OMEPRAZOLE- omeprazole_capsule, delayed release

20 kg 6 to 16 years 20 mg Adults 2 (mean 76 kg) 23 to 29 years (n=12) Single Dosing C max 3 288 (n=10) 495 (n=49) 668 AUC 3 511 (n=7) 1140 (n=32) 1220 Repeated Dosing C max 3 539 (n=4) 851 (n=32) 1458 AUC 3 1179 (n=2) 2276 (n=23) 3352 Following comparable mg/kg doses of omeprazole, younger children (2 to 5 years of age) have lower AUCs than children 6 to 16 years of age or adults; AUCs of the latter two groups did not differ [see Dosage and Administration ( 2 1 to 11 Months of Age A population pharmacokinetics model was used to determine appropriate doses of omeprazole in pediatric patients 1 month to less than 1 year of age for treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD. The model was based on data from 64 children 0. 5 month to 16 year of age. Only limited data were available in children below the age of 1 year. Pediatric doses were simulated in the age group of 1 to 11 month, to achieve comparable omeprazole exposures with adults following treatment with 20 mg once daily [see Dosage and Administration ( 2. 2 Race/Ethnicity [See Clinical Pharmacology ( 12. 5 Renal Impairment In patients with chronic renal impairment (creatinine clearance between 10 and 62 mL/min/1. 73 m 2 Hepatic Impairment In patients with chronic hepatic disease classified as Child-Pugh Class A (n=3), B (n=4) and C (n=1), the bioavailability increased to approximately 100% compared to healthy subjects, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in healthy subjects of 0. 5 to 1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in healthy subjects [see Dosage and Administration ( 2. 6 Drug Interaction Studies Effect of Omeprazole on Other Drugs 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. Antiretrovirals For some antiretroviral drugs, such as rilpivirine, atazanavir and nelfinavir, decreased serum concentrations have been reported when given together with omeprazole [see Drug Interactions ( 7 Rilpivirine: Following multiple doses of rilpivirine (150 mg, daily) and omeprazole (20 mg, daily), AUC was decreased by 40%, C max min Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C max min Atazanavir: Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, C max min Saquinavir: Following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. AUC was increased by 82%, C max min Clopidogrel In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period. In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction [see Warnings and Precautions ( 5. 6 7 Mycophenolate Mofetil Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA [see Drug Interactions ( 7 Cilostazol Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C max max [see Drug Interactions ( 7 Diazepam Concomitant administration of omeprazole 20 mg once daily and diazepam 0. 1 mg/kg given intravenously resulted in 27% decrease in clearance and 36% increase in diazepam half-life [see Drug Interactions ( 7 Digoxin Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [see Drug Interactions ( 7 Effect of Other Drugs on Omeprazole Voriconazole Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C max 0-24 [see Drug Interactions ( 7 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 [see Indications and Usage ( 1. 2 Helicobacter pylori Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology 1 Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. 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 registered Table 8 Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes 1. Includes only patients with pretreatment clarithromycin susceptibility test results 2. Susceptible (S) MIC <= 0. 25 mcg/mL, Intermediate (I) MIC 0. 5 en dash 1 mcg/mL, Resistant (R) MIC >= 2 mcg/mL Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes 1 Clarithromycin Pretreatment Results Clarithromycin Post-treatment Results H. pylori Post-treatment susceptibility results S 2 I 2 R 2 No MIC Dual Therapy en dash (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed by omeprazole 20 mg once daily for another 14 days) (Studies 4, 5) Susceptible 2 108 72 1 26 9 Intermediate 2 1 1 Resistant 2 4 4 Triple Therapy en dash (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice daily for 10 days en dash Studies 1, 2, 3; followed by omeprazole 20 mg once daily for another 18 days en dash Studies 1, 2) Susceptible 2 171 153 7 3 8 Intermediate 2 Resistant 2 14 4 1 6 3 Patients not eradicated of H. pylori 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 Susceptibility Test for Helicobacter pylori For susceptibility testing information about Helicobacter pylori 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 Campylobacter Clostridium difficile 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 