1.1 Duodenal Ulcer (adults)

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.

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.

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.

Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.1) and Dosage and Administration (2)].

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 Microbiology section (12.4)], and the clarithromycin package insert, Microbiology section.

1.2 Gastric Ulcer (adults)

Omeprazole Delayed-Release Capsules is indicated for short-term treatment (4-8 weeks) of active benign gastric ulcer in adults [see Clinical Studies (14.2)].

1.3 Treatment of Gastroesophageal Reflux Disease (GERD) (adults and pediatric patients)

1.4 Maintenance of Healing of Erosive Esophagitis (adults and pediatric patients)

Omeprazole Delayed-Release Capsules is indicated to maintain healing of erosive esophagitis in pediatric patients and adults.

Controlled studies do not extend beyond 12 months [see Clinical Studies (14.4)].

1.5 Pathological Hypersecretory Conditions (adults)

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.

2.1 Short-Term Treatment of Active Duodenal Ulcer

The recommended adult oral dose of Omeprazole Delayed-Release Capsules is 20 mg once daily. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy.

2.2 H. pylori Eradication for the Reduction of the Risk of Duodenal Ulcer Recurrence

2.3 Gastric Ulcer

The recommended adult oral dose is 40 mg once daily for 4-8 weeks.

2.4 Gastroesophageal Reflux Disease (GERD)

The recommended adult oral dose for the treatment of patients with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4 weeks. The recommended adult oral dose for the treatment of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4 to 8 weeks.

2.5 Maintenance of Healing of Erosive Esophagitis

The recommended adult oral dose is 20 mg daily [see Clinical Studies (14.4)].

2.6 Pathological Hypersecretory Conditions

The dosage of Omeprazole Delayed-Release Capsules in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 120 mg three times daily have been administered. Daily dosages of greater than 80 mg should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have been treated continuously with Omeprazole Delayed-Release Capsules for more than 5 years.

2.7 Pediatric Patients

For the treatment of GERD and maintenance of healing of erosive esophagitis, the recommended daily dose for pediatric patients 2 to 16 years of age is as follows:

On a per kg basis, the doses of omeprazole required to heal erosive esophagitis in pediatric patients are greater than those for adults.

Alternative administrative options can be used for pediatric patients unable to swallow an intact capsule [see Dosage and Administration (2.8)].

2.8 Alternative Administration Options

Omeprazole Delayed-Release Capsule is available as a delayed-release capsule.

For patients who have difficulty swallowing capsules, the contents of an Omeprazole Delayed-Release Capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the microtablets inside the capsule should be carefully emptied on the applesauce. The microtablets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the microtablets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The microtablets should not be chewed or crushed. The microtablets/applesauce mixture should not be stored for future use.

5.1 Concomitant Gastric Malignancy

Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy.

5.2 Atrophic Gastritis

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole.

5.3 Clostridium difficile associated diarrhea

Published observation studies suggest that PPI therapy like Omeprazole Delayed-Release Capsules 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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with Omeprazole Delayed-Release Capsules, refer to WARNINGS and PRECAUTIONS sections of those package inserts.

5.4 Interaction with Clopidogrel

Avoid concomitant use of Omeprazole Delayed-Release Capsules 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 inhibit 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 Delayed-Release Capsules, consider alternative anti-platelet therapy [see Drug Interactions (7.3) and Pharmacokinetics (12.3)].

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 established treatment guidelines [see Dosage and Administration (2) and Adverse Reactions (6.3)].

5.6 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 (6.3)].

5.7 Concomitant Use of Omeprazole Delayed-Release Capsules 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 [see Drug Interactions (7.3)]. Avoid concomitant use of Omeprazole Delayed-Release Capsules with St. John's Wort or rifampin.

5.8 Interactions with Diagnostic 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.

5.9 Concomitant use of Omeprazole Delayed-Release Capsules 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 (7.7)].

6.1 Clinical Trials Experience with Omeprazole Delayed-Release Capsules Monotherapy

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 data described below reflects exposure to Omeprazole Delayed-Release Capsules in 3096 patients from worldwide clinical trials (465 patients from US studies and 2,631 patients from international studies). Indications clinically studied in US trials included duodenal ulcer, resistant ulcer, and Zollinger-Ellison syndrome. The international clinical trials were double blind and open-label in design. The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) from Omeprazole Delayed-Release Capsules-treated patients enrolled in these studies included headache (6.9%), abdominal pain (5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and flatulence (2.7%).

