mg/kg/day resulted in a marked decrease in symptoms, endoscopic and histologic signs of esophagitis, and intragastric acidity. In an 8-week trial of 115 patients (aged 0.7 to 21.8 months) receiving omeprazole 0.5 to 1.5 mg/kg/day, symptoms were reduced in all groups. A more rapid onset of symptomatic improvement was noted in patients receiving larger doses.
Infants 10 kg and more: 10 mg PO once daily is the FDA-approved dose. Alternatively, 0.5 mg/kg/day PO once daily for 6 weeks has been studied and doses up to 1.5 mg/kg/day PO have been reported. In 12 infants (aged 2.9 +/- 0.9 months) with peptic esophagitis (grade 2) who did not respond to cimetidine, 0.5 mg/kg/day resulted in a marked decrease in symptoms, endoscopic and histologic signs of esophagitis, and intragastric acidity. In an 8-week trial of 115 patients (aged 0.7 to 21.8 months) receiving omeprazole 0.5 to 1.5 mg/kg/day, symptoms were reduced in all groups. A more rapid onset of symptomatic improvement was noted in patients receiving larger doses.
Children 5 to 9 kg: 5 mg PO once daily is the FDA-approved dose. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Individualize dosage to attain clinical goals.
Children 10 to 19 kg: 10 mg PO once daily is the FDA-approved dose. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Individualize dosage to attain clinical goals; typical doses range from 10 to 20 mg/day PO, although some studies have used higher dosages.
Children 20 kg or more: 20 mg PO once daily is the FDA-approved dose. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Individualize dosage to attain clinical goals; typical doses range from 10 to 20 mg/day PO, although some studies have used higher dosages.
Adolescents: 20 mg PO once daily. Alternatively, a dose range of 0.7 to 3.3 mg/kg/day PO is recommended by the American Academy of Pediatrics (AAP). Individualize dosage to attain clinical goals.

For the treatment of eosinophilic esophagitis*:
Oral dosage:
Children and Adolescents: 1 mg/kg/dose (Max: 40 mg/dose) PO twice daily for 8 to 12 weeks, then reduce dose to the lowest dose that maintains remission.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, 0.7 mg/kg/day PO has been used off-label for GERD. Single doses up to 1.5 mg/kg/day PO have been studied in a pharmacokinetic trial.
-Infants
3 to 4 kg: 2.5 mg/day PO is the FDA-approved maximum; however, doses up to 1.5 mg/kg/day have been used off-label.
5 to 9 kg: 5 mg/day PO is the FDA-approved maximum; however, doses up to 1.5 mg/kg/day have been used off-label.
10 kg or more: 10 mg/day PO is the FDA-approved maximum; however, doses up to 40 mg/day have been used off-label.
-Children
5 to 9 kg: 5 mg/day PO is the FDA-approved maximum; however, doses up to 3.3 mg/kg/day have been used off-label.
10 to 19 kg: 10 mg/day PO is the FDA-approved maximum; however, doses up to 3.3 mg/kg/day (Max: 40 mg/day) have been used off-label.
20 kg or more: 20 mg/day PO is the FDA-approved maximum; however, doses up to 80 mg/day have been used off-label.
-Adolescents
40 mg/day PO is the FDA-approved maximum; however, doses up to 80 mg/day have been used off-label.

Patients with Hepatic Impairment Dosing
Consider dosage reduction in patients with hepatic impairment, especially for maintenance of healing of erosive esophagitis; specific guidelines are not available.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Intermittent hemodialysis
Because omeprazole is highly protein bound, it is not likely to be significantly removed by hemodialysis. No dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Omeprazole belongs to the class of GI antisecretory agents, the substituted benzimidazoles, which suppress gastric acid secretion by inhibiting the (H+, K+)-ATPase enzyme system of parietal cells. Following activation in an acidic pH, omeprazole binds irreversibly to the (H+, K+)-ATPase pump on the secretory surface of the parietal cell membrane. Subsequently, the secretion of hydrogen ions into the gastric lumen is inhibited. Omeprazole is characterized as a gastric acid pump inhibitor because it blocks the final step of gastric acid production. It inhibits both basal and stimulus-induced acid secretion. Intragastric pH of patients receiving omeprazole is often higher and affected longer than during therapy with H2-antagonists. Omeprazole is also more effective than either H2-antagonists or sucralfate in the treatment of gastroesophageal reflux disease (GERD).

Significant in vitro activity against Helicobacter pylori (H. Pylori) has been demonstrated for omeprazole. Omeprazole monotherapy increases the clearance rate of H. pylori; however, eradication does not occur without antimicrobial therapy.

Pharmacokinetics: Omeprazole is administered orally. Omeprazole is 95% bound to plasma proteins. Extensive hepatic metabolism occurs, and the metabolites have minimal antisecretory activity. Plasma clearance averages 500 to 600 mL/minute in normal subjects. The plasma half-life in healthy patients is 0.5 to 1 hour. Secretory activity returns to normal 3 to 5 days after therapy is discontinued. Approximately 72% to 80% of a dose is excreted renally, and 18% to 23% is excreted in the feces.

Serum gastrin levels increase during the initial 1 to 2 weeks of therapy, and median increases in gastrin are greater than the increases produced by H2-receptor antagonists. Gastrin levels return to baseline within 1 to 2 weeks following discontinuance of therapy. Gastrin concentrations in patients with Zollinger-Ellison syndrome are not affected.

Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2C9, CYP2C19, and CYP3A4
Omeprazole is metabolized by the CYP2C19 isoenzyme (primary) and by the CYP3A4 isoenzyme (secondary). Omeprazole inhibits the CYP2C19 isoenzyme in vitro and in vivo and the CYP2C9 isoenzyme in vitro. Omeprazole is a time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of co-administered drugs that are CYP2C19 substrates. In addition, administration of omeprazole increases intragastric pH and can alter the systemic exposure of certain drugs that exhibit pH-dependent solubility. Omeprazole does not appear to inhibit CYP3A4 activity. In vitro, omeprazole induces the CYP1A2 isoenzyme.


-Route-Specific Pharmacokinetics
Oral Route
Due to a significant first-pass effect, bioavailability after oral doses of 20 to 40 mg of the delayed-release omeprazole capsules is 30% to 40%, but may approach 100% in patients with hepatic impairment. Upon repeated administration, the bioavailability increases slightly. The AUC and Cmax for delayed-release oral suspension are 87% and 88% of those for delayed-release oral capsules, respectively. Omeprazole is rapidly absorbed following oral administration and distributes throughout the body tissues, concentrating in the gastric parietal cells. The drug's onset of action is 1 hour, and the duration of inhibition is greater than 72 hours.


-Special Populations
Pediatrics
Neonates
In neonates, omeprazole clearance is slower than that of older children and adults (0.12 to 0.20 L/hour/kg vs. 0.45 L/hour/kg) and the half-life is longer (1.6 to 2.1 hours vs. 0.75 to 1.2 hours).

Infants and Children
The bioavailability of omeprazole increases by 165 to 64% with repeated dosing in children, compared to values obtained after a single dose. This is thought to occur due to both decreased first-pass elimination and reduced systemic clearance due to inhibition of CYP2C19 by omeprazole. The mean volume of distribution is approximately 0.4 L/kg in pediatric patients, which is similar to that of an adult (0.31to 0.34 L/kg). The half-life of omeprazole is approximately 1 hour in pediatric patients and the clearance of omeprazole appears to be faster for pediatric patients than for adults. Following comparable mg per kg doses of omeprazole, younger children (2 to 5 years) have a lower mean AUC, half-life, and Cmax than older children (6 to 16 years) or adults; the mean AUC of the latter 2 groups do not differ. Since omeprazole is metabolized by CYP2C19 and CYP3A4, some of the differences in pharmacokinetic parameters may be explained by the maturation changes in these enzyme systems. These hepatic enzymes have reduced activity at birth, but reach adult levels of activity in early infancy. Hepatic P450 enzyme activity levels then exceed adult enzymatic activity levels throughout childhood and revert back to adult levels some time during adolescence. The pharmacokinetics of omeprazole are dose dependant, with nonlinear increases in plasma concentration with increasing doses.

Hepatic Impairment
In patients with chronic hepatic disease, the bioavailability of buffered omeprazole solution increases to approximately 100%, reflecting decreased first-pass effect. Additionally, the half-life increases to nearly 3 hours in chronic hepatic impairment as compared to the mean half-life of 1 hour in normal subjects. Plasma clearance averages 70 mL/minute, compared to a value of 500 to 600 mL/minute in normal subjects. Although the impact of hepatic disease has not been studied in pediatric patients, similar findings are expected. In a 5-year-old child with impaired hepatic function, the elimination was delayed, clearance was slower (0.16 L/hour/kg) and the half-life was longer (2.76 hours) than that of healthy children.

Renal Impairment
In renal impairment, the bioavailability of omeprazole is slightly increased. Because omeprazole inactive metabolites are primarily excreted in the urine, elimination of these metabolites slows in proportion to decreased CrCl. In a study that included 4 children with impaired renal function, the pharmacokinetic parameters of omeprazole in 3 of the children were in the range of those seen for the 9 children with normal renal function. The fourth child also had concomitant hepatic impairment, so the pharmacokinetic parameters were outside of the normal range in this child.

Ethnic Differences
Asian patients exhibit a 4-fold increase in AUC of omeprazole compared to White patients.

Other
Critically Ill
In critically ill pediatric patients immediately after liver and/or intestinal transplantation, omeprazole elimination was slower and the mean half-life was longer (4.9 +/- 3.5 hours and 5.1 +/- 2.4 hours after single and multiple doses, respectively) compared with healthy children and adults. The investigators contribute some of the findings to slower metabolism secondary to residual effects of pre-transplant hepatic failure, inflammation, and cytokine production.

CYP2C19 Poor Metabolizers
CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or reduced enzymatic function. Patients carrying 2 fully functional alleles are extensive metabolizers and those carrying 2 loss-of-function alleles are poor metabolizers. In extensive metabolizers, omeprazole is primarily metabolized by CYP2C19. The systemic exposure to omeprazole varies with a patient's metabolism status, with poor metabolizers having the greatest exposure and extensive metabolizers having the least exposure. Approximately 3% of White patients and 15 to 20% of Asian patients are CYP2C19 poor metabolizers. In pharmacokinetic studies of single 20 mg omeprazole dose, the AUC of omeprazole in Asian subjects was approximately 4-fold of that in White subjects.