two fully functional alleles are extensive metabolizers and those carrying two 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: poor metabolizers > intermediate metabolizers > extensive metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers. In a pharmacokinetic study of single 20 mg omeprazole dose, the AUC of omeprazole in Asian subjects was approximately four-fold of that in Caucasians [see Dosage and Administration ( 2.">Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H + + 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 + + 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 1. Single Studies Parameter Omeprazole 20 mg Omeprazole 40 mg Max Min Max Min % Decrease in Basal Acid Output 78 1 58 to 80 94 1 80 to 93 % Decrease in Peak Acid Output 79 1 50 to 59 88 1 62 to 68 % Decrease in 24-hr. Intragastric Acidity 80 to 97 92 to 94 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 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. 10 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. double-blind controlled study of omeprazole 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. 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 0-24h Absorption Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma concentrations of omeprazole occurring within 0. 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. Based on a relative bioavailability study, the AUC and C max The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole delayed-release capsules. The systemic exposure (C max max 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 hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. Excretion Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity. Combination Therapy with Antimicrobials Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of omeprazole were increased (C max 0-24 1/2 The plasma concentrations of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean C max min 0-8 max min 0-8 Table 6 Clarithromycin Tissue Concentrations 2 hours after Dose 1 1. Mean +/- SD (mcg/g) Tissue Clarithromycin Clarithromycin+ Omeprazole Antrum 10. 01 (n = 5) 19. 71 (n = 5) Fundus 20. 64 (n = 5) 24. 37 (n = 5) Mucus 4. 74 (n = 4) 39. 79 (n = 4) Specific Populations Age: Geriatric Population The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. 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. Age: Pediatric Population 2 to 16 Years of Age The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age: Table 7 Pharmacokinetic Parameters of Omeprazole Following Single and Repeated Oral Administration in Pediatric Populations Compared with Adults 1. Data from single and repeated dose studies. Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules. Data from a single and repeated dose study. Plasma concentration adjusted to an oral dose of 1 mg/kg. Single or Repeated Oral Dosing/Parameter Children 1 <= 20 kg 2 to 5 years 10 mg Children 1 > 20 kg 6 to 16 years 20 mg Adults 2 (mean 76 kg) 23 to 29 years (n=12) Single Dosing C max 3 288 (n=10) 495 (n=49) 668 AUC 3 511 (n=7) 1140 (n=32) 1220 Repeated Dosing C max 3 539 (n=4) 851 (n=32) 1458 AUC 3 1179 (n=2) 2276 (n=23) 3352 Following comparable mg/kg doses of omeprazole, younger children (2 to 5 years of age) have lower AUCs than children 6 to 16 years of age or adults; AUCs of the latter two groups did not differ [see Dosage and Administration ( 2 1 to 11 Months of Age A population pharmacokinetics model was used to determine appropriate doses of omeprazole in pediatric patients 1 month to less than 1 year of age for treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD. The model was based on data from 64 children 0. 5 month to 16 year of age. Only limited data were available in children below the age of 1 year. Pediatric doses were simulated in the age group of 1 to 11 month, to achieve comparable omeprazole exposures with adults following treatment with 20 mg once daily [see Dosage and Administration ( 2. 2 Race/Ethnicity [See Clinical Pharmacology ( 12. 5 Renal Impairment In patients with chronic renal impairment (creatinine clearance between 10 and 62 mL/min/1. 73 m 2 Hepatic Impairment In patients with chronic hepatic disease classified as Child-Pugh Class A (n=3), B (n=4) and C (n=1), the bioavailability increased to approximately 100% compared to healthy subjects, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in healthy subjects of 0. 5 to 1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in healthy subjects [see Dosage and Administration ( 2. 