omeprazole 20 MG Delayed Release Oral Capsule [Prilosec]

INDICATIONS AND USAGE Omeprazole Delayed-Release Capsules is a proton pump inhibitor (PPI) indicated for the: Treatment of active duodenal ulcer in adults (1.1) Eradication of Helicobacter pylori to reduce the risk of duodenal ulcer recurrence in adults (1.2) Treatment of active benign gastric ulcer in adults (1.3) Treatment of symptomatic gastroesophageal reflux disease (GERD) in patients 1 year of age and older (1.4) Treatment of erosive esophagitis (EE) due to acid-mediated GERD in patients 1 year of age and older (1.5) Maintenance of healing of EE due to acid-mediated GERD in patients 1 year of age and older (1.6) Pathologic hypersecretory conditions in adults (1.7) The safety and effectiveness of Omeprazole Delayed-Release Capsules in pediatric patients < 1 year of age have not been established ( 8.4 ). 1.1 Treatment of Active Duodenal Ulcer Omeprazole Delayed-Release Capsules is indicated for short-term treatment of active duodenal ulcer in adults. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. 1.2 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. Triple Therapy Omeprazole Delayed-Release Capsules in combination with clarithromycin and amoxicillin, is indicated for treatment of patients with H. pylori infection and duodenal ulcer disease (active or up to 1-year history) to eradicate H. pylori in adults. Dual Therapy Omeprazole Delayed-Release Capsules in combination with clarithromycin is indicated for treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H . pylori in adults. Among patients who fail therapy, Omeprazole Delayed-Release Capsules with clarithromycin is more likely to be associated with the development of clarithromycin resistance as compared with triple therapy. In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [see C l i nical Pharmacology (12.4) and the clarithromycin prescribing information, Microbiology section ]. 1.3 Treatment of Active Benign Gastric Ulcer Omeprazole Delayed-Release Capsules is indicated for short-term treatment (4 to 8 weeks) of active benign gastric ulcer in adults. 1.4 Treatment of Symptomatic Gastroesophageal Reflux Disease (GERD) Omeprazole Delayed-Release Capsules is indicated for the treatment of heartburn and other symptoms associated with GERD for up to 4 weeks in patients 1 year of age and older. 1.5 Treatment of Erosive Esophagitis (EE) Due to Acid-Mediated GERD Pediatric Patients 1 Year of Age to Adults Omeprazole Delayed-Release Capsules is indicated for the short-term treatment (4 to 8 weeks) of EE due to acid-mediated GERD that has been diagnosed by endoscopy in patients 1 year of age and older. The efficacy of Omeprazole Delayed-Release Capsules used for longer than 8 weeks in patients with EE has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of EE or GERD symptoms (e.g., heartburn), additional 4 to 8 week courses of Omeprazole Delayed-Release Capsules may be considered. The safety and effectiveness of Omeprazole Delayed-Release Capsules in pediatric patients < 1 year of age have not been established ( 8.4 ). 1.6 Maintenance of Healing of EE Due to Acid-Mediated GERD Omeprazole Delayed-Release Capsules is indicated for the maintenance healing of EE due to acid-mediated GERD in patients 1 year of age and older. Controlled studies do not extend beyond 12 months. 1.7 Pathological Hypersecretory Conditions Omeprazole Delayed-Release Capsules is indicated for the long-term treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) in adults.