Additional adverse reactions that were reported with an incidence ≥ 1% included acid regurgitation (1.9%), upper respiratory infection (1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia (1.3%), back pain (1.1%), and cough (1.1%).

The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less.

The clinical trial safety profile in pediatric patients who received Omeprazole Delayed-Release Capsules was similar to that in adult patients. Unique to the pediatric population, however, adverse reactions of the respiratory system were most frequently reported in the 2 to 16 year age group (18.5%). Similarly, accidental injuries were reported frequently in the 2 to 16 year age group (3.8%) [see Use in Specific Populations (8.4)].

6.2 Clinical Trials Experience with Omeprazole Delayed-Release Capsules in Combination Therapy for H. pylori Eradication

In clinical trials using either dual therapy with Omeprazole Delayed-Release Capsules and clarithromycin, or triple therapy with Omeprazole Delayed-Release Capsules, clarithromycin, and amoxicillin, no adverse reactions unique to these drug combinations were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, or amoxicillin alone.

6.3 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of Omeprazole Delayed-Release Capsules. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.

Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria, (see also Skin below); fever; pain; fatigue; malaise;

Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema

Endocrine: Gynecomastia

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with Omeprazole Delayed-Release Capsules. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]

Infections and Infestations: Clostridium difficile associated diarrhea

Metabolism and Nutritional disorders: Hypoglycemia, hypomagnesemia, hyponatremia, weight gain

Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture

Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo

Respiratory: Epistaxis, pharyngeal pain

Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis

Special Senses: Tinnitus, taste perversion

Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision

Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain

Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis

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. Coadministration 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.

7.2 Drugs for Which Gastric pH Can Affect Bioavailability

Because of its profound and long lasting inhibition of gastric acid secretion, it is theoretically possible that omeprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, ampicillin esters, iron salts and erlotinib 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). Therefore, patients may need to be monitored when digoxin is taken concomitantly with omeprazole. In the clinical trials, antacids were used concomitantly with the administration of Omeprazole Delayed-Release Capsules.

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 Delayed-Release Capsules.

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 × 1 day, then 200 mg × 6 days) was given with omeprazole (40 mg once daily × 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 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 CYP 2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in crossover study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4-7 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 b.i.d. to 50 mg b.i.d. 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 (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John's Wort or rifampin with omeprazole.

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 [see Warnings and Precautions (5.8) and Clinical Pharmacology (12)].

7.6 Combination Therapy with Clarithromycin

Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [see Contraindications in prescribing information for clarithromycin].

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 [see Warnings and Precautions (5.9)].

8.1 Pregnancy

8.3 Nursing Mothers

Omeprazole is present in human milk. Omeprazole concentrations were measured in breast milk of a woman following oral administration of 20 mg. The peak concentration of omeprazole in breast milk was less than 7% of the peak serum concentration. This concentration would correspond to 0.004 mg of omeprazole in 200 mL of milk. Caution should be exercised when Omeprazole Delayed-Release Capsules is administered to a nursing woman.

8.4 Pediatric Use

Use of Omeprazole Delayed-Release Capsules in pediatric and adolescent patients 2 to 16 years of age for the treatment of GERD is supported by a) extrapolation of results, already included in the currently approved labeling, from adequate and well-controlled studies that supported the approval of Omeprazole Delayed-Release Capsules for adults, and b) safety and pharmacokinetic studies performed in pediatric and adolescent patients. [see Clinical Pharmacology, Pharmacokinetics, Pediatric for pharmacokinetic information (12.3) and Dosage and Administration (2),Adverse Reactions (6.1) and Clinical Studies, (14.6)]. The safety and effectiveness of Omeprazole Delayed-Release Capsules for the treatment of GERD in patients < 1 year of age have not been established. The safety and effectiveness of Omeprazole Delayed-Release Capsules for other pediatric uses have not been established.

Juvenile Animal Data

In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 57 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight  and femur length, and decreases in overall growth [see Nonclinical Toxicology (13.2)].

8.5 Geriatric Use

Omeprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Pharmacokinetic studies have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. However, no dosage adjustment is necessary in the elderly [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

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

8.7 Renal Impairment

No dosage reduction is necessary [see Clinical Pharmacology (12.3)].

8.8 Asian Population

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

12.1 Mechanism of Action

Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

Omeprazole and clarithromycin dual therapy and omeprazole, clarithromycin and amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the Indications and Usage section (1.1).

Helicobacter

Helicobacter pylori- Pretreatment Resistance

Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3% (41/439) in omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3).

Amoxicillin pretreatment susceptible isolates (≤ 0.25 mcg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 mcg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin and amoxicillin study arm. One patient had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 mcg/mL by Etest®.

Patients not eradicated of H. pylori following omeprazole/clarithromycin/amoxicillin triple therapy or omeprazole/clarithromycin dual therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy, omeprazole/clarithromycin/amoxicillin triple therapy, or other regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the triple therapy clinical trials, 84.9% (157/185) of the patients in the omeprazole/clarithromycin/amoxicillin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs.

Susceptibility Test for Helicobacter pylori

For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.

Effects on Gastrointestinal Microbial Ecology

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57 times a human dose of 20 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 6 times a human dose of 20 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.2 to 6.5 times the human dose on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 57 times the human dose on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay.

Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance.

In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [see Warnings and Precautions (5)]. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.

13.2 Animal Toxicology and/or Pharmacology

 Reproduction Studies

Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 57 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole [see Pregnancy, Animal Data (8.1)].

Juvenile Animal Study

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 57 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

14.1 Duodenal Ulcer Disease

14.2 Gastric Ulcer

In a U.S. multicenter, double-blind, study of omeprazole 40 mg once daily, 20 mg once daily, and placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were obtained.

For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg was significantly more effective than 20 mg at 8 weeks.

In a foreign, multinational, double-blind study of 602 patients with endoscopically diagnosed gastric ulcer, omeprazole 40 mg once daily, 20 mg once daily, and ranitidine 150 mg twice a day were evaluated.

14.3 Gastroesophageal Reflux Disease (GERD)

14.4 Erosive Esophagitis

In a U.S. multicenter double-blind placebo controlled study of 20 mg or 40 mg of Omeprazole Delayed-Release Capsules in patients with symptoms of GERD and endoscopically diagnosed erosive esophagitis of grade 2 or above, the percentage healing rates (per protocol) were as follows:

In this study, the 40 mg dose was not superior to the 20 mg dose of Omeprazole Delayed-Release Capsules in the percentage healing rate. Other controlled clinical trials have also shown that Omeprazole Delayed-Release Capsules is effective in severe GERD. In comparisons with histamine H2-receptor antagonists in patients with erosive esophagitis, grade 2 or above, Omeprazole Delayed-Release Capsules in a dose of 20 mg was significantly more effective than the active controls. Complete daytime and nighttime heartburn relief occurred significantly faster (p < 0.01) in patients treated with Omeprazole Delayed-Release Capsules than in those taking placebo or histamine H2- receptor antagonists.

In this and five other controlled GERD studies, significantly more patients taking 20 mg omeprazole (84%) reported complete relief of GERD symptoms than patients receiving placebo (12%).

14.5 Pathological Hypersecretory Conditions

In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple endocrine adenomas, Omeprazole Delayed-Release Capsules significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg every other day to 360 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery, and below 5 mEq/hr in patients with prior gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients [see Dosage and Administration (2)]. Omeprazole Delayed-Release Capsules was well tolerated at these high dose levels for prolonged periods (> 5 years in some patients). In most ZE patients, serum gastrin levels were not modified by Omeprazole Delayed-Release Capsules. However, in some patients serum gastrin increased to levels greater than those present prior to initiation of omeprazole therapy. At least 11 patients with ZE syndrome on long-term treatment with Omeprazole Delayed-Release Capsules developed gastric carcinoids. These findings are believed to be a manifestation of the underlying condition, which is known to be associated with such tumors, rather than the result of the administration of Omeprazole Delayed-Release Capsules [see Adverse Reactions (6)].

14.6 Pediatric GERD

Storage

Store Omeprazole Delayed-Release Capsules in a tight container protected from light and moisture. Store at 20° - 25°C (68° - 77°F) (See USP Controlled Room Temperature). Dispense in a tight and light-resistant container.