6 Drug Interaction Studies Effect of Omeprazole on Other Drugs 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. Antiretrovirals For some antiretroviral drugs, such as rilpivirine, atazanavir and nelfinavir, decreased serum concentrations have been reported when given together with omeprazole [see Drug Interactions ( 7 Rilpivirine: Following multiple doses of rilpivirine (150 mg, daily) and omeprazole (20 mg, daily), AUC was decreased by 40%, C max min Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C max min Atazanavir: Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, C max min Saquinavir: Following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. AUC was increased by 82%, C max min Clopidogrel In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period. In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction [see Warnings and Precautions ( 5. 6 7 Mycophenolate Mofetil Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA [see Drug Interactions ( 7 Cilostazol Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C max max [see Drug Interactions ( 7 Diazepam Concomitant administration of omeprazole 20 mg once daily and diazepam 0. 1 mg/kg given intravenously resulted in 27% decrease in clearance and 36% increase in diazepam half-life [see Drug Interactions ( 7 Digoxin Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [see Drug Interactions ( 7 Effect of Other Drugs on Omeprazole Voriconazole Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C max 0-24 [see Drug Interactions ( 7 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 [see Indications and Usage ( 1. 2 Helicobacter pylori Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology 1 Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. 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 registered Table 8 Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes 1. Includes only patients with pretreatment clarithromycin susceptibility test results 2. Susceptible (S) MIC <= 0. 25 mcg/mL, Intermediate (I) MIC 0. 5 en dash 1 mcg/mL, Resistant (R) MIC >= 2 mcg/mL Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes 1 Clarithromycin Pretreatment Results Clarithromycin Post-treatment Results H. pylori Post-treatment susceptibility results S 2 I 2 R 2 No MIC Dual Therapy en dash (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed by omeprazole 20 mg once daily for another 14 days) (Studies 4, 5) Susceptible 2 108 72 1 26 9 Intermediate 2 1 1 Resistant 2 4 4 Triple Therapy en dash (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice daily for 10 days en dash Studies 1, 2, 3; followed by omeprazole 20 mg once daily for another 18 days en dash Studies 1, 2) Susceptible 2 171 153 7 3 8 Intermediate 2 Resistant 2 14 4 1 6 3 Patients not eradicated of H. pylori 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 Susceptibility Test for Helicobacter pylori For susceptibility testing information about Helicobacter pylori 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 Campylobacter Clostridium difficile 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 two fully functional alleles are extensive metabolizers and those carrying two 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: poor metabolizers > intermediate metabolizers > extensive metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers. In a pharmacokinetic study of single 20 mg omeprazole dose, the AUC of omeprazole in Asian subjects was approximately four-fold of that in Caucasians [see Dosage and Administration ( 2.

Omeprazole delayed-release capsules are proton pump inhibitor (PPI) indicated for the: 1. 7 Omeprazole delayed-release capsules are 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. 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, are 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 are indicated for treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H. 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 Clinical Pharmacology ( 12. 4 ] Omeprazole delayed-release capsules are indicated for short-term treatment (4 to 8 weeks) of active benign gastric ulcer in adults. Omeprazole delayed-release capsules are 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. Pediatric Patients 1 Year of Age to Adults Omeprazole delayed-release capsules are 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. , heartburn), additional 4 to 8 week courses of omeprazole may be considered. Pediatric Patients 1 Month to Less than 1 Year of Age Omeprazole delayed-release capsules are indicated for the short-term treatment (up to 6 weeks) of EE due to acid-mediated GERD in pediatric patients 1 month to less than 1 year of age. Omeprazole delayed-release capsules are 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. Omeprazole delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions (e. , Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) in adults.

DOSAGE AND ADMINISTRATION
* if ulcer present, continue omeprazole 20 mg once daily for an additional 18 days. ** if ulcer present, continue omeprazole 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 ( 8. 7 Indication Recommended Adult ( 2. 2 Treatment of Active Duodenal Ulcer 20 mg once daily for 4 weeks; some patients may require an additional 4 weeks ( 2. pylori Triple Therapy: Omeprazole 20 mg Each drug twice daily for 10 days ( 2. 1 Dual Therapy: Omeprazole 40 mg once daily for 14 days** 2. 1 Active Benign Gastric Ulcer 40 mg once daily for 4 to 8 weeks ( 2. 1 Symptomatic GERD 20 mg once daily for up to 4 weeks (2. 2 EE due to Acid-Mediated GERD 20 mg once daily for 4 to 8 weeks ( 2. 2 Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily ( 2. 2 Pathological Hypersecretory Conditions Starting dose is 60 mg once daily (varies with individual patient, see full prescribing information) as long as clinically indicated ( 2. 1 Table 1 shows the recommended dosage of omeprazole in adult patients by indication. Table 1 Recommended Dosage Regimen of Omeprazole in Adults by Indication 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 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. , heartburn), additional 4 to 8 week courses of omeprazole may be considered. 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. 5 Indication Dosage of Omeprazole Treatment Duration Treatment of Active Duodenal Ulcer 20 mg once daily 4 weeks 1 Helicobacter pylori Triple Therapy 10 days Dual Therapy 14 days Active Benign Gastric Ulcer 40 mg once daily 4 to 8 weeks Treatment of Symptomatic GERD 20 mg once daily Up to 4 weeks Treatment of EE due to Acid-Mediated GERD 20 mg once daily 4 to 8 weeks 2 Maintenance of Healing of EE due to Acid-Mediated GERD 20 mg once daily 3 Controlled studies do not extend beyond 12 months. Pathological Hypersecretory Conditions Starting dose is 60 mg once daily; adjust to patient needs As long as clinically indicated. Table 2 shows the recommended dosage of Omeprazole in pediatric patients by indication. Table 2 Recommended Dosage Regimen of Omeprazole in Pediatric Patients by Indication 1. The efficacy of omeprazole delayed-release capsules used for longer than 8 weeks in patients with EE has not been established. , heartburn), additional 4 to 8 week courses of omeprazole delayed-release capsules may be considered. Indication Omeprazole 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 1 month to less than 1 year 3 to less than 5 kg: 2. 5 mg Once daily up to 6 weeks 5 to less than 10 kg: 5 mg 10 kg and greater: 10 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 Omeprazole Delayed-Release Capsules .
INSTRUCTIONS FOR USE
Omeprazole (oh mep'' ra zole) Delayed-Release Capsules, USP Omeprazole delayed-release capsules Taking omeprazole delayed-release capsules with applesauce: 1. 2. 3.

The following serious adverse reactions are described below and elsewhere in labeling: [see Warnings and Precautions ( 5. 2 Clostridium difficile [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4) [see Warnings and Precautions ( 5. 6) [see Warnings and Precautions ( 5. 8 [see Warnings and Precautions ( 5. 9 see Warnings and Precautions ( 5. 13 Adults: 6 Pediatric patients (1 to 16 years of age): 8. 4 To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. , with an incidence rate >= 2%) from omeprazole-treated patients enrolled in these studies included headache (7%), abdominal pain (5%), nausea (4%), diarrhea (4%), vomiting (3%), and flatulence (3%). Additional adverse reactions that were reported with an incidence >= 1% included acid regurgitation (2%), upper respiratory infection (2%), constipation (2%), dizziness (2%), rash (2%), asthenia (1%), back pain (1%), and cough (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 frequently reported in the 1 month to <1 year age group, the 1 to <2 year age group, and the 2 to 16 year age group (42%, 75%, and 19%, respectively). In addition, otitis media was frequently reported in the 1 month to <1 year age group (22%), fever was frequently reported in the 1 to <2 year age group (33% ), and accidental injuries were frequently reported in the 2 to 16 year age group (4%) [see Use in Specific Populations ( 8. 4 In clinical trials using either dual therapy with omeprazole and clarithromycin, or triple therapy with omeprazole, 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. Dual Therapy (omeprazole/clarithromycin) Adverse reactions observed in controlled clinical trials using combination therapy with omeprazole and clarithromycin (n = 346) that differed from those previously described for omeprazole alone were taste perversion (15%), tongue discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu-syndrome (1%). (For more information on clarithromycin, refer to the clarithromycin prescribing information, Adverse Reactions section. ) Triple Therapy (omeprazole/clarithromycin/amoxicillin) The most frequent adverse reactions observed in clinical trials using combination therapy with omeprazole, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone. (For more information on clarithromycin or amoxicillin, refer to the respective prescribing information, Adverse Reactions sections. ) 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; systemic lupus erythematosus 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, fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with ZE 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. 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 Metabolism and Nutritional disorders Hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain [see Warnings and Precautions ( 5. 9 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, cutaneous lupus erythematosus 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, erectile dysfunction Hematologic Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis.

4 4 7 4 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 2 6 [see Drug Interactions ( 7 .

Risk Summary There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3. 4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person). Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg esomeprazole or 40 mg omeprazole (based on body surface area for a 60 kg person). Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data]. The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H 2 A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero A population-based retrospective cohort study covering all live births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2. 6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H 2 2 A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% with first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2. 8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Omeprazole Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69. 1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6. 1 mg/kg/day (about 3. 4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13. 0 mg/kg/day (about 3. 4 to 34 times an oral human doses of 40 mg on a body surface area basis), administered prior to mating through the lactation period. Esomeprazole The data described below was generated from studies using esomeprazole, an enantiomer of omeprazole. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole. No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3. 4 to 68 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 17 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3. 4 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg /kg/day (about 3. When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age. Risk Summary Limited data suggest omeprazole may be present in human milk. There are no clinical data on the effects of omeprazole on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for omeprazole and any potential adverse effects on the breastfed infant from omeprazole or from the underlying maternal condition. The safety and effectiveness of omeprazole have been established in pediatric patients 1 to 16 years for the treatment of symptomatic GERD, treatment of EE due to acidmediated GERD, and maintenance of healing of EE due to acid-mediated GERD. Use of omeprazole in this age group is supported by adequate and well-controlled studies in adults and uncontrolled safety, efficacy and pharmacokinetic studies performed in pediatric and adolescent patients [see Clinical Pharmacology ( 12. 8 The safety and effectiveness of omeprazole have been established in pediatric patients 1 month to less than 1 year of age for the treatment of EE due to acid-mediated GERD and is supported by adequate and well-controlled studies in adults and safety, pharmacokinetic, and pharmacodynamic studies performed in pediatric patients [see Clinical Pharmacology ( 12. 3 In the pediatric population, adverse reactions of the respiratory system were frequently reported in the entire (1 month to 16 year) age group. Otitis media was frequently reported in the 1 month to <1 year age group, fever was frequently reported in the 1 to <2 year age group, and accidental injuries were frequently reported in the 2 to 16 year age group [see Adverse Reactions ( 6. 1 The safety and effectiveness of omeprazole have not been established in: o o o o H. pylori o o Juvenile Animal Data Esomeprazole, an enantiomer of omeprazole, was shown to decrease body weight, body weight gain, femur weight, femur length, and overall growth at oral doses about 34 to 68 times a daily human dose of 40 mg esomeprazole or 40 mg omeprazole based on body surface area in a juvenile rat toxicity 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 68 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole 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 esomeprazole or 40 mg omeprazole 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. Omeprazole was administered to over 2000 elderly individuals (>= 65 years of age) in clinical trials in the U. 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 In patients with hepatic impairment (Child-Pugh Class A, B, or C) exposure to omeprazole substantially increased compared to healthy subjects. Dosage reduction of omeprazole to 10 mg once daily is recommended for patients with hepatic impairment for maintenance of healing of EE [see Dosage and Administration ( 2. 3 In studies of healthy subjects, Asians had approximately a four-fold higher exposure than Caucasians. Dosage reduction of omeprazole to 10 mg once daily is recommended for Asian patients for maintenance of healing of EE [see Dosage and Administration ( 2.

Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with Omeprazole delayed-release capsules and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 3 Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics Antiretrovirals Clinical Impact The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. [see Clinical Pharmacology ( 12. 3 [see clinical Pharmacology ( 12. 3 Intervention Rilpivirine-containing products: Concomitant use with omeprazole delayed-release capsule is contraindicated [see Contraindications ( 4 Atazanavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs. Warfarin Clinical Impact Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. Methotrexate Clinical Impact Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5. 11 Intervention A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. CYP2C19 Substrates (e. , clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clopidogrel Clinical Impact Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12. Intervention Avoid concomitant use with omeprazole delayed-release capsules. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5. 6) Citalopram Clinical Impact Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12. 3 Intervention Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. Cilostazol Clinical Impact Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12. 3 Intervention Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. Phenytoin Clinical Impact Potential for increased exposure of phenytoin. Intervention Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. Diazepam Clinical Impact Increased exposure of diazepam [see Clinical Pharmacology ( 12. 3 Intervention Monitor patients for increased sedation and reduce the dose of diazepam as needed. Digoxin Clinical Impact Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12. 3 Intervention Monitor digoxin concentrations. See digoxin prescribing information. Drugs Dependent on Gastric pH for Absorption (e. , iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole delayed-release capsules and MMF. Use omeprazole delayed-release capsules with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12. 3 Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. Intervention See Contraindications, Warnings Precautions Drug Interactions Tacrolimus Clinical Impact Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Intervention Monitor tacrolimus whole blood concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5. 2 Intervention Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e. , for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Interaction with Secretin Stimulation Test Clinical Impact Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. Intervention Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12. 2 False Positive Urine Tests for THC Clinical Impact There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. Intervention An alternative confirmatory method should be considered to verify positive results. Other Clinical Impact There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e. , cyclosporine, disulfiram). Intervention Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole delayed-release capsules. Table 4 Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12. 3 Intervention St. John's Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings And Precautions ( 5. 9 CYP2C19 or CYP3A4 Inhibitors Clinical Impact Increased exposure of omeprazole [see Clinical Pharmacology ( 12. 3 Intervention Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See full prescribing information for a list of clinically important drug interactions.

OVERDOSAGE
Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience. [see Adverse Reactions ( 6 If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.
NONCLINICAL TOXICOLOGY
In two 24 month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44 and 140.8 mg/kg/day (about 0.4 to 34 times a human dose of 40 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 3.4 times a human dose of 40 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 0.1 to 3.9 times the human dose of 40 mg/day, based 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 34 times the human dose of 40 mg/day 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 in vivo in vivo in vitro in vitro in vivo Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times an oral human dose of 40 mg 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 2
CLINICAL STUDIES
In a multicenter, double-blind, placebo-controlled study of 147 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 2 and 4 weeks was significantly higher with omeprazole 20 mg once daily than with placebo (p <= 0. Treatment of Active Duodenal Ulcer % of Patients Healed 1. 01) Omeprazole 20 mg a. (n = 99) Placebo a. (n = 48) Week 2 41 1 13 Week 4 75 1 27 Complete daytime and nighttime pain relief occurred significantly faster (p <= 0. 01) in patients treated with omeprazole 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received omeprazole had complete relief of daytime pain (p <= 0. 05) and nighttime pain (p <= 0. In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with omeprazole 20 mg once daily than with ranitidine 150 mg b. (n = 145) Ranitidine 150 mg twice daily (n = 148) Week 2 42 34 Week 4 82 1 63 Healing occurred significantly faster in patients treated with omeprazole than in those treated with ranitidine 150 mg b. In a foreign multinational randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 20 mg and 40 mg of omeprazole were compared with 150 mg b. of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of omeprazole were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of omeprazole, and at 8 weeks there was no significant difference between any of the active drugs. 01) Omeprazole Ranitidine 20 mg (n = 34) 40 mg (n = 36) 150 mg twice daily (n = 35) Week 2 83 1 83 1 53 Week 4 97 1 100 1 82 Week 8 100 100 94 Triple Therapy (omeprazole/clarithromycin/amoxicillin) Three U. , randomized, double-blind clinical studies in patients with H. pylori registered* H. pylori The combination of omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H. Table 9 Per-Protocol and Intent-to-Treat H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval] 1. Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer within 5 years, study 3) and H. pylori registered* 2. Patients were included in the analysis if they had documented H. 05) versus clarithromycin plus amoxicillin. Omeprazole + clarithromycin + amoxicillin Clarithromycin + amoxicillin Per-Protocol 1 Intent-to-Treat 2 Per-Protocol 1 Intent-to-Treat 2 Study 1 77 3 69 3 43 [31, 56] 37 [27, 48] (n = 64) (n = 80) (n = 67) ( n = 84) Study 2 78 3 73 3 41 [29, 54] 36 [26, 47] (n = 65) (n = 77) (n = 68) ( n = 83) Study 3 90 3 83 3 33 [24, 44] 32 [23, 42] (n = 69) (n = 84) (n = 93) ( n = 99) Dual Therapy (omeprazole/clarithromycin) Four randomized, double-blind, multi-center studies (4, 5, 6, and 7) evaluated omeprazole 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days, followed by omeprazole 20 mg once daily, (Studies 4, 5, and 7) or by omeprazole 40 mg once daily (Study 6) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori The combination of omeprazole and clarithromycin was effective in eradicating H. pylori Eradication Rates (Per-Protocol Analysis at 4 to 6 Weeks) % of Patients Cured [95% Confidence Interval] 1. Statistically significantly higher than clarithromycin monotherapy (p < 0. Statistically significantly higher than omeprazole monotherapy (p < 0. 05) Omeprazole + Clarithromycin Omeprazole Clarithromycin U. Studies Study 4 74 [60, 85] 1,2 0 [0, 7] 31 [ 18, 47] (n = 53) (n = 54) (n = 42) Study 5 64 [51, 76] 1,2 0[0, 6] 39 [24, 55] (n = 61) (n = 59) (n = 44) Non U. Studies Study 6 83 [71, 92] 2 1 [0, 7] N/A (n = 60) (n = 74) Study 7 74 [64, 83] 2 1 [0, 6] N/A (n = 86) (n = 90) Ulcer healing was not significantly different when clarithromycin was added to omeprazole therapy compared with omeprazole therapy alone. The combination of omeprazole and clarithromycin was effective in eradicating H. pylori Table 11 Duodenal Ulcer Recurrence Rates by H. pylori Eradication Status % of Patients with Ulcer Recurrence 1. Combined results for omeprazole + clarithromycin, omeprazole, and clarithromycin treatment arms 3. Combined results for omeprazole + clarithromycin and omeprazole treatment arms 4. 01) versus proportion with duodenal ulcer recurrence who were not H. pylori H pylori 1 H pylori 1 U. Studies 2 6 months post-treatment Study 4 35 4 60 (n = 49) (n = 88) Study 5 8 4 60 (n =53) (n = 106) Non U. Studies 3 6 months post-treatment Study 6 5 4 46 (n = 43) (n =78) Study 7 6 4 43 (n =53) (n = 107) 12 months post-treatment Study 6 5 4 68 (n =39) (n =71) In a U. 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. Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated) 1. 01) omeprazole 40 mg or 20 mg versus placebo 2. 05) omeprazole 40 mg versus 20 mg Omeprazole 20 mg once daily (n = 202) Omeprazole 40 mg once daily (n = 214) Placebo (n = 104) Week 4 47. 8 Week 8 74. 1 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. 01) omeprazole 40 mg versus ranitidine 2. 01) omeprazole 40 mg versus 20 mg Omeprazole 20 mg once daily (n = 200) Omeprazole 40 mg once daily (n = 187) Ranitidine 150 mg twice daily (n = 199) Week 4 63. 3 Week 8 81. 4 A placebo-controlled study was conducted in Scandinavia to compare the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD patients without EE. Result are shown below. % Successful Symptomatic Outcome 1 1. Defined as complete resolution of heartburn 2. 005) versus 10 mg 3. 005) versus placebo Omeprazole 20 mg a. Omeprazole 10 mg a. All patients 46 2,3 31 3 13 (n = 205) (n = 199) (n = 105) Patients with confirmed GERD 56 2,3 36 3 14 (n = 115) (n = 109) (n = 59) In a U. 