ESOMEPRAZOLE MAGNESIUM- esomeprazole magnesium_capsule, delayed release

Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H + + Antisecretory Activity Table 3: Effect on Intragastric pH on Day 5 (N=36) Parameter Esomeprazole Magnesium Delayed-Release Capsules Esomeprazole Magnesium Delayed-Release Capsules % Time Gastric 70% 2 53% pH >4 1 (16. 7 h) Coefficient of variation 26% 37% Median 24 Hour pH 4. 1 Coefficient of variation 16% 27% 1. In a second study, the effect on intragastric pH of esomeprazole magnesium delayed-release capsules 40 mg administered once daily over a five day period was similar to the first study, (% time with pH > 4 was 68% or 16. [see Nonclinical Toxicology (13. 1) 2 Absorption max max max Table 4: Pharmacokinetic Parameters of Esomeprazole Magnesium Delayed-Release Capsules on Day 5 Following Oral Dosing for 5 Days Parameter 1 Esomeprazole Magnesium Delayed-Release Capsules 40 mg Esomeprazole Magnesium Delayed-Release Capsules AUC (µmol. 2 (59%) C max 4. 1 (45%) T max 1. max Elimination Metabolism Excretion max max max Specific Populations Age: Geriatric Population max Age: Pediatric Population 1 to 11 Years of Age Table 6: Summary of PK Parameters in 1 to 11 Year Olds with GERD following 5 Days of Once-Daily Oral Esomeprazole Treatment Parameter 1 to 5 Year Olds 6 to 11 Year Olds 10 mg (N=8) 10 mg (N=7) 20 mg (N=6) AUC (µmol. 28 C max 1 2. 73 t max 2 1. 75 t ½ λz 1 0. 73 C1/F (L/h) 1 5. Years of Age max max Table 7: Comparison of PK Parameters in 12 to 17 Year Olds with GERD and Adults with Symptomatic GERD Following the Repeated Daily Oral Dose Administration of Esomeprazole 1 12 to 17 Year Olds (N=28) Adults (N=36) 20 mg 40 mg 20 mg 40 mg AUC (µmol. 7 t max 2 1. 5 Data presented are geometric means for AUC, C max ½λ z max 1. Gender max [see Dosage and Administration (2) 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 8: 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.

Esomeprazole magnesium delayed-release capsules are a proton pump inhibitor indicated for the following: Treatment of gastroesophageal reflux disease (GERD). 1 Risk reduction of NSAID-associated gastric ulcer. 3 Pathological hypersecretory conditions, including Zollinger-Ellison syndrome. 4 Healing of Erosive Esophagitis 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 erosive esophagitis. 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. Maintenance of Healing of Erosive Esophagitis Esomeprazole magnesium delayed-release capsules are indicated to maintain symptom resolution and healing of erosive esophagitis. Controlled studies do not extend beyond 6 months. Esomeprazole magnesium delayed-release capsules are indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in patients at risk for developing gastric ulcers. Patients are considered to be at risk due to their age (>= 60) and/or documented history of gastric ulcers. Triple Therapy (esomeprazole magnesium delayed-release capsules plus amoxicillin and clarithromycin): Esomeprazole magnesium delayed-release capsules, in combination with amoxicillin and clarithromycin, is indicated for the treatment of patients with H. pylori [see Dosage and Administration (2) Clinical Studies (14) [see Clinical Pharmacology (12. 4) Esomeprazole magnesium delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.

Esomeprazole magnesium is supplied as delayed-release capsules for oral administration. The recommended dosages are outlined in Table 1. Esomeprazole magnesium delayed-release capsules should be taken at least one hour before meals. Table 1: Recommended Dosage Schedule for Esomeprazole Magnesium Delayed-Release Capsules Indication Dose Frequency Gastroesophageal Reflux Disease (GERD) Healing of Erosive Esophagitis 20 mg or 40 mg Once Daily for 4 to 8 Weeks 1 Maintenance of Healing of Erosive Esophagitis 20 mg Once Daily 2 Symptomatic Gastroesophageal Reflux Disease 20 mg Once Daily for 4 Weeks 3 Pediatric GERD 12 to 17 Year Olds Healing of Erosive Esophagitis 20 mg or 40 mg Once Daily for 4 to 8 Weeks Symptomatic GERD 20 mg Once Daily for 4 Weeks 1 to 11 Year Olds 4 Short-term Treatment of Symptomatic GERD 10 mg Once Daily for up to 8 Weeks Healing of Erosive Esophagitis weight < 20 kg 10 mg Once Daily for 8 Weeks weight > 10 mg or 20 mg Once Daily for 8 Weeks Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg Once Daily for up to 6 months 2 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: Esomeprazole Magnesium Delayed-Release Capsules 40 mg Once Daily for 10 Days Amoxicillin 1000 mg Twice Daily for 10 Days Clarithromycin 500 mg Twice Daily for 10 Days Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome 40 mg 6 Twice Daily 7 1. [See Clinical Studies (14. [see Drug Interactions (7) Please refer to amoxicillin and clarithromycin prescribing information for Contraindications, Warnings, and dosing in elderly and renally-impaired patients. [see Clinical Pharmacology (12. 3) Table 2: Administration Options Administration Options (See text following table for additional instructions. ) Dosage Form Route Options Delayed-Release Capsules Oral Capsule can be swallowed whole. Delayed-Release Capsules Nasogastric Tube Capsule can be opened and the intact granules emptied into a syringe and delivered through the nasogastric tube. Esomeprazole magnesium delayed-release capsules should be swallowed whole. Indication Dose Frequency Gastroesophageal Reflux Disease (GERD) Adults 20 mg or 40 mg Once daily for 4 to 8 weeks 12 to 17 years 20 mg or 40 mg Once daily for up to 8 weeks 1 to 11 years 10 mg or 20 mg Once daily for up to 8 weeks Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg Once daily for up to 6 months H. pylori (Triple Therapy): Esomeprazole Magnesium Delayed-Release Capsules 40 mg Once daily for 10 days Amoxicillin 1000 mg Twice daily for 10 days Clarithromycin 500 mg Twice daily for 10 days Pathological Hypersecretory Conditions 40 mg Twice daily See full prescribing information for administration options.

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) Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5. 5) Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5. 7) Hypomagnesemia [see Warnings and Precautions (5. 8) Fundic Gland Polyps [see Warnings and Precautions (5. 12) Most common adverse reactions ( 6. 1 Adults (>= 18 years) (incidence >= 1%) are headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth. Pediatric (1 to 17 years) (incidence >= 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 Body as a Whole: Cardiovascular: Endocrine: Gastrointestinal: Hematologic: Hepatic: Metabolic/Nutritional: Musculoskeletal: Nervous System/Psychiatric: Reproductive: Respiratory: [see Clinical Pharmacology (12) Pediatrics [see Clinical Studies (14. 2) ] Combination Treatment with Amoxicillin and Clarithromycin The following adverse reactions have been identified during post-approval use of esomeprazole magnesium delayed-release capsules. 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: Musculoskeletal and Connective Tissue: Nervous System: Psychiatric: Renal and Urinary: Reproductive System and Breast: Respiratory, Thoracic, and Mediastinal: Skin and Subcutaneous Tissue: cutaneous lupus erythematosus.

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) For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with esomeprazole magnesium delayed-release capsules, refer to the CONTRAINDICATIONS section of their package inserts. Patients with known hypersensitivity to proton pump inhibitors (PPIs) (angioedema and anaphylaxis have occurred).

Risk Summary There are no adequate and well-controlled studies with esomeprazole magnesium delayed-release capsules 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. 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 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 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 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. The safety and effectiveness of esomeprazole magnesium delayed-release capsules have been established in pediatric patients 1 to 17 years of age for short-term treatment (up to eight weeks) of GERD. However, the safety and effectiveness of esomeprazole magnesium have not been established in patients less than 1 month of age. [see Dosage and Administration (2) Adverse Reactions (6. 1) Clinical Pharmacology (12. 3) Clinical Studies (14. 3) Juvenile Animal Data 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.

May affect plasma levels of antiretroviral drugs en dash use with atazanavir and nelfinavir is not recommended; if saquinavir is used with esomeprazole magnesium delayed-release capsules, monitor for toxicity and consider saquinavir dose reduction. 1 May interfere with drugs for which gastric pH affects bioavailability (e. , ketoconazole, iron salts, erlotinib, digoxin and mycophenolate mofetil). Patients treated with esomeprazole magnesium delayed-release capsules and digoxin may need to be monitored for digoxin toxicity. 2 Combined inhibitor of CYP2C19 and 3A4 may raise esomeprazole levels. 3 Clopidogrel: Esomeprazole magnesium delayed-release capsules decrease exposure to the active metabolite of clopidogrel. 3 May increase systemic exposure of cilostazol and an active metabolite. Consider dose reduction. 3 Tacrolimus: Esomeprazole magnesium delayed-release capsules may increase serum levels of tacrolimus. 5 Methotrexate: Esomeprazole magnesium delayed-release capsules may increase serum levels of methotrexate. 7 Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction. Reduced concentrations of atazanavir and nelfinavir max min max min Increased concentrations of saquinavir max min Due to its effects on gastric acid secretion, esomeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Esomeprazole is an enantiomer of omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Co-administration of digoxin with esomeprazole magnesium delayed-release capsules is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with esomeprazole magnesium delayed-release capsules. [see Clinical Pharmacology (12. 3) Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro in vivo [see Clinical Pharmacology (12. 3) max max max max Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors [see Warnings and Precautions (5. 10) Clinical Pharmacology (12. 2) Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus. Co-administration of esomeprazole, clarithromycin, and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin [see Clinical Pharmacology (12. 4) [see Warnings and Precautions in prescribing information for clarithromycin] [see Contraindications in prescribing information for clarithromycin]. Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.

OVERDOSAGE
A single oral dose of esomeprazole at 510 mg/kg (about 124 times the human dose on a body surface area basis), was lethal to rats. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions. Adverse Reactions .
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 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 20 mg (the approved dose for this indication) were evaluated in patients with endoscopically diagnosed erosive esophagitis in four multicenter, double-blind, randomized studies. The healing rates at Weeks 4 and 8 were evaluated and are shown in the Table 9: Table 9: Erosive Esophagitis Healing Rate (Life-Table Analysis) Study No. of Patients Treatment Groups Week 4 Week 8 Significance Level 1 1 588 Esomeprazole magnesium delayed-release capsules 20 mg 68. 588 Omeprazole 20 mg 69. 3% 2 654 Esomeprazole magnesium delayed-release capsules 40 mg 75. 001 656 Esomeprazole magnesium delayed-release capsules 20 mg 70. 05 650 Omeprazole 20 mg 64. 9% 3 576 Esomeprazole magnesium delayed-release capsules 40 mg 71. 572 Omeprazole 20 mg 68. 8% 4 1216 Esomeprazole magnesium delayed-release capsules 40 mg 81. 001 1209 Omeprazole 20 mg 68. = not significant (p > 0. 05) In these same studies of patients with erosive esophagitis, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in the Table 10: Table 10: Sustained Resolution 1 Study No. of Patients Treatment Groups Cumulative Percent 2 Significance Level 3 Day 14 Day 28 1 573 Esomeprazole magnesium delayed-release capsules 20 mg 64. 555 Omeprazole 20 mg 64. 9% 2 621 Esomeprazole magnesium delayed-release capsules 40 mg 64. 001 620 Esomeprazole magnesium delayed-release capsules 20 mg 62. 626 Omeprazole 20 mg 56. 6% 3 568 Esomeprazole magnesium delayed-release capsules 40 mg 65. 551 Omeprazole 20 mg 65. 1% 4 1187 Esomeprazole magnesium delayed-release capsules 40 mg 67. 001 1188 Omeprazole 20 mg 62. 05) 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 erosive esophagitis. Long-Term Maintenance of Healing of Erosive Esophagitis Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients with endoscopically confirmed, healed erosive esophagitis to evaluate esomeprazole magnesium 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. The percentages of patients that maintained healing of erosive esophagitis at the various time points are shown in the Figures 2 and 3: Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with esomeprazole magnesium delayed-release capsules compared to placebo. 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 erosive esophagitis was 93. 7% for six months and 89. 4% for one year. Figure 2: Maintenance of Healing Rates by Month (Study 177) Figure 3: Maintenance of Healing Rates by Month (Study 178) Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 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 >= 6-month history of heartburn episodes, no erosive esophagitis 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) 1 to 11 Years of Age Patients were endoscopically characterized as to the presence or absence of erosive esophagitis. Two multicenter, double-blind, placebo-controlled studies were conducted in 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 70. 7% female, 29. 3% male, 82. 9% Caucasian, 5. 5% Black, 3. 7% 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 (>=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-a-day experienced significant reduction in gastric ulcer occurrences relative to placebo treatment at 26 weeks. See Table 11. No additional benefit was seen with esomeprazole magnesium delayed-release capsules 40 mg over esomeprazole magnesium delayed-release capsules 20 mg. These studies did not demonstrate significant reduction in the development of NSAID-associated duodenal ulcer due to the low incidence. Table 11: Cumulative Percentage of Patients without Gastric Ulcers at 26 Weeks 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. 3 1 Triple Therapy ( esomeprazole magnesium delayed-release capsules/amoxicillin/ clarithromycin): H. pylori registered Table 12: H. pylori Study Treatment Group Per-Protocol 1 Intent-to-Treat 2 191 Esomeprazole magnesium delayed-release capsules plus amoxicillin and clarithromycin 84% 3 77% 3 Esomeprazole magnesium delayed-release capsules plus clarithromycin 55% 52% 193 Esomeprazole magnesium delayed-release capsules plus 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 plus 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 patients (15 males and 6 females, 18 Caucasian and 3 Black, mean age of 55. 5 years) with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, esomeprazole magnesium delayed-release capsules significantly inhibited gastric acid secretion. Initial dose was 40 mg twice daily in 19/21 patients and 80 mg twice daily in 2/21 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 40 mg twice daily, 13 (72%) had their BAO controlled with the original dosing regimen at the final visit. See Table 13. Table 13: Adequate Acid Suppression at Final Visit by Dose Regimen 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.
MEDICATION GUIDE
Esomeprazole Magnesium Delayed-Release Capsules USP (es'''' oh mep'' ra zole mag nee'' zee um) Read the Medication Guide that comes with esomeprazole magnesium delayed-release capsules before you start taking esomeprazole magnesium delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about esomeprazole magnesium delayed-release capsules? Esomeprazole magnesium delayed-release capsules may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor. Esomeprazole magnesium delayed-release capsules can cause serious side effects, including: A type of kidney problem (acute tubulointerstitial Diarrhea. (Clostridium difficile) Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away. Bone fractures. Certain types of lupus erythematosus. Esomeprazole magnesium delayed-release capsules can have other serious side effects. See “What are the possible side effects of esomeprazole magnesium delayed-release capsules?” What are esomeprazole magnesium delayed-release capsules? Esomeprazole magnesium delayed-release capsules are a prescription medicine called a proton pump inhibitor (PPI). Esomeprazole magnesium delayed-release capsules reduce the amount of acid in your stomach. Esomeprazole magnesium delayed-release capsules are used in adults: for 4 to 8 weeks to treat the symptoms of gastroesophageal reflux disease (GERD). Esomeprazole magnesium delayed-release capsules may also be prescribed to heal acid-related damage to the lining of the esophagus (erosive esophagitis), and to help continue this healing. GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping. for up to 6 months to reduce the risk of stomach ulcers in some people taking pain medicines called non-steroidal anti-inflammatory drugs (NSAIDs). to treat patients with a stomach infection ( Helicobacter pylori for the long-term treatment of conditions where your stomach makes too much acid, including Zollinger-Ellison Syndrome. Zollinger-Ellison Syndrome is a rare condition in which the stomach produces a more than normal amount of acid. For children and adolescents 1 year to 17 years of age, esomeprazole magnesium delayed-release capsules may be prescribed for up to 8 weeks for short-term treatment of GERD. Who should not take esomeprazole magnesium delayed-release capsules? Do not take esomeprazole magnesium delayed-release capsules if you: are allergic to esomeprazole magnesium or any of the ingredients in esomeprazole magnesium delayed-release capsules. See the end of this Medication Guide for a complete list of ingredients in esomeprazole magnesium delayed-release capsules. are allergic to any other PPI medicine. What should I tell my doctor before taking esomeprazole magnesium delayed-release capsules? Before you take esomeprazole magnesium delayed-release capsules, tell your doctor if you: have been told that you have low magnesium levels in your blood. have liver problems. are pregnant or plan to become pregnant. It is not known if esomeprazole magnesium delayed-release capsules can harm your unborn baby. are breastfeeding or planning to breastfeed. Esomeprazole magnesium may pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take esomeprazole magnesium delayed-release capsules. Tell your doctor about all of the medicines you take Especially tell your doctor if you take: warfarin (Coumadin, Jantoven) ketoconazole (Nizoral) voriconazole (Vfend) atazanavir (Reyataz) nelfinavir (Viracept) saquinavir (Fortovase) products that contain iron digoxin (Lanoxin) St.John’s Wort ( Hypericum perforatum Rifampin (Rimactane, Rifater, Rifamate) cilostazol (Pletal) diazepam (Valium) tacrolimus (Prograf) erlotinib (Tarceva) methotrexate clopidogrel (Plavix) mycophenolate mofetil (Cellcept) How should I take esomeprazole magnesium delayed-release capsules? Take esomeprazole magnesium delayed-release capsules exactly as prescribed by your doctor. Do not change your dose or stop esomeprazole magnesium delayed-release capsules without talking to your doctor. Take esomeprazole magnesium delayed-release capsules at least 1 hour before a meal. Swallow esomeprazole magnesium delayed-release capsules whole. Never chew or crush esomeprazole magnesium delayed-release capsules If you have difficulty swallowing esomeprazole magnesium delayed-release capsules, you may open the capsule and empty the contents into a tablespoon of applesauce. Do not crush or chew the granules. Be sure to swallow the applesauce right away. Do not store it for later use. If you forget to take a dose of esomeprazole magnesium delayed-release capsules, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose on time. Do not take a double dose to make up for a missed dose. If you take too much esomeprazole magnesium, call your doctor or local poison control center right away, or go to the nearest hospital emergency room. See the “Instructions for Use” at the end of this Medication Guide for instructions how to mix and give esomeprazole magnesium delayed-release capsules, through a nasogastric tube or gastric tube. What are the possible side effects of esomeprazole magnesium delayed-release capsules? Esomeprazole magnesium delayed-release capsules can cause serious side effects, including: See “What is the most important information I should know about esomeprazole magnesium delayed-release capsules?” Vitamin B-12 deficiency Low magnesium levels in your body You may or may not have symptoms of low magnesium. Tell your doctor right away if you have any of these symptoms: seizures muscle weakness dizziness spasms of the hands and feet abnormal or fast heart beat cramps or muscle aches jitteriness spasm of the voice box jerking movements or shaking (tremors) Your doctor may check the level of magnesium in your body before you start taking esomeprazole magnesium delayed-release capsules or during treatment if you will be taking esomeprazole magnesium delayed-release capsules for a long period of time. Stomach growths (fundic gland polyps). The most common side effects with esomeprazole magnesium delayed-release capsules may include: headache abdominal pain diarrhea constipation nausea dry mouth gas drowsiness Other side effects: Serious allergic reactions. rash throat tightness face swelling difficulty breathing Your doctor may stop esomeprazole magnesium delayed-release capsules if these symptoms happen. Tell your doctor if you have any side effects that bother you or that do not go away. These are not all the possible side effects with esomeprazole magnesium delayed-release capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store esomeprazole magnesium delayed-release capsules? Store esomeprazole magnesium delayed-release capsules at room temperature between 20° to 25°C (68° to 77°F). Keep the container of esomeprazole magnesium delayed-release capsules closed tightly. Keep esomeprazole magnesium delayed-release capsules and all medicines out of the reach of children. General information about esomeprazole magnesium delayed-release capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use esomeprazole magnesium delayed-release capsules for a condition for which it was not prescribed. Do not give esomeprazole magnesium delayed-release capsules to other people, even if they have the same symptoms you have. They may harm them. This Medication Guide summarizes the most important information about esomeprazole magnesium delayed-release capsules. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about esomeprazole magnesium delayed-release capsules that is written for health professionals. For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876. What are the ingredients in esomeprazole magnesium delayed-release capsules? Active ingredient: Inactive ingredients in esomeprazole magnesium delayed-release capsules (including the capsule shells): Instructions for Use For instructions on taking Delayed-Release Capsules, see the section of this leaflet called “How should I take esomeprazole magnesium delayed-release capsules?” Esomeprazole magnesium delayed-release capsules may be given through a nasogastric tube (NG tube) or gastric tube, as prescribed by your doctor. Follow the instructions below: 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. Give the medicine right away. Do not give the granules if they have dissolved or have broken into pieces. Attach the syringe to the NG tube. Give the medicine in the syringe through the NG tube into the stomach. After giving the granules, flush the NG tube with more water. This Medication Guide has been approved by the U.S. Food and Drug Administration. The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. www.aurobindousa.com/medication-guides Aurobindo Pharma USA, Inc. Manufactured by: Aurobindo Pharma Limited

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