ESOMEPRAZOLE MAGNESIUM- esomeprazole magnesium_capsule, delayed release

Esomeprazole 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. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, esomeprazole 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. Antisecretory Activity Adults The effect of esomeprazole on intragastric pH was determined in adult patients with symptomatic GERD in two separate studies. In the first study of 36 patients, esomeprazole magnesium 40 mg and 20 mg delayed-release capsules were administered once daily over 5 days as shown in Table 5: Table 5: Effect of Esomeprazole on Intragastric pH on Day 5 (N=36) Following Once Daily Dosing of Esomeprazole Magnesium Delayed-Release Capsules in Adult Patients with Symptomatic GERD 1. Parameter Esomeprazole Magnesium Delayed-Release Capsules 40 mg once daily 20 mg once daily % Time Gastric 1 70% 2 53% Coefficient of variation 26% 37% Median 24 Hour pH 4. 1 Coefficient of variation 16% 27% In a second study, the effect on intragastric pH of esomeprazole magnesium 40 mg delayed-release capsules administered once daily over a five-day period was similar to the first study, (% time with pH > 4 was 68% or 16. Serum Gastrin Effects The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials of oral esomeprazole for up to 8 weeks and in over 1,300 patients for up to 12 months. The mean fasting gastrin level increased in a dose-related manner. The increase in serum gastrin concentrations reached a plateau within two to three months of therapy and returned to baseline levels within four 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 3,000 patients (both pediatrics 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 [see Nonclinical Toxicology (13. 1) In over 1,000 patients treated with oral esomeprazole (10 mg, 20 mg or 40 mg/day) for up to 12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa. Endocrine Effects Esomeprazole had no effect on thyroid function in adults when given esomeprazole 20 mg or 40 mg delayed-release capsules once daily for 4 weeks. Other effects of esomeprazole on the endocrine system were assessed in studies of omeprazole. Oral doses of omeprazole 30 mg or 40 mg once daily for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin, or secretin. Absorption Esomeprazole magnesium delayed-release capsules showed similar bioavailability after a single dose (40 mg) administration in 94 healthy male and female subjects under fasting conditions. After oral administration, peak plasma levels (C max max max The AUC after administration of a single 40 mg dose of esomeprazole magnesium delayed-release capsules is decreased by 43% to 53% after food intake compared to fasting conditions [see Dosage and Administration (2. 3) Table 6: Geometric Mean (95% CI) Pharmacokinetic Parameters of Esomeprazole on Day 5 Following Once Daily Dosing of Esomeprazole Magnesium Delayed-Release Capsules in Adult Patients with Symptomatic GERD 1. max Parameter 1 Esomeprazole magnesium delayed-release capsules 40 mg once daily (n=36) 20 mg once daily (n=36) AUC (micromol. 2 (59%) C max 4. 1 (45%) T max 1. 2 Esomeprazole 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 esomeprazole. Compared to the first dose, the systemic exposure (C max 0-24h Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 micromol/L. The apparent volume of distribution at steady state in healthy subjects is approximately 16 L. Elimination Metabolism Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole’s metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite. Excretion The plasma elimination half-life of esomeprazole is approximately 1 to 1. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces. Combination Therapy with Amoxicillin and Clarithromycin Esomeprazole magnesium delayed-release capsules 40 mg once daily was given in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and C max The pharmacokinetic parameters for amoxicillin and clarithromycin were similar during combination therapy and administration of each drug alone. However, the mean AUC and C max Specific Populations The AUC and C max Pediatric Patients 12 Years to 17 Years of Age The pharmacokinetics of esomeprazole magnesium delayed-release capsules were studied in 28 adolescent patients with GERD aged 12 to 17 years inclusive, in a single center study. Patients were randomized to receive esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily for 8 days. Mean C max max Table 9: Comparison of Esomeprazole Pharmacokinetic Parameters Following Once Daily Dosing of Esomeprazole Magnesium Delayed-Release Capsules in Pediatric Patients 12 Years to 17 Years with GERD and Adults with Symptomatic GERD 1 1. Parameter Esomeprazole Magnesium Delayed-Release Capsules 12 Years to 17 Years (N=28) Adults (N=36) 20 mg once daily for 8 days 40 mg once daily for 8 days 20 mg once daily for 5 days 40 mg once daily for 5 days AUC (micromol. 7 t max 2 1. 5 Data presented are geometric means for AUC, C max ½λ z max Male and Female Patients The AUC and C max Patients with Renal Impairment The pharmacokinetics of esomeprazole magnesium delayed-release capsules in patients with renal impairment are not expected to be altered relative to healthy subjects as less than 1% of esomeprazole is excreted unchanged in urine. Patients with Hepatic Impairment The steady state pharmacokinetics of esomeprazole obtained after administration of esomeprazole magnesium delayed-release capsules 40 mg orally once daily to patients with mild (Child-Pugh Class A, n=4), moderate (Child-Pugh Class B, n=4), and severe (Child-Pugh Class C, n=4) hepatic impairment were compared to those obtained in 36 male and female GERD patients with normal liver function. In patients with mild and moderate hepatic impairment, the AUCs were within the range that could be expected in patients with normal liver function. In patients with severe hepatic impairment the AUCs were 2 to 3 times higher than in the patients with normal liver function [see Use in Specific Populations (8. 6) Drug Interaction Studies Effect of Esomeprazole/Omeprazole on Other Drugs In vitro in vivo 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 [see Contraindications (4) 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. The AUC was increased by 82%, C max min Clopidogrel In a crossover study, healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day as the maintenance dosage for 28 days) alone and with esomeprazole (40 mg orally once daily at the same time as clopidogrel) for 29 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period when clopidogrel and esomeprazole were administered together. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite [see Warnings and Precautions (5. 7) Drug Interactions (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 C max [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 Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam. Increased plasma levels of diazepam were observed 12 hours after dosing and onwards. However, at that time, the plasma levels of diazepam were below the therapeutic interval, and thus this interaction is unlikely to be of clinical relevance. 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) Other Drugs Concomitant administration of esomeprazole and either naproxen (non-selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of these NSAIDs. Effect of Other Drugs on Esomeprazole/Omeprazole St. John’s Wort In a cross-over study in 12 healthy male subjects, St. John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C max max [see Drug Interactions (7) 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) Other Drugs Co-administration of esomeprazole with oral contraceptives, diazepam, phenytoin, quinidine, naproxen (non-selective NSAID) did not seem to change the pharmacokinetic profile of esomeprazole. Esomeprazole magnesium delayed-release capsules, amoxicillin, and clarithromycin triple therapy has been shown to be active against most strains of Helicobacter pylori (H. pylori) in vitro [see Indications and Usage (1) Clinical Studies (14) H. pylori Table 10: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes 1 Clarithromycin Pretreatment Results H. pylori negative (Eradicated) H. pylori positive (Not Eradicated) Post-treatment susceptibility results S 2 I 2 R 2 No MIC Susceptible 2 162 4 0 2 14 Intermediate 2 1 0 0 0 0 Resistant 2 13 1 0 13 2 1. Patients not eradicated of H. pylori Helicobacter pylori Salmonella Campylobacter Clostridium difficile CYP2C19, a polymorphic enzyme, is involved in the metabolism of esomeprazole. 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. The systemic exposure to esomeprazole 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. Systemic esomeprazole exposures were modestly higher (approximately 17%) in CYP2C19 intermediate metabolizers (IM; n=6) compared to extensive metabolizers (EM; n=17) of CYP2C19. Similar pharmacokinetic differences were noted across these genotypes in a study of Chinese healthy subjects that included 7 EMs and 11 IMs. There is very limited pharmacokinetic information for poor metabolizers (PM) from these studies. At steady state following once daily administration of esomeprazole 40 mg, the ratio of AUC in poor metabolizers to AUC in the rest of the population (EMs) is approximately 1. This change in exposure is not considered clinically meaningful.

Esomeprazole magnesium delayed-release capsules are a proton pump inhibitor (PPI). Esomeprazole magnesium delayed-release capsules are indicated for the: Short-term treatment in the healing of erosive esophagitis (EE) in adults and pediatric patients 12 years to 17 years of age. 1 Maintenance of healing of EE in adults. 2 Short-term treatment of heartburn and other symptoms associated GERD in adults and pediatric patients 12 years to 17 years of age. 3 Risk reduction of nonsteroidal anti-inflammatory drugs (NSAID)-associated gastric ulcer in adults at risk for developing gastric ulcers due to age (60 years and older) and/or documented history of gastric ulcers. 4 Helicobacter pylori 1. 5 Long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome in adults. 6 Adults Esomeprazole magnesium delayed-release capsules are indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed EE in adults. For those patients who have not healed after 4 to 8 weeks of treatment, an additional 4- to 8- week course of esomeprazole magnesium delayed-release capsules may be considered. Pediatric Patients 12 Years to 17 Years of Age Esomeprazole magnesium delayed-release capsules are indicated for the short-term treatment (4 to 8 weeks) for the healing of EE in pediatric patients 12 years to 17 years of age. Esomeprazole magnesium delayed-release capsules are indicated for the maintenance of healing of EE in adults. Controlled studies do not extend beyond 6 months. Adults Esomeprazole magnesium delayed-release capsules are indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults. Pediatric Patients 12 Years to 17 Years of Age Esomeprazole magnesium delayed-release capsules are indicated for short-term treatment (4 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 12 years to 17 years of age. Esomeprazole magnesium delayed-release capsules are indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in adult patients at risk for developing gastric ulcers. Patients are considered to be at risk due to their age (60 years and older) and/or documented history of gastric ulcers. Eradication of H. pylori Triple Therapy Esomeprazole magnesium delayed-release capsules in combination with amoxicillin and clarithromycin is indicated for the treatment of adult patients with H. pylori 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) and the prescribing information for clarithromycin Esomeprazole magnesium delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome, in adults.

DOSAGE AND ADMINISTRATION
1 2 3 4 Population Recommended Adult ( 2. 2 Healing of EE (12 years and older) Adults 20 mg or 40 mg 1 12 years to 17 years 20 mg or 40 mg 1 Maintenance of Healing of EE Adults 20 mg once daily. Controlled studies do not extend beyond 6 months Treatment of Symptomatic GERD Adults 20 mg once daily for 4 weeks some patients may require an additional 4 weeks 12 years to 17 years 20 mg once daily for 4 weeks Risk Reduction of NSAID-Associated Gastric Ulcer Adults 20 mg or 40 mg 1 2 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Adults Esomeprazole magnesium delayed-release capsules 40 mg 1 Amoxicillin 1000 mg twice daily for 10 days 3 Clarithromycin 500 mg twice daily for 10 days 3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Adults Starting dosage is 40 mg twice daily 4 Preparation and Administration Information Swallow capsules whole; do not crush or chew. For patients who cannot swallow intact capsule, the capsule can be opened, and the contents mixed with applesauce. 3 Opened capsules can be administered through a nasogastric tube. 3 Table 1 shows the recommended adult dosage of esomeprazole magnesium delayed-release capsules by indication. The duration of esomeprazole magnesium delayed-release capsules treatment should be based on available safety and efficacy data specific to the defined indication and dosing frequency and individual patient medical needs. Esomeprazole magnesium delayed-release capsules should only be initiated and continued if the benefits outweigh the risks of treatment. Table 1: Recommended Dosage of Esomeprazole Magnesium Delayed-Release Capsules in Adults by Indication 1. [see Use in Specific Populations (8. [see Clinical Studies (14. 6) Adult Indication Recommended Dosage of Esomeprazole Magnesium Delayed-Release Capsules Treatment Duration Healing of EE 20 mg or 40 mg 1 4 to 8 weeks 2 Maintenance of Healing of EE 20 mg once daily Controlled studies do not extend beyond 6 months Treatment of Symptomatic GERD 20 mg once daily 4 weeks; if symptoms do not resolve completely, consider an additional 4 weeks Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg 1 Controlled studies do not extend beyond 6 months Esomeprazole magnesium delayed-release capsules 40 mg once daily 1 3 3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Starting dosage is 40 mg twice daily 4 [see Clinical Studies (14. 7) As long as clinically indicated Table 2 shows the recommended dosage of esomeprazole magnesium delayed-release capsules in pediatric patients by indication. Table 2: Recommended Dosage of Esomeprazole Magnesium Delayed-Release Capsules in Pediatric Patients by Indication Indication Patient Age Recommended Dosage Duration Healing of EE 12 years to 17 years Esomeprazole magnesium delayed-release capsules: 4 to 8 Weeks Treatment of Symptomatic GERD 12 years to 17 years Esomeprazole magnesium delayed-release capsules: 4 weeks Take esomeprazole magnesium delayed-release capsules at least one hour before meals [see Clinical Pharmacology (12. 3) Antacids may be used concomitantly with esomeprazole magnesium delayed-release capsules. Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time. Do not take 2 doses at the same time. Esomeprazole Magnesium Delayed-Release Capsules Administer esomeprazole magnesium delayed-release capsules orally or via a nasogastric tube, as described below. Oral Administration Swallow esomeprazole magnesium delayed-release capsules whole; do not chew or crush the capsules. For patients who have difficulty swallowing capsules, esomeprazole magnesium delayed-release capsules can be opened, and the contents sprinkled on applesauce. Use with other foods has not been evaluated and is not recommended. Add one tablespoon of applesauce to an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. Open the esomeprazole magnesium delayed-release capsule and carefully empty the granules inside the capsule onto the applesauce. Mix the granules with the applesauce. Administer the mixture immediately. Do not chew or crush the granules Discard any remaining mixture. Do not store the mixture for future use. Administration via Nasogastric Tube Open the esomeprazole magnesium delayed-release capsule and empty the granules into a 60 mL catheter-tipped syringe. Mix the granules with 50 mL of water. Replace the plunger and shake the catheter-tipped syringe vigorously for 15 seconds. Hold the catheter-tipped syringe with the tip up and check for any granules remaining in the tip. Attach the catheter-tipped syringe to a nasogastric tube and deliver the contents of the syringe through the nasogastric tube into the stomach. After administering the granules, flush the nasogastric tube with additional water. Use the mixture immediately after preparation. Do not administer the granules if they have dissolved or disintegrated.
Instructions for Use
Esomeprazole Magnesium (es'''' oh mep'' ra zole mag nee'' zee um) Delayed-Release Giving esomeprazole magnesium delayed-release capsules with water through a nasogastric tube (NG tube) Esomeprazole magnesium delayed-release capsules: Open the capsule and empty the granules into a 60 mL catheter tipped syringe. Mix with 50 mL of water. Use only a catheter tipped syringe to give esomeprazole magnesium delayed-release capsules through a NG tube. Replace the plunger and shake the syringe well for 15 seconds. Hold the syringe with the tip up and check for granules in the tip. Do not give the granules if they have dissolved or have broken into pieces. Attach the syringe to the NG tube. Give the medicine right away in the syringe through the NG tube into the stomach. After giving the granules, flush the NG tube with more water. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Aurobindo Pharma USA, Inc. Aurobindo Pharma Limited

The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5. 2) Clostridium difficile [see Warnings and Precautions (5. 3) Bone Fracture [see Warnings and Precautions (5. 4) Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5. 5) Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5. 6) Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5. 8) Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5. 9) Fundic Gland Polyps [see Warnings and Precautions (5. 13) Most common adverse reactions ( 6. 1 Adults (>= 18 years) (>=1%) are: headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth. Pediatrics (1 to 17 years) (>=2%) are: headache, diarrhea, abdominal pain, nausea, and somnolence. To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. Adults The safety of esomeprazole magnesium delayed-release capsules was evaluated in over 15,000 patients (aged 18 to 84 years) in clinical trials worldwide including over 8,500 patients in the United States and over 6,500 patients in Europe and Canada. Over 2,900 patients were treated in long-term studies for up to 6 to 12 months. The safety in the treatment of healing of EE in adults was assessed in four randomized comparative clinical trials, which included 1,240 patients who received esomeprazole magnesium delayed-release capsules 20 mg once daily, 2,434 patients on esomeprazole magnesium delayed-release capsules 40 mg once daily, and 3,008 patients on omeprazole 20 mg once daily. The most frequently occurring adverse reactions (at least 1%) in all three groups were headache (5. 5%, 5%, and 3. 8%, respectively) and diarrhea (no difference among the three groups). Nausea, flatulence, abdominal pain, constipation, and dry mouth occurred at similar rates among patients taking esomeprazole magnesium delayed-release capsules or omeprazole. Less common adverse reactions with an incidence of less than 1% are listed below by body system: Body as a Whole: Cardiovascular: Endocrine: Gastrointestinal: Hearing: Hematologic: Hepatic: Metabolic/Nutritional: Musculoskeletal: Nervous System/Psychiatric: Reproductive: Respiratory: Skin and Appendages: Special Senses: Urogenital: Visual: The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole magnesium delayed-release capsules, were reported in 1% or less of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone [see Clinical Pharmacology (12. 2) Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration. The incidence of adverse reactions during 6-month trials for the maintenance of healing of EE with esomeprazole magnesium delayed-release capsules 20 mg once daily was similar to placebo. There were no differences in types of adverse reactions seen during maintenance treatment up to 12 months compared to short-term treatment. Two placebo-controlled studies were conducted in 710 adult patients for the treatment of symptomatic GERD. The most common adverse reactions that were reported were: diarrhea (4%), headache (4%), and abdominal pain (4%). Combination Treatment with Esomeprazole Magnesium Delayed-Release Capsules, Amoxicillin and Clarithromycin In clinical trials of H. pylori In clinical trials using of esomeprazole magnesium delayed-release capsules, amoxicillin and clarithromycin, no additional increased laboratory abnormalities particular to these drug combinations were observed. For more information on adverse reactions and laboratory changes with amoxicillin or clarithromycin, refer to Adverse Reactions section of the respective prescribing information. Pediatrics 1 Year to 17 Years of Age The safety of esomeprazole magnesium delayed-release capsules was evaluated in 316 pediatric and adolescent patients aged 1 year to 17 years in four clinical trials for the treatment of symptomatic GERD [see Clinical Studies (14. 3) The following adverse reactions have been identified during post-approval use of esomeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system: Blood and Lymphatic: Eye: Gastrointestinal: Hepatobiliary: Immune System: Infections and Infestations: Clostridium difficile- Metabolism and nutritional disorders: [see Warnings and Precautions (5. 9) Musculoskeletal and Connective Tissue: Nervous System: Psychiatric: Renal and Urinary: Reproductive System and Breast: Respiratory, Thoracic, and Mediastinal: Skin and Subcutaneous Tissue: Adverse reactions associated with omeprazole may also be expected to occur with esomeprazole. See the full prescribing information for omeprazole for complete safety information.

Esomeprazole magnesium delayed-release capsules are 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, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5. 2) Adverse Reactions (6. 2) For information about contraindications of amoxicillin and clarithromycin, indicated in combination with esomeprazole magnesium delayed-release capsules for H. pylori Proton pump inhibitors (PPIs), including esomeprazole magnesium delayed-release capsules, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7) Known hypersensitivity to substituted benzimidazoles or any component of the formulation. ( 4 Patients receiving rilpivirine-containing products. ( 4 7 Refer to the Contraindications section of the prescribing information for amoxicillin and clarithromycin, when administered in combination with esomeprazole magnesium delayed-release capsules.

Risk Summary There are no adequate and well-controlled studies with esomeprazole in pregnant women. Esomeprazole is the S-isomer of omeprazole. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use (see Data) Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg (based on a body surface area basis 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. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age (see ) 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 Esomeprazole is the S-isomer of omeprazole. Four 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 1999, 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 Esomeprazole 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 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 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 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 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 on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in a 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 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. Risk Summary Esomeprazole is the S-isomer of omeprazole and limited data suggest that omeprazole may be present in human milk. There are no clinical data on the effects of esomeprazole 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 esomeprazole magnesium and any potential adverse effects on the breastfed infant from esomeprazole magnesium or from the underlying maternal condition. Healing of EE Pediatric Patients 1 Year to 17 Years of Age The safety and effectiveness of esomeprazole magnesium delayed-release capsules have been established in pediatric patients 12 years to 17 years for short-term treatment (4 to 8 weeks) for healing of EE. Use of esomeprazole magnesium delayed-release capsules for this indication is supported by evidence from adequate and well-controlled studies in adults with additional safety and pharmacokinetic data in pediatric patients 1 year to 17 years of age. The safety profile in pediatric patients 1 year to 17 years of age was similar to adults [see Adverse Reactions (6. 1) Clinical Pharmacology (12. 3) Clinical Studies (14. 4) Symptomatic GERD Pediatric Patients 1 Year to 17 Years of Age The safety and effectiveness of esomeprazole magnesium delayed-release capsules have been established in pediatric patients 12 years to 17 years of age for the short-term treatment (4 weeks) of heartburn and other symptoms associated with GERD. 4) Other Conditions The safety and effectiveness of esomeprazole magnesium delayed-release capsules for the risk reduction of NSAID-associated gastric ulcer, H. pylori Juvenile Animal Toxicity Studies In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology (13. 2) Of the total number of patients who received esomeprazole magnesium delayed-release capsules in clinical trials, 1459 were 65 to 74 years of age and 354 patients were 75 years of age and older. In patients with severe hepatic impairment (Child-Pugh Class C) exposure to esomeprazole substantially increased compared to healthy subjects. Dosage modification of esomeprazole magnesium delayed-release capsules is recommended for patients with severe hepatic impairment for the healing of EE, risk reduction of NSAID-associated gastric ulcer, H. pylori [see Dosage and Administration (2. 3) In patients with mild to moderate liver impairment (Child-Pugh Classes A and B), no dosage adjustment is necessary.

Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with esomeprazole 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 Esomeprazole 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. Decreased exposure of some antiretroviral drugs (e. , rilpivirine atazanavir, and nelfinavir) when used concomitantly with esomeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12. 3) Increased exposure of other antiretroviral drugs (e. , saquinavir) when used concomitantly with esomeprazole may increase toxicity [see Clinical Pharmacology (12. 3) There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole. Intervention: Rilpivirine-containing products: [see Contraindications (4) Atazanavir: Nelfinavir: Saquinavir: Other antiretrovirals: Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including esomeprazole, 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 the target INR range. Methotrexate Clinical Impact: Concomitant use of esomeprazole 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. 12) Intervention: A temporary withdrawal of esomeprazole magnesium delayed-release capsules may be considered in some patients receiving high-dose methotrexate. 2C19 Substrates (e. , clopidogrel, citalopram, cilostazol) Clopidogrel Clinical Impact: Concomitant use of esomeprazole 40 mg resulted 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 esomeprazole magnesium delayed-release capsules Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5. 7) 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 cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12. 3) Intervention: Consider reducing the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. Digoxin Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology (12. 3) Intervention: Monitor digoxin concentrations and adjust the dose, if needed, to maintain therapeutic drug concentrations. See prescribing information for digoxin. 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. Intervention: See Contraindications, Warnings Precautions Drug Interactions Drugs Dependent on Gastric pH for Absorption (e. , iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Esomeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole is an enantiomer, 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 esomeprazole magnesium delayed-release capsules and MMF. Use esomeprazole magnesium delayed-release capsules with caution in transplant patients receiving MMF [see Clinical Pharmacology (12. 3) Tacrolimus Clinical Impact: Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Intervention: Monitor tacrolimus whole blood concentrations and consider reducing the dose, if needed, to maintain therapeutic drug 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. 11) Clinical Pharmacology (12. 2) Intervention: Discontinue esomeprazole magnesium delayed-release capsules 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: Discontinue esomeprazole magnesium delayed-release capsules 4 weeks prior to testing [see Clinical Pharmacology (12. 2) False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening test for tetrahydrocannabinol (THC) in patients receiving PPIs. Intervention: An alternative confirmatory method should be considered to verify positive results. Table 4: Clinically Relevant Interactions Affecting Esomeprazole When Co-Administered with Other Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of esomeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12. 3) Intervention: St. John’s Wort, rifampin: [see Warnings and Precautions (5. 10) Ritonavir-containing products: Voriconazole Clinical Impact: Increased exposure of esomeprazole [see Clinical Pharmacology (12. 3) Intervention: Dose adjustment of esomeprazole magnesium delayed-release capsules is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dosage adjustment may be considered. See full prescribing information for a list of clinically important drug interactions.