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 EE of grade 2 or above, the percentage healing rates (per protocol) were as follows: 1. 01) omeprazole versus placebo. 20 mg Omeprazole (n = 83) 40 mg Omeprazole (n = 87) Placebo (n = 43) Week 4 39 1 45 1 7 Week 8 74 1 75 1 14 In this study, the 40 mg dose was not superior to the 20 mg dose of omeprazole in the percentage healing rate. Other controlled clinical trials have also shown that omeprazole is effective in severe GERD. In comparisons with histamine H 2 2 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%). double-blind, randomized, multicenter, placebo-controlled study, two dose regimens of omeprazole were studied in patients with endoscopically confirmed healed esophagitis. Results to determine maintenance of healing of EE are shown below. Life Table Analysis 1. 01) omeprazole 20 mg once daily versus omeprazole 20 mg 3 consecutive days per week or placebo. Omeprazole 20 mg once daily (n = 138) Omeprazole 20 mg 3 days Per week (n = 137) Placebo (n = 131) Percent in endoscopic remission at 6 months 70 1 34 11 In an international multicenter double-blind study, omeprazole 20 mg daily and 10 mg daily were compared with ranitidine 150 mg twice daily in patients with endoscopically confirmed healed esophagitis. The table below provides the results of this study for maintenance of healing of EE. 01) omeprazole 20 mg once daily versus omeprazole 10 mg once daily or Ranitidine. 03) omeprazole 10 mg once daily versus Ranitidine. Omeprazole 20 mg once daily (n = 131) Omeprazole 10 mg once daily (n = 133) Ranitidine 150 mg twice daily (n = 128) Percent in endoscopic remission at 12 months 1 2 46 In patients who initially had grades 3 or 4 erosive esophagitis, for maintenance after healing 20 mg daily of omeprazole was effective, while 10 mg did not demonstrate effectiveness. 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 [see Adverse Reactions ( 6 Treatment of Symptomatic GERD The effectiveness of omeprazole for the treatment of symptomatic GERD in pediatric patients 1 to 16 years of age is based in part on data obtained from 125 pediatric patients in two uncontrolled clinical studies. The first study enrolled 12 pediatric patients 1 to 2 years of age with a history of clinically diagnosed GERD. Patients were administered a single dose of omeprazole (0. 5 mg/kg, 1 mg/kg, or 1. 5 mg/kg) for 8 weeks as an open capsule in 8. 4% sodium bicarbonate solution. Seventy-five percent (9/12) of the patients had vomiting/regurgitation episodes decreased from baseline by at least 50%. The second study enrolled 113 pediatric patients 2 to 16 years of age with a history of symptoms suggestive of symptomatic GERD. Patients were administered a single dose of omeprazole (10 mg or 20 mg, based on body weight) for 4 weeks either as an intact capsule or as an open capsule in applesauce. Successful response was defined as no moderate or severe episodes of either pain-related symptoms or vomiting/regurgitation during the last 4 days of treatment. Results showed success rates of 60% (9/15; 10 mg omeprazole) and 59% (58/98; 20 mg omeprazole), respectively. Treatment of EE due to Acid-Mediated GERD In an uncontrolled, open-label dose-titration study, for the treatment of EE in pediatric patients 1 to 16 years of age required doses that ranged from 0. 5 mg/kg/day (80 mg/day). Doses were initiated at 0. 7 mg/kg/day. Doses were increased in increments of 0. 7 mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than 6% of a 24-hour study). After titration, patients remained on treatment for 3 months. Forty-four percent of the patients were healed on a dose of 0. 7 mg/kg body weight; most of the remaining patients were healed with 1. 4 mg/kg after an additional 3 months'' treatment. EE was healed in 51 of 57 (90%) children who completed the first course of treatment in the healing phase of the study. In addition, after 3 months of treatment, 33% of the children had no overall symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation/vomiting. Maintenance of Healing of EE due to Acid-Mediated GERD In an uncontrolled, open-label study of maintenance of healing of EE in 46 pediatric patients, 1 to 16 years of age, 54% of patients required half the healing dose. The remaining patients increased the healing dose (0. 7 to a maximum of 2. 8 mg/kg/day) either for the entire maintenance period, or returned to half the dose before completion. Of the 46 patients who entered the maintenance phase, 19 (41%) had no relapse during follow-up (range 4 to 25 months). In addition, maintenance therapy in EE patients resulted in 63% of patients having no overall symptoms.
REFERENCES
1. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard

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