DOSAGE AND ADMINISTRATION Indications Recommended Adult ( Error! Hyperlink reference not valid.) and Pediatric Dosage ( Error! Hyperlink reference not valid.) Treatment of Active Duodenal Ulcer 20 mg once daily for 4 weeks; some patients may require an additional 4 weeks ( Error! Hyperlink reference not valid. ) H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: Omeprazole Delayed-Release Capsules 20 mg Each drug twice daily for 10 days ( Error! Hyperlink reference not valid. )* Amoxicillin 1000 mg Clarithromycin 500 mg Dual Therapy: Omeprazole Delayed-Release Capsules 40 mg once daily for 14 days** Clarithromycin 500 mg three times daily for 14 days ( Error! Hyperlink reference not valid. ) Active Benign Gastric Ulcer 40 mg once daily for 4 to 8 weeks ( Error! Hyperlink reference not valid. ) Symptomatic GERD 20 mg once daily for up to 4 weeks ( Error! Hyperlink reference not valid. ) See full prescribing information for weight based dosing in pediatric patients 1 year of age and older ( Error! Hyperlink reference not valid. ) EE due to Acid-Mediated GERD 20 mg once daily for 4 to 8 weeks ( Error! Hyperlink reference not valid. )*** See full prescribing information for weight based dosing in pediatric patients 1 year of age and older ( Error! Hyperlink reference not valid. ) Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily ( Error! Hyperlink reference not valid. )**** See full prescribing information for weight based dosing in pediatric patients 1 year of age and older ( Error! Hyperlink reference not valid. ) Pathological Hypersecretory Conditions Starting dose is 60 mg once daily (varies with individual patient, see full prescribing information) as long as clinically indicated ( Error! Hyperlink reference not valid. ) * if ulcer present, continue Omeprazole Delayed-Release Capsules 20 mg once daily for an additional 18 days. ** if ulcer present, continue Omeprazole Delayed-Release Capsules 20 mg once daily for an additional 14 days. *** an additional 4 weeks of treatment may be given if no response; if recurrence additional 4 to 8 week courses may be considered. **** studied for 12 months. Reduce the dosage to 10 mg once daily for patients with hepatic impairment (Child Pugh Class A, B, or C) and Asian patients ( Error! Hyperlink reference not valid. ) 2.1 Recommended Adult Dosage Regimen by Indication Table 1 shows the recommended dosage of Omeprazole Delayed-Release Capsules in adult patients by indication. Table 1: Recommended Dosage Regimen of Omeprazole Delayed-Release Capsules in Adults by Indication Indication Dosage of Omeprazole Delayed-Release Capsules Treatment Duration Treatment of Active Duodenal Ulcer 20 mg once daily 4 weeks 1 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy Omeprazole Delayed-Release Capsules 20 mg Amoxicillin 1000 mg Clarithromycin 500 mg Take all three drugs twice daily 10 days In patients with an ulcer present at the time of initiation of therapy, continue Omeprazole Delayed-Release Capsules 20 mg once daily for an additional 18 days for ulcer healing and symptom relief. Dual Therapy Omeprazole Delayed-Release Capsules 40 mg once daily Clarithromycin 500 mg three times daily 14 days In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of Omeprazole Delayed-Release Capsules 20 mg once daily is recommended for ulcer healing and symptom relief. Active Benign Gastric Ulcer 40 mg once daily 4 to 8 weeks Treatment of Symptomatic GERD 20 mg once daily Up to 4 weeks Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily 4 to 8 weeks 2 Pathological Hypersecretory Conditions 20 mg once daily 3 Controlled studies do not extend beyond 12 months. 1. Most patients heal within 4 weeks; some patients may require an additional 4 weeks of therapy to achieve healing. 2. The efficacy of Omeprazole Delayed-Release Capsules used for longer than 8 weeks in patients with EE has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of EE or GERD symptoms (e.g., heartburn), additional 4 to 8 week courses of Omeprazole Delayed-Release Capsules may be considered. 3. Dosage reduction to 10 mg once daily is recommended for patients with hepatic impairment (Child-Pugh Class A, B or C) and Asian patients when used for the maintenance of healing of EE [see Use in Specific Populations ( 8 .6 , 8 .7 ) and Clinical Pharmacology ( 1 2 .3 , 12 .5 )]. 2.2 Recommended Pediatric Dosage Regimen by Indication Table 2 shows the recommended dosage of Omeprazole Delayed-Release Capsules in pediatric patients by indication. Table 2: Recommended Dosage Regimen of Omeprazole Delayed-Release Capsules in Pediatric Patients by Indication Indication Omeprazole Delayed-Release Capsules Dosage Regimen and Duration Patient Age Weight-Based Dose (mg) Regimen and Duration Treatment of Symptomatic GERD 1 to 16 years 5 to less than 10 kg: 5 mg Once daily for up to 4 weeks 10 to less than 20 kg: 10 mg 20 kg and greater: 20 mg Treatment of EE due to Acid-Mediated GERD 1 to 16 years 5 to less than 10 kg: 5 mg Once daily for 4 to 8 weeks 1 10 to less than 20 kg: 10 mg 20 kg and greater: 20 mg Maintenance of Healing of EE due to Acid-Mediated GERD 1 to 16 years 5 to less than 10 kg: 5 mg Once daily. Controlled studies do not extend beyond 12 months 10 to less than 20 kg: 10 mg 20 kg and greater: 20 mg 1. The efficacy of Omeprazole Delayed-Release Capsules used for longer than 8 weeks in patients with EE has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of EE or GERD symptoms (e.g., heartburn), additional 4 to 8 week courses of Omeprazole Delayed-Release Capsules may be considered. 2.3 Administration Instructions Take Omeprazole Delayed-Release Capsules before meals. Antacids may be used concomitantly with Omeprazole Delayed-Release Capsules. Missed doses: If a dose is missed, administer as soon as possible. However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose. Omeprazole Delayed-Release Capsules Swallow Omeprazole Delayed-Release Capsules whole; do not chew. For patients unable to swallow an intact capsule, Omeprazole Delayed-Release Capsules can be opened and administered as follows: Place one tablespoon of applesauce into a clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. Open the capsule. Carefully empty all of the microtablets inside the capsule on the applesauce. Mix the microtablets with the applesauce. Swallow applesauce and microtablets immediately with a glass of cool water to ensure complete swallowing of the microtablets. Do not chew or crush the microtablets. Do not save the applesauce and microtablets for future use.