OVERDOSAGE
Manifestations in patients exposed to omeprazole, the racemic mixture, at doses up to 2,400 mg (120 times the usual recommended clinical dose) include confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen at recommended dosages. See the full prescribing information for omeprazole for complete safety information. No specific antidote for esomeprazole is known. Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive. 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
The carcinogenic potential of esomeprazole magnesium delayed-release capsules was assessed using studies of omeprazole, of which esomeprazole is an enantiomer. In two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1. 8, 44, and 140. 8 mg/kg/day (about 0. 4 to 34 times the human dose of 40 mg/day 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 the human dose of 40 mg/day on a body surface area basis) for 1 year, 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 1 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 2 years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. in vivo in vivo in vitro in vitro in vivo in vivo Reproduction Studies Reproduction studies have been performed 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) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole [see Use in Specific Populations (8. 1) Juvenile Animal Study A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.
CLINICAL STUDIES
The healing rates of esomeprazole magnesium delayed-release capsules 40 mg, esomeprazole magnesium delayed-release capsules 20 mg, and omeprazole delayed-release capsules 20 mg (the approved dose for this indication) once daily were evaluated in adult patients with endoscopically diagnosed EE in four multicenter, double-blind, randomized studies. The healing rates at Weeks 4 and 8 were evaluated and are shown in Table 11: Table 11: EE Healing Rate (Life-Table Analysis) in Adults with EE Treated with Esomeprazole Magnesium Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies N. = not significant (p > 0. of Patients Treatment Group EE Healing Rates Significance Level 1 Week 4 Week 8 1 588 Esomeprazole magnesium delayed-release capsules 20 mg 68. 2 654 Esomeprazole magnesium delayed-release capsules 40 mg 75. 001 3 576 Esomeprazole magnesium delayed-release capsules 40 mg 71. 4 1216 Esomeprazole magnesium delayed-release capsules 40 mg 81. 001 In these same studies of patients with EE, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in Table 12: Table 12: Sustained Resolution 1 1. of Patients Treatment Group Cumulative Percent 2 Significance Level 3 Day 14 Day 28 1 573 Esomeprazole magnesium delayed-release capsules 20 mg 64. 2 621 Esomeprazole magnesium delayed-release capsules 40 mg 64. 001 3 568 Esomeprazole magnesium delayed-release capsules 40 mg 65. 4 1187 Esomeprazole magnesium delayed-release capsules 40 mg 67. 001 In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive days with no heartburn) was 5 days for esomeprazole magnesium delayed-release capsules 40 mg, 7 to 8 days for esomeprazole magnesium delayed-release capsules 20 mg and 7 to 9 days for omeprazole 20 mg. There are no comparisons of 40 mg of esomeprazole magnesium delayed-release capsules with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of EE. Two multicenter, randomized, double-blind placebo-controlled 4-arm studies were conducted in adult patients with endoscopically confirmed, healed EE to evaluate esomeprazole magnesium delayed-release capsules 40 mg (n=174), 20 mg (n=180), 10 mg (n=168) or placebo (n=171) once daily over six months of treatment. No additional clinical benefit was seen with esomeprazole magnesium delayed-release capsules 40 mg over esomeprazole magnesium delayed-release capsules 20 mg. Esomeprazole magnesium delayed-release capsules 40 mg once daily is not a recommended regimen for the maintenance of healing of EE in adults. The percentages of patients that maintained healing of EE at the various time points are shown in the Figures 2 and 3: In both studies, the proportion of patients on esomeprazole magnesium delayed-release capsules who remained in remission and were free of heartburn and other GERD symptoms was well differentiated from placebo. In a third multicenter open label study of 808 patients treated for 12 months with esomeprazole magnesium delayed-release capsules 40 mg, the percentage of patients that maintained healing of EE was 93. 7% for six months and 89. 4% for one year. Figure 2: Maintenance of Healing Rates of EE in Adults by Month (Study 177) Figure 3: Maintenance of EE Healing Rates in Adults by Month (Study 178) Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 adult patients comparing four weeks of treatment with esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily versus placebo for resolution of GERD symptoms. Patients had at least a 6-month history of heartburn episodes, no EE by endoscopy, and heartburn on at least four of the seven days immediately preceding randomization. Figure 4: Percent of Patients Symptom-Free of Heartburn by Day (Study 225) Figure 5: Percent of Patients Symptom-Free of Heartburn by Day (Study 226) 12 Years to 17 Years of Age Two multicenter, double-blind, placebo-controlled studies were conducted in adult patients at risk of developing gastric and/or duodenal ulcers associated with continuous use of non-selective and COX-2 selective NSAIDs. A total of 1429 patients were randomized across the 2 studies. Patients ranged in age from 19 to 89 (median age 66 years) with 71% female, 29% male; 83% Caucasian, 5% Black, 4% Asian, and 8% Others. At baseline, the patients in these studies were endoscopically confirmed not to have ulcers but were determined to be at risk for ulcer occurrence due to their age (at least 60 years) and/or history of a documented gastric or duodenal ulcer within the past 5 years. Patients receiving NSAIDs and treated with esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily experienced significant reduction in gastric ulcer occurrences relative to placebo treatment at 26 weeks. See Table 13. No additional benefit was seen with esomeprazole magnesium delayed-release capsules 40 mg over esomeprazole magnesium delayed-release capsules 20 mg. Esomeprazole magnesium delayed-release capsules 40 mg once daily is not a recommended regimen for the risk reduction of NSAID-associated gastric ulcer in adults. These studies did not demonstrate significant reduction in the development of NSAID-associated duodenal ulcer due to the low incidence. Table 13: Cumulative Percentage of Patients at Least 60 Years of Age Taking NSAIDS Without Gastric Ulcers at 26 Weeks in Two Randomized Placebo-Controlled Studies Study No. of Patients Treatment Group % of Patients Remaining Gastric Ulcer Free 1 1 191 Esomeprazole magnesium delayed-release capsules 20 mg 95. 4 194 Esomeprazole magnesium delayed-release capsules 40 mg 96. 7 184 Placebo 88. 2 2 267 Esomeprazole magnesium delayed-release capsules 20 mg 94. 7 271 Esomeprazole magnesium delayed-release capsules 40 mg 95. 3 257 Placebo 83. Two multicenter, randomized, double-blind studies were conducted in adult patients using a 10-day treatment regimen of triple therapy (esomeprazole magnesium delayed-release capsules, amoxicillin and clarithromycin). The first study (191) compared esomeprazole magnesium delayed-release capsules 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to esomeprazole magnesium delayed-release capsules 40 mg once daily plus clarithromycin 500 mg twice daily. The second study (193) compared esomeprazole magnesium delayed-release capsules 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to esomeprazole magnesium delayed-release capsules 40 mg once daily. pylori registered Table 14: H. pylori Study Treatment Group Per-Protocol 1 Intent-to-Treat 2 191 Esomeprazole magnesium delayed-release capsules, amoxicillin and clarithromycin 84% 3 77% 3 Esomeprazole magnesium delayed-release capsules and clarithromycin 55% 52% 193 Esomeprazole magnesium delayed-release capsules, amoxicillin and clarithromycin 85% 4 78% 4 Esomeprazole magnesium delayed-release capsules 5% 4% 1. The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10-day treatment regimen in the esomeprazole magnesium delayed-release capsules, amoxicillin and clarithromycin group was 75% (n=156) and 57% (n=60) respectively, in the 191 and 193 studies (per-protocol analysis). In a multicenter, open-label dose-escalation study of 21 adult patients (15 males and 6 females, 18 Caucasian and 3 Black, mean age of 56 years) with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, esomeprazole magnesium delayed-release capsules significantly inhibited gastric acid secretion. The initial dosage of esomeprazole magnesium delayed-release capsules was 40 mg twice daily in 19 patients and 80 mg twice daily in 2 patients. Total daily doses ranging from 80 mg to 240 mg for 12 months maintained gastric acid output below the target levels of 10 mEq/h in patients without prior gastric acid-reducing surgery and below 5 mEq/hr in patients with prior gastric acid-reducing surgery. At the Month 12 final visit, 18/20 (90%) patients had Basal Acid Output (BAO) under satisfactory control (median BAO = 0. 17 mmol/hr). Of the 18 patients evaluated with a starting dose of esomeprazole magnesium delayed-release capsules 40 mg twice daily, 13 (72%) had their BAO controlled with the original dosing regimen at the final visit. See Table 15. Table 15: Adequate Acid Suppression at Final Visit by Dosage Regimen in Adult Patients with Pathological Hypersecretory Conditions Esomeprazole magnesium delayed-release capsules dose at the Month 12 visit BAO under adequate control at the Month 12 visit (N=20) 1 40 mg twice daily 13/15 80 mg twice daily 4/4 80 mg three times daily 1/1 1.

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