WARNINGS AND PRECAUTIONS Gastric Malignancy: In adults, symptomatic response does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. (5.1) Acute Tubulointerstitial Nephritis: Discontinue treatment and evaluate patients. (5.2) Clostridium difficile-Associated Diarrhea : PPI therapy may be associated with increased risk. (5.3) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.4) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.5 ) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue omeprazole and refer to specialist for evaluation (5.6) Interaction with Clopidogrel: Avoid concomitant use of omeprazole. ( 5.7 , 7 ) Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.8 ) Hypomagnesemia and Mineral Metabolism: Reported rarely with prolonged treatment with PPIs. (5.9) Interaction with St. John’s Wort or Rifampin: Avoid concomitant use of omeprazole. ( 5.10 , 7 ) Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Increased Chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors; temporarily stop omeprazole at least 14 days before assessing CgA levels. ( 5.11 , 7 ) Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider a temporary withdrawal of omeprazole ( 5.12 , 7 ). Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.13 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy. 5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (e.g., malaise, nausea, 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 delayed-release capsules and evaluate patients with suspected acute TIN [see Contraindications ( 4 )]. 5.3 Clostridium difficile -Associated Diarrhea Published observational studies suggest that PPI therapy like omeprazole 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, refer to Warnings and Precautions sections of the corresponding prescribing information. 5.4 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 (2.1) , Adverse Reactions (6.3) ]. 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions ( 6.3 )]. Discontinue omeprazole delayed-release capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily 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, 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 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, consider alternative anti-platelet therapy [see Drug Interactions (7) 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 in patients treated with omeprazole. 5.9 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemi

CONTRAINDICATIONS Omeprazole Delayed-Release Capsules is contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6 )] . Proton pump inhibitors (PPIs), including Omeprazole Delayed-Release Capsules, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions ( 7 )]. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with Omeprazole Delayed-Release Capsules, refer to the CONTRAINDICATIONS section of their package inserts. Patients with known hypersensitivity to substituted benzimidazoles or any component of the formulation. ( Error! Hyperlink reference not valid. ) Patients receiving rilpivirine-containing products. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) Refer to the Contraindications section of the prescribing information for clarithromycin and amoxicillin, when administered in combination with Omeprazole Delayed-Release Capsules. ( Error! Hyperlink reference not valid. )

CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Antisecretory Activity After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H + /K + ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days. Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of omeprazole in healthy subjects and patients are shown below. The “max” value represents determinations at a time of maximum effect (2 to 6 hours after dosing), while “min” values are those 24 hours after the last dose of omeprazole. Table 5: Range of Mean Values from Multiple Studies of the Mean Antisecretory Effects of Omeprazole After Multiple Daily Dosing Omeprazole 20 mg Omeprazole 40 mg Parameter Max Min Max Min % Decrease in Basal Acid Output 78 1 58-80 94 1 80-93 % Decrease in Peak Acid Output 79 1 50-59 88 1 62-68 % Decrease in 24–hr Intragastric Acidity 80-97 92-94 1. Single Studies Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24-hour intragastric acidity in some patients. Serum Gastrin Effects In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H 2 -receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy. Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.11 )] . Enterochromaffin-like (ECL) Cell Effects Human gastric biopsy specimens have been obtained from more than 3000 patients (both children and adults) treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions. Other Effects Systemic effects of omeprazole in the CNS, cardiovascular and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single intravenous dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased. As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment. The course of Barrett’s esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of Omeprazole Delayed-Release Capsules 40 mg twice daily for 12 months followed by 20 mg twice daily for 12 months or ranitidine 300 mg twice daily for 24 months. No clinically significant impact on Barrett’s mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett’s mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett’s mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter. 12.3 Pharmacokinetics Omeprazole is a time-dependent inhibitor of CYP2C19, resulting in autoinhibition and nonlinear pharmacokinetics. The systemic exposure increases in a more than dose proportional manner after multiple oral doses of omeprazole. Compared to the first dose, the systemic exposure (C max and AUC 0-24h ) at steady state following once a day dosing increased by 61% and 62%, respectively, compared to after the first dose for the 20 mg dose of Omeprazole Delayed-Release Capsules and increased by 118% and 175%, respectively, for the 40 mg dose of Omeprazole Delayed-Release Capsules. Absorption Omeprazole Delayed-Release Capsules contain an enteric-coated microtablet formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the microtablets leave the stomach. Absorption is rapid, with peak plasma concentrations of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30 to 40% at doses of 20 to 40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500 to 600 mL/min. The bioavailability of omeprazole increases slightly upon repeated administration of Omeprazole Delayed-Release Capsules. The systemic exposure (C max and AUC) are similar when a 40 mg Omeprazole Delayed-Release Capsules is administered with and without applesauce. However, administration of a 20 mg Omeprazole Delayed-Release Capsules with applesauce, results in a mean 25% reduction in Cmax without a significant change in AUC compared to administration without applesauce. The clinical relevance of this finding is unknown. Distribution Protein binding is approximately 95%. Elimination Metabolism Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyo