ESOMEPRAZOLE MAGNESIUM 5 MG FOR SUSPENSION | WHITE (WHITE TO PALE BROWNISH) CIPLA USA INC. 6909750831

Table 1 shows the recommended adult dosage of Esomeprazole magnesium for delayed release oral suspension by indication. The duration of esomeprazole magnesium 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 for delayed release oral suspension treatment should only be initiated and continued if the benefits outweigh the risks of treatment. Table 1: Recommended Dosage of Esomeprazole magnesium for delayed release oral suspension in Adults Indication Adult Indication Recommended Dosage of Esomeprazole magnesium for delayed release oral suspension Treatment Duration 1. A maximum dosage of 20 mg once daily is recommended for patients with severe liver impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6)] . 2. Most patients are healed within 4 to 8 weeks. For patients who do not heal after 4 to 8 weeks, an additional 4 to 8 weeks of treatment may be required to achieve healing [see Clinical Studies (14.1)] . 3. Refer to the amoxicillin and clarithromycin prescribing information for dosage adjustments in elderly and renally-impaired patients. 4. A starting dosage of 20 mg twice daily is recommended for patients with severe liver impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6)] . Healing of EE 20 mg or 40 mg1 once daily 4 to 8 weeks2 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 mg1 once daily Controlled studies do not extend beyond 6 months H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (Triple Therapy) Esomeprazole magnesium 40 mg once daily1 10 days Amoxicillin 1000 mg twice daily3 10 days Clarithromycin 500 mg twice daily3 10 days Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Starting dosage is 40 mg twice daily4; individualize the regimen to patient needs.Dosages of up to 240 mg/day have been administered [see Clinical Studies ( 14.7 )] . As long as clinically indicated

Gastric Malignancy : In adults, symptomatic response does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. (5.1) Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients.. (5.2) Clostridium difficile -Associated Diarrhea : PPI therapy may be associated with increased risk. (5.3) Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.4) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. (5.5) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue esomeprazole magnesium for delayed release oral suspension and refer to specialist for evaluation. (5.6) Interaction with Clopidogrel : Avoid concomitant use of esomeprazole magnesium for delayed release oral suspension. (5.7) Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. (5.8) Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. (5.9) Interaction with St. John's Wort or Rifampin : Avoid concomitant use of esomeprazole magnesium for delayed release oral suspension. (5.10, 7) Interactions with Diagnostic Investigations for Neuroendocrine Tumors : Increased chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors, temporarily stop esomeprazole magnesium for delayed release oral suspension at least 14 days before assessing CgA levels. (5.11, 12.2) Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider temporary withdrawal of esomeprazole magnesium for delayed release oral suspension. (5.12, 7) Fundic Gland Polyps : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy (5.13)

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 20 mg once daily, 2,434 patients on esomeprazole magnesium 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 or omeprazole. Less common adverse reactions with an incidence of less than 1% are listed below by body system: Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, leg edema, malaise, pain, rigors; Cardiovascular: flushing, hypertension, tachycardia; Endocrine: goiter; Gastrointestinal: bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, frequent stools, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting; Hearing: earache, tinnitus; Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia; Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased; Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease; Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica; Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect; Reproductive: dysmenorrhea, menstrual disorder, vaginitis; Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis; Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria; Special Senses: otitis media, parosmia, taste loss, taste perversion; Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria; Visual: conjunctivitis, vision abnormal. The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole magnesium, 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 )]. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine. 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 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, Amoxicillin and Clarithromycin In clinical trials of H. pylori eradication of to reduce duodenal ulcer recurrence, no additional adverse reactions specific to the combination of Nexium delayed-release capsules, amoxicillin and clarithromycin were observed and were similar to those observed with esomeprazole magnesium, amoxicillin, or clarithromycin alone. The most frequently reported adverse reactions for patients who received esomeprazole magnesium, amoxicillin and clarithromycin for 10 days were diarrhea (9%), taste perversion (4%), and abdominal pain (4%). No adverse reactions were observed at higher rates with esomeprazole magnesium, amoxicillin and clarithromycin than were observed with esomeprazole magnesium alone. In clinical trials using of esomeprazole magnesium, 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 Nexium delayed-release capsules and esomeprazole magnesium for delayed-release oral suspension 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)]. In 109 pediatric patients aged 1 year to 11 years, the most frequently reported (at least 1%) treatment-related adverse reactions in these patients were diarrhea (3%), headache (2%) and somnolence (2%). In 149 pediatric patients aged 12 years to 17 years the most frequently reported adverse reactions (at least 2%) were headache (8%), abdominal pain (3%), diarrhea (2%), and nausea (2%). 1 Month to Less Than 1 Year of Age The safety of esomeprazole magnesium was evaluated in 167 infants from 1 month to less than 1 year of age with GERD in three clinical trials [see Use in Specific Populations (8.4)]. In a study that included 43 pediatric patients, the most frequently reported adverse reactions (at least 5%) with esomeprazole magnesium were irritability and vomiting. In a study that included 98 pediatric patients, administered esomeprazole magnesium for up to 6 weeks (including 39 patients randomized to the withdrawal phase), reported adverse reactions were: abdominal pain (1%), regurgitation (1%), tachypnea (1%), and increased ALT (1%).

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. o Decreased exposure of some antiretroviral drugs (e.g., 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)]. o Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. o There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole. Intervention: Rilpivirine-containing products : Concomitant use with esomeprazole magnesium is contraindicated [see Contraindications (4)] . Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with esomeprazole magnesium. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals : See prescribing information for specific antiretroviral drugs Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including 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 may be considered in some patients receiving high-dose methotrexate. 2C19 Substrates (e.g., 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 (12.3)]. There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. Intervention: Avoid concomitant use with esomeprazole magnesium 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. Amoxicillin also has drug interactions. Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. Drugs Dependent on Gastric pH for Absorption (e.g., 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 and MMF. Use esomeprazole magnesium with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)] . See the prescribing information for other drugs dependent on gastric pH for absorption. 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 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.g. 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 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: Avoid concomitant use with [see Warnings and Precautions (5.10)]. Ritonavir-containing products: see prescribing information for specific drugs Voriconazole Clinical Impact: Increased exposure of esomeprazole [see Clinical Pharmacology (12.3)]. Intervention: Dose adjustment of esomeprazole magnesium is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dosage adjustment may be considered. See prescribing information for voriconazole. See full prescribing information for a list of clinically important drug interactions. ( 7 )

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). 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. In the U.S. 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 H2-receptor antagonists or other controls. 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 to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. 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 2.9% and 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 H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% with first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Omeprazole Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis), administered prior to mating through the lactation period. Esomeprazole No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 41 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg 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 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). 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. A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

Healing of EE Pediatric Patients 1 Year to 17 Years of Age The safety and effectiveness of Nexium esomeprazole magnesium delayed-release capsules and esomeprazole magnesium for delayed-release oral suspension have been established in pediatric patients 12 years to 17 years for short-term treatment (4 to 8 weeks) for healing of EE. The safety and effectiveness of esomeprazole magnesium for delayed release oral suspension have been established in pediatric patients 1 year to 11 years for short-term treatment (up to 8 weeks) for healing of EE. Use of esomeprazole magnesium 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 )]. Pediatric Patients 1 Month to Less Than 1 Year of Age The safety and effectiveness of esomeprazole magnesium for delayed-release oral suspension have been established in pediatric patients 1 month to less than 1 year of age for short-term treatment (up to 6 weeks) of EE due to acid-mediated GERD. Use of esomeprazole magnesium for this indication is supported by evidence from adequate and well-controlled studies in adults with additional safety, pharmacokinetic, and pharmacodynamic data in pediatric patients 1 month to less than 1 year of age. The safety profile in pediatric patients 1 month to less than 1 year of age was similar to adults [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.2 , 12.3 )]. The safety and effectiveness of esomeprazole magnesium for the treatment of EE due to acid-mediated GERD in pediatric patients less than 1 month of age have not been established. Symptomatic GERD Pediatric Patients 1 Year to 17 Years of Age The safety and effectiveness of Nexium esomeprazole magnesium delayed-release capsules and esomeprazole magnesium for delayed-release oral suspension 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. The safety and effectiveness of esomeprazole magnesium for delayed release oral suspension have been established in pediatric patients 1 year to 11 years of age for the short-term treatment (up to 8 weeks) of heartburn and other symptoms associated with GERD. Use of Esomeprazole magnesium 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 )]. The safety and effectiveness of esomeprazole magnesium for the treatment of symptomatic GERD in pediatric patients less than 1 year of age have not been established. Infants 1 Month to Less Than 1 Year of Age Esomeprazole magnesium was not found to be effective in a multicenter, randomized, double-blind, controlled, treatment-withdrawal study of 98 infants aged 1 month to 11 months for the treatment of symptomatic GERD. Patients were enrolled if they had either a clinical diagnosis of suspected GERD, symptomatic GERD, or endoscopically proven GERD. Twenty of 98 enrolled patients underwent endoscopy, and 6 patients were found to have EE on endoscopy at baseline. All patients received esomeprazole magnesium for delayed-release oral suspension once daily during a two-week, open-label phase of the study. There were 80 patients who attained a pre-specified level of symptom improvement and who entered the double-blind phase, in which they were randomized in equal proportions to receive esomeprazole magnesium or placebo for the next four weeks. Efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the four-week, treatment-withdrawal phase. There was no statistically significant difference between esomeprazole magnesium and placebo in the rate of discontinuation due to symptom worsening; therefore, these results do not support the use of esomeprazole magnesium for the treatment of symptomatic GERD in infants 1 month to less than 1 year of age. Other Conditions The safety and effectiveness of esomeprazole magnesium for the risk reduction of NSAID-associated gastric ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence and treatment of pathological hypersecretory conditions have not been established in pediatric patients. 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 )].

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, Nexium 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 Nexium Delayed-Release Capsules in Adult Patients with Symptomatic GERD Parameter Nexium Delayed-Release Capsules 1. Gastric pH was measured over a 24-hour period 2. p<0.01 esomeprazole magnesium 40 mg vs. esomeprazole magnesium 20 mg 40 mg once daily 20 mg once daily % Time Gastric pH >41 (Hours) 70%2 (16.8 h) 53%(12.7 h) Coefficient of variation 26% 37% Median 24 Hour pH 4.92 4.1 Coefficient of variation 16% 27% In a second study, the effect on intragastric pH of Nexium 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 16.3 hours). Pediatrics In infants (1 to 11 months old, inclusive) with GERD given esomeprazole magnesium for delayed-release oral suspension 1 mg/kg once daily, the percent time with intragastric pH > 4 increased from 29% at baseline to 69% on Day 7, which is similar to the pharmacodynamic effect in adults. 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 Nexium 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 Nexium delayed-release capsules and esomeprazole magnesium for delayed release oral suspension 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 (Cmax) of esomeprazole occur at approximately 1.5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 micromol*hr/L on Day 1 to 11.2 micromol*hr/L on Day 5 after 40 mg once daily dosing. The AUC after administration of a single 40 mg dose of Nexium delayed-release capsules is decreased by 43% to 53% after food intake compared to fasting conditions [see Dosage and Administration ( 2.3 )]. The pharmacokinetics of esomeprazole in adult patients with symptomatic GERD following repeated once daily administration of 20 mg and 40 mg Nexium delayed-release capsules over a period of five days are shown in Table 6: Table 6: Geometric Mean (95% CI) Pharmacokinetic Parameters of Esomeprazole on Day 5 Following Once Daily Dosing of Nexium Delayed-Release Capsules in Adult Patients with Symptomatic GERD Parameter 1 (CV) Nexium delayed-release capsules 1. Values represent the geometric mean, except the Tmax, which is the arithmetic mean; CV = Coefficient of variation 40 mg once daily (n=36) 20 mg once daily(n=36) AUC (micromol h/L) 12.6 (42%) 4.2 (59%) Cmax (micromol/L ) 4.7 (37%) 2.1 (45%) Tmax (hours) 1.6 1.6 t1/2 (hours) 1.5 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 (Cmax and AUC0-24h) at steady state following once a day dosing increased by 43% and 90%, respectively, compared to after the first dose for the 20 mg dose and increased by 95% and 159%, respectively, for the 40 mg dose Distribution 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 1.5 hours. 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 Nexium 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 Cmax of esomeprazole increased by 70% and 18%, respectively during combination therapy compared to treatment with esomeprazole alone. The observed increase in esomeprazole exposure during co-administration with amoxicillin and clarithromycin is not expected to be clinically relevant. The pharmacokinetic parameters for amoxicillin and clarithromycin were similar during combination therapy and administration of each drug alone. However, the mean AUC and Cmax for 14-hydroxyclarithromycin increased by 19% and 22%, respectively, during combination therapy compared to treatment with clarithromycin alone. This increase in exposure to 14-hydroxyclarithromycin is not considered to be clinically relevant. Specific Populations Geriatric Patients The AUC and Cmax values of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. This increase in exposure is not considered clinically relevant. Pediatric Patients 1 Month to 11 Months of Age The pharmacokinetic parameters following repeated dose administration of esomeprazole magnesium 1 mg/kg once daily for 7 to 8 days in 1 month to 11-month-old infants with GERD are summarized in Table 7. Table 7: Summary of Esomeprazole Pharmacokinetic Parameters Following Once Daily Dosing of Oral Esomeprazole Magnesium for 7 to 8 Days in 1 Month to 1 Year Old Infants with GERD Parameter Esomeprazole Magnesium 1 mg/kg Orally Once Daily AUC (micromol h/L) (n=7)1 3.51 Css,max (micromol/L) (n=15)1 0.87 t (h) (n=8)1 0.93 tmax (h) (n=15)2 3.0 1. Geometric mean 2. Median Subsequent pharmacokinetic simulation analyses showed that for pediatric patients 1 month to 11 months of age, a dosage regimen of 2.5 mg once daily (body weight 3 to 5 kg), 5 mg once daily (body weight more than 5 to 7.5 kg) and 10 mg once daily for (body weight more than 7.5 to 12 kg) would achieve comparable steady-state plasma exposures (AUC) to that observed with 10 mg once daily in patients 1 year to 11 year of age and 20 mg once daily in patients 12 years to 18 years of age, as well as adults. Apparent clearance (CL/F) increases with age in pediatric patients with GERD from 1 month to 2 years of age. 1 Year to 11 Years of Age The pharmacokinetics of esomeprazole were studied in pediatric patients with GERD aged 1 year to 11 years. Following once daily dosing with esomeprazole magnesium for delayed-release oral suspension for 5 days, the total exposure (AUC) for the 10 mg dosage in patients aged 6 years to 11 years was similar to that seen with the 20 mg dosage in adults and adolescents aged 12 years to 17 years. The total exposure for the 10 mg dosage in patients aged 1 year to 5 years was approximately 30% higher than the 10 mg dosage in patients aged 6 years to 11 years. The total exposure for the 20 mg dosage in patients aged 6 years to 11 years was higher than that observed with the 20 mg dosage in patients aged 12 years to 17 years and adults, but lower than that observed with the 40 mg dosage in 12 to 17 year-olds and adults. See Table 8. Table 8: Summary of Esomeprazole Pharmacokinetic Parameters Following Once Daily Dosing of Esomeprazole magnesium for Delayed-Release Oral Suspension for 5 Days in 1 Year to 11 Year Old Patients with GERD Parameter Esomeprazole magnesium For Delayed-Release Oral Suspension 1 Year to 5 Years 6 Years to 11 Years 10 mg once daily (N=8) 10 mg once daily (N=7) 20 mg once daily (N=6) AUC (micromol h/L)1 4.83 3.70 6.28 Cmax (micromol/L)1 2.98 1.77 3.73 tmax (h)2 1.44 1.79 1.75 t z (h)1 0.74 0.88 0.73 Cl/F (L/h)1 5.99 7.84 9.22 1. Geometric mean 2. Arithmetic mean 12 Years to 17 Years of Age The pharmacokinetics of esomeprazole 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 20 mg or 40 mg once daily for 8 days. Mean Cmax and AUC values of esomeprazole were not affected by body weight or age; and more than dose-proportional increases in mean Cmax and AUC values were observed between the two dose groups in the study. Overall, esomeprazole magnesium pharmacokinetics in adolescent patients aged 12 to 17 years were similar to those observed in adult patients with symptomatic GERD. See Table 9. Table 9: Comparison of Esomeprazole Pharmacokinetic Parameters Following Once Daily Dosing of Nexium Delayed-Release Capsules in Pediatric Patients 12 Years to 17 Years with GERD and Adults with Symptomatic GERD1 Parameter Nexium Delayed-Release Capsules 1Data obtained from two independent studies 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 h/L) 3.65 13.86 4.2 12.6 Cmax (micromol/L) 1.45 5.13 2.1 4.7 tmax (h) 2.00 1.75 1.6 1.6 t1/2 z (h) 0.82 1.22 1.2 1.5 Data presented are geometric means for AUC, Cmax and t1/2 z, and median value for tmax. Male and Female Patients The AUC and Cmax values of esomeprazole were slightly higher (13%) in females than in males at steady state when dosed orally. This increase in exposure is not considered clinically relevant. Patients with Renal Impairment The pharmacokinetics of esomeprazole magnesium 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 Nexium 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 and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. 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%, Cmax by 40%, and Cmin by 33% for rilpivirine [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%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Atazanavir: Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. 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%, Cmax by 75%, and Cmin by 106%. The mechanism behind this interaction is not fully elucidated. 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 ) and 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 Cmax and 23% reduction in the AUC of MPA [see Drug Interactions ( 7 )]. Cilostazol Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. The Cmax and AUC of one of the active metabolites, 3,4-dihydro-cilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and the above mentioned active metabolite [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 (Cmax and AUC both decreased by 38%) and extensive metabolizers (Cmax and AUC decreased by 50% and 44%, respectively) [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 Cmax and AUC0-24 of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [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, amoxicillin, and clarithromycin triple therapy has been shown to be active against most strains of Helicobacter pylori (H. pylori) in vitro and in clinical infections [see Indications and Usage ( 1 ) and Clinical Studies ( 14 )]. Helicobacter pylori: Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were determined. Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC 1 mcg/mL) to H. pylori was 15% (66/445) at baseline in all treatment groups combined. A total of > 99% (394/395) of patients had H. pylori isolates that were considered to be susceptible (MIC 0.25 mcg/mL) to amoxicillin at baseline. One patient had a baseline H. pylori isolate with an amoxicillin MIC = 0.5 mcg/mL. Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes: The baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results at the Day 38 visit are shown in the Table 10: Table 10: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes1 for Triple Therapy (Nexium Delayed-Release Capsules 40 mg once daily, Amoxicillin 1000 mg twice daily and Clarithromycin 500 mg twice daily for 10 days) Clarithromycin Pretreatment Results H. pylori H. pylori 1. Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results 2. Susceptible (S) MIC 0.25 mcg/mL, Intermediate (I) MIC = 0.5 mcg/mL, Resistant (R) MIC 1.0 mcg/mL S2 I2 R2 No MIC Susceptible2 182 162 4 0 2 14 Intermediate2 1 1 0 0 0 0 Resistant2 29 13 1 0 13 2 Patients not eradicated of H. pylori following triple therapy with esomeprazole magnesium, amoxicillin and clarithromycin will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, when possible. Patients with clarithromycin resistant H. pylori should not be re-treated with a clarithromycin-containing regimen. Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In patients treated with esomeprazole magnesium, amoxicillin and clarithromycin in clinical trials, 83% (176/212) of the patients who had pretreatment amoxicillin susceptible MICs ( 0.25 mcg/mL) were eradicated of H. pylori, and 17% (36/212) were not eradicated of H. pylori. Of the 36 patients who were not eradicated of H. pylori, 16 had no post-treatment susceptibility test results and 20 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Fifteen of the patients who were not eradicated of H. pylori also had post-treatment H. pylori isolates with clarithromycin resistant MICs. There were no patients with H. pylori isolates who developed treatment emergent resistance to amoxicillin. Susceptibility Test for Helicobacter pylori: For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin. Effects on Gastrointestinal Microbial Ecology: Decreased gastric acidity due to any means, including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with PPIs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile in hospitalized patients.

The carcinogenic potential of esomeprazole magnesium 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 1.7, 3.4, 13.8, 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. Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on reproductive performance of parental animals.

The healing rates of Nexium delayed-release capsules 40 mg, Nexium 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 Nexium Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies Study No. of Patients Treatment Groups EE Healing Rates Significance Level Week 4 Week 8 N.S. = not significant (p > 0.05) 1. log-rank test vs. omeprazole 20 mg 1 588 Esomeprazole magnesium 20 mg 68.7% 90.6% N.S. 588 Omeprazole 20 mg 69.5% 88.3% 2 654 Esomeprazole magnesium 40 mg 75.9% 94.1% p < 0.001 656 Esomeprazole magnesium 20 mg 70.5% 89.9% p < 0.05 650 Omeprazole 20 mg 64.7% 86.9% 3 576 Esomeprazole magnesium 40 mg 71.5% 92.2% N.S. 572 Omeprazole 20 mg 68.6% 89.8% 4 1216 Esomeprazole magnesium 40 mg 81.7% 93.7% p < 0.001 1209 Omeprazole 20 mg 68.7% 84.2% 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 Resolution1 of Heartburn in Adults with EE Treated with Nexium Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies) Cumulative Percent 1. Defined as 7 consecutive days with no heartburn reported in daily patient diary. 2. Defined as the cumulative proportion of patients who have reached the start of sustained resolution. 3. log-rank test vs. omeprazole 20 mg. N.S. = not significant (p > 0.05) Study No. of Patients Treatment Group Day 14 Day 28 Significance Level 3 1 573 Esomeprazole magnesium 20 mg 64.3% 72.7% N.S. 555 Omeprazole 20 mg 64.1% 70.9% 2 621 Esomeprazole magnesium 40 mg 64.8% 74.2% p < 0.001 620 Esomeprazole magnesium 20 mg 62.9% 70.1% N.S. 626 Omeprazole 20 mg 56.5% 66.6% 3 568 Esomeprazole magnesium 40 mg 65.4% 73.9% N.S. 551 Omeprazole 20 mg 65.5% 73.1% 4 1187 Esomeprazole magnesium 40 mg 67.6% 75.1% p < 0.001 1188 Omeprazole 20 mg 62.5% 70.8% 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 40 mg, 7 to 8 days for esomeprazole magnesium 20 mg and 7 to 9 days for omeprazole 20 mg. There are no comparisons of 40 mg of esomeprazole magnesium with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of EE.

Two multicenter, randomized, double-blind studies were conducted in adult patients using a 10-day treatment regimen of triple therapy (Esomeprazole magnesium, amoxicillin and clarithromycin). The first study (191) compared Nexium delayed-release capsules 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to Nexium delayed-release capsules 40 mg once daily plus clarithromycin 500 mg twice daily. The second study (193) compared Nexium delayed-release capsules 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to Nexium delayed-release capsules 40 mg once daily. H. pylori eradication rates, defined as at least two negative tests and no positive tests from CLOtest , histology and/or culture, at 4 weeks post-therapy were significantly higher in the esomeprazole magnesium, amoxicillin and clarithromycin group than in the esomeprazole magnesium and clarithromycin group or the esomeprazole magnesium alone group. The results are shown in Table 14: Table 14: H. pylori Eradication Rates at 4 Weeks after 10 Day Treatment Regimen % of Adult Patients Cured [95% Confidence Interval] (Number of Patients) Study Treatment Group Per-Protocol1 Intent-to-Treat2 1. Patients were included in the analysis if they had H. pylori infection documented at baseline, had at least one endoscopically verified duodenal ulcer 0.5 cm in diameter at baseline or had a documented history of duodenal ulcer disease within the past 5 years, and were not protocol violators. Patients who dropped out of the study due to an adverse reaction related to the study drug were included in the analysis as not H. pylori eradicated. 2. Patients were included in the analysis if they had documented H. pylori infection at baseline, had at least one documented duodenal ulcer at baseline, or had a documented history of duodenal ulcer disease, and took at least one dose of study medication. All dropouts were included as not H. pylori eradicated. 3. p < 0.05 compared to esomeprazole magnesium plus clarithromycin. 4. p < 0.05 compared to esomeprazole magnesium alone. 191 Esomeprazole magnesium, amoxicillin and clarithromycin 84%3 [78, 89](n=196) 77%3 [71, 82](n=233) Esomeprazole magnesium, clarithromycin 55%[48, 62](n=187) 52%[45, 59](n=215) 193 Esomeprazole magnesium, amoxicillin and clarithromycin 85%4 [74, 93](n=67) 78%4 [67, 87](n=74) Esomeprazole magnesium 5%[0, 23](n=22) 4%[0, 21](n=24) The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10 day treatment regimen in the esomeprazole magnesium plus amoxicillin and clarithromycin group was 75% (n=156) and 57% (n=60) respectively, in the 191 and 193 studies (per-protocol analysis).

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Acute Tubulointerstitial Nephritis Advise the patient or caregiver to call the patient s healthcare provider immediately if they experience signs and/or symptoms associated with suspected acute TIN [see Warnings and Precautions ( 5.2 )]. Clostridium difficile -Associated Diarrhea Advise the patient or caregiver to immediately call the patient s healthcare provider if they experience diarrhea that does not improve [see Warnings and Precautions ( 5.3 )]. Bone Fracture Advise the patient or caregiver to report any fractures, especially of the hip, wrist or spine, to the patient s healthcare provider [see Warnings and Precautions ( 5.4 )]. Severe Cutaneous Adverse Reactions Advise the patient or caregiver to discontinue esomeprazole magnesium and immediately call the patient s healthcare provider for at first appearance of a severe cutaneous adverse reaction or other sign of hypersensitivity signs or symptoms associated with Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.5 )]. Cutaneous and Systemic Lupus Erythematosus Advise the patient or caregiver to immediately call the patient s healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions ( 5.6 )]. Cyanocobalamin (Vitamin B-12) Deficiency Advise the patient or caregiver to report any clinical symptoms that may be associated with cyanocobalamin deficiency to the patient s healthcare provider if they have been receiving esomeprazole magnesium for longer than 3 years [see Warnings and Precautions ( 5.8 )]. Hypomagnesemia and Mineral Metabolism Advise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to the patient s healthcare provider, if they have been receiving esomeprazole magnesium for at least 3 months [see Warnings and Precautions ( 5.9 )]. Drug Interactions Advise the patient or caregiver to report to their healthcare provider if starting treatment with rilpivirine-containing products, clopidogrel, St. John s Wort or rifampin; or, if they take high-dose methotrexate [see Contraindications ( 4 ), Warnings and Precautions ( 5.7 , 5.10 , 5.12 )]. Administration Take esomeprazole magnesium for delayed-release oral suspension at least one hour before meals. Antacids may be used concomitantly with esomeprazole magnesium. Administer esomeprazole magnesium for delayed-release oral suspension orally or via a nasogastric or gastric tube, as described in the Instructions for Use. Brands listed are trademarks of their respective owners. Manufactured by: Cipla Ltd., Kurkumbh-413802, Maharashtra, India Manufactured for: Cipla USA, Inc. 10 Independence Boulevard, Suite 300 Warren, NJ 07059 Revised: 11/2023

MEDICATION GUIDEEsomeprazole magnesium (es-oh-MEP-ra-zole mag-NEE-zee-um) for Delayed-Release Oral Suspension What is the most important information I should know about Esomeprazole magnesium for Delayed-Release Oral Suspension? Esomeprazole magnesium for Delayed-Release Oral Suspension may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor. Esomeprazole magnesium for Delayed-Release Oral Suspension can cause serious side effects, including: A type of kidney problem (acute tubulointerstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including Esomeprazole magnesium for Delayed-Release Oral Suspension, may develop a kidney problem called acute tubulointerstitial nephritis that can happen at any time during treatment with Esomeprazole magnesium for Delayed-Release Oral Suspension. Call your doctor right away if you have a decrease in the amount that you urinate or if you have blood in your urine. Diarrhea caused by an infection (Clostridium difficile) in your intestines. Call your doctor right away if you have watery stools or stomach pain that does not go away. You may or may not have a fever. Bone fractures (hip, wrist, or spine). Bone fractures in the hip, wrist, or spine may happen in people who take multiple daily doses of PPI medicines and for a long period of time (a year or longer). Tell your doctor if you have a bone fracture, especially in the hip, wrist, or spine. Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body s immune cells attack other cells or organs in the body). Some people who take PPI medicines, including Esomeprazole magnesium for Delayed-Release Oral Suspension, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun. Talk to your doctor about your risk of these serious side effects. Esomeprazole magnesium for Delayed-Release Oral Suspension can have other serious side effects. See What are the possible side effects of Esomeprazole magnesium for Delayed-Release Oral Suspension? What is Esomeprazole magnesium for Delayed-Release Oral Suspension? A prescription medicine called a proton pump inhibitor (PPI) used to reduce the amount of acid in your stomach. Esomeprazole magnesium for Delayed-Release Oral Suspension is used in adults for: 4 to 8 weeks for the healing and symptom relief of acid-related damage to the esophagus (erosive esophagitis or EE). Your doctor may prescribe another 4-8 weeks of Esomeprazole magnesium for Delayed-Release Oral Suspension in patients whose EE does not heal. maintaining healing of EE. 4-8 weeks to treat heartburn and other symptoms that happen with gastroesophageal reflux disease (GERD). up to 6 months to reduce the risk of stomach ulcers in some people taking pain medicines called non-steroidal anti-inflammatory drugs (NSAIDs). treating patients with a stomach infection (Helicobacter pylori) and a stomach ulcer, along with the antibiotics amoxicillin and clarithromycin. 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. Esomeprazole magnesium for Delayed-Release Oral Suspension is used in children and adolescents 12 to 17 years of age for: 4 to 8 weeks to heal EE. 4 weeks to treat heartburn and other symptoms that happen with GERD. Esomeprazole magnesium for Delayed-Release Oral Suspension is used in children 1 to 11 years of age for: 8 weeks to heal EE. up to 8 weeks to treat heartburn and other symptoms that happen with GERD. Esomeprazole magnesium for Delayed-Release Oral Suspension is used in children 1 month to less than 1 year of age to treat GERD with EE for up to 6 weeks. It is not known if esomeprazole magnesium is safe and effective in children under 1 month of age for the treatment of GERD with EE. It is not known if esomeprazole magnesium is safe and effective in children less than 1 year of age for the treatment of GERD symptoms. It is not known if esomeprazole magnesium is safe and effective in children to reduce the risk of stomach ulcers in children who take medicines called NSAIDs, to treat Helicobacter pylori stomach infection to lower the risk of a stomach ulcer returning, and to treat conditions where your stomach makes too much acid. Do not take Esomeprazole magnesium for Delayed-Release Oral Suspension if you are: allergic to esomeprazole magnesium, any other PPI medicine, or any of the ingredients in Esomeprazole magnesium for Delayed-Release Oral Suspension. See the end of this Medication Guide for a complete list of ingredients in Esomeprazole magnesium for Delayed-Release Oral Suspension. Tell your doctor right away or get emergency medical help if you get any of the following symptoms of an allergic reaction with Esomeprazole magnesium for Delayed-Release Oral Suspension: rash face swelling throat tightness difficulty breathing taking a medicine that contains rilpivirine (EDURANT, COMPLERA, ODEFSEY) used to treat HIV-1 (Human Immunodeficiency Virus). Before taking Esomeprazole magnesium for Delayed-Release Oral Suspension, tell your doctor about all of your medical conditions, including if you: have low magnesium levels, low calcium levels and low potassium levels in your blood. have liver problems. are pregnant or plan to become pregnant. It is not known if esomeprazole magnesium will 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 for Delayed-Release Oral Suspension. Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your doctor if you take: clopidogrel (Plavix), methotrexate (Otrxup, Rasuvo, Trexall, XATMEP), digoxin (LANOXIN), rilpivirine (EDURANT), St. John s Wort (Hypericum perforatum), or rifampin (Rimactane, Rifater, Rifamate). How should I take Esomeprazole magnesium for Delayed-Release Oral Suspension? Take Esomeprazole magnesium for Delayed-Release Oral Suspension exactly as prescribed by your doctor. Do not change your dose or stop Esomeprazole magnesium for Delayed-Release Oral Suspension without talking to your doctor. Take Esomeprazole magnesium for Delayed-Release Oral Suspension at least 1 hour before a meal. Antacids may be taken with Esomeprazole magnesium for Delayed-Release Oral Suspension. If you forget to take a dose of Esomeprazole magnesium for Delayed-Release Oral Suspension, 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 for Delayed-Release Oral Suspension, call your doctor or local poison control center right away at 1-800-222-1222, or go to the nearest hospital emergency room. See the Instructions for Use at the end of this Medication Guide for instructions how to take Esomeprazole magnesium for Delayed-Release Oral Suspension, and how to mix and give Esomeprazole magnesium for Delayed-Release Oral Suspension for delayed-release oral suspension through a nasogastric tube or gastric tube. What are the possible side effects of Esomeprazole magnesium for Delayed-Release Oral Suspension? Esomeprazole magnesium for Delayed-Release Oral Suspension can cause serious side effects, including: See What is the most important information I should know about Esomeprazole magnesium for Delayed-Release Oral Suspension? Low vitamin B-12 levels in your body can happen in people who have taken esomeprazole magnesium for a long time (more than 3 years). Tell your doctor if you have symptoms of low vitamin B-12 levels, including shortness of breath, lightheadedness, irregular heartbeat, muscle weakness, pale skin, feeling tired, mood changes, and tingling or numbness in the arms and legs. Low magnesium levels in your body can happen in people who have taken esomeprazole magnesium for at least 3 months. Tell your doctor right away if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and spasms of hands, feet or voice. Stomach growths (fundic gland polyps). People who take PPI medicines for a long time have an increased risk of developing a certain type of stomach growths called fundic gland polyps, especially after taking PPI medicines for more than 1 year. Severe skin reactions. Esomeprazole magnesium can cause rare but severe skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening: Skin rash which may have blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet). You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes. Stop taking Esomeprazole magnesium for Delayed-Release Oral Suspension and call your doctor right away. These symptoms may be the first sign of a severe skin reaction. The most common side effects of esomeprazole magnesium include: These are not all the possible side effects of Esomeprazole magnesium for Delayed-Release Oral Suspension. headache diarrhea nausea gas stomach (abdominal) pain constipation dry mouth 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 for Delayed-Release Oral Suspension? Store Esomeprazole magnesium for Delayed-Release Oral Suspension at room temperature between 68°F to 77°F (20°C to 25°C). Keep Esomeprazole magnesium for Delayed-Release Oral Suspension and all medicines out of the reach of children. General information about the safe and effective use of Esomeprazole magnesium for Delayed-Release Oral Suspension. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Esomeprazole magnesium for Delayed-Release Oral Suspension for a condition for which it was not prescribed. Do not give Esomeprazole magnesium for Delayed-Release Oral Suspension to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about Esomeprazole magnesium for Delayed-Release Oral Suspension that is written for health professionals. What are the ingredients in Esomeprazole magnesium for Delayed-Release Oral Suspension? Active ingredient: esomeprazole magnesium dihydrate Inactive granules in Esomeprazole magnesium for Delayed-Release Oral Suspension: anhydrous citric acid, crospovidone, dextrose anhydrous, ferric oxide yellow, hydroxypropyl cellulose, hydroxypropyl methyl cellulose E-15, magnesium stearate, methacrylic acid and ethyl acrylate copolymer dispersion, plasACRYL HTP-20, polysorbate 80, purified water, sugar sphere, talc and xanthan gum. The plasticizer plasACRYL HTP-20 have the following inactive ingredients: glyceryl monostearate, polysorbate 80, triethyl citrate. Manufactured by: Cipla Ltd., Kurkumbh-413802, Maharashtra, India Manufactured for: Cipla USA, Inc. 10 Independence Boulevard, Suite 300 Warren, NJ 07059 For more information, call 1-866-604-3268. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2023

Instructions for Use Esomeprazole magnesium ( es-oh-MEP-ra-zole mag-NEE-zee-um ) for Delayed-Release Oral Suspension Taking Esomeprazole magnesium For Delayed-Release Oral Suspension in water: Esomeprazole magnesium For Delayed-Release Oral Suspension comes in foil packets containing 2.5 mg or 5 mg of esomeprazole. Use an oral syringe to measure the amount of water needed to mix your dose. Ask your pharmacist for an oral syringe. If your prescribed dose is 2.5 mg or 5 mg, add 5 mL of water to a container. Add the contents of a foil packet containing the dose prescribed by your doctor. If you or your child are instructed to use more than one foil packet for the prescribed dose, follow the mixing instructions provided by your pharmacist or doctor. Stir. Leave the mixture for 2 to 3 minutes to thicken. Stir and drink the mixture within 30 minutes. If not used within 30 minutes, throw away this dose and mix a new dose. If any medicine remains in the container after drinking, add more water, stir, and drink right away. For young children, you can give the dose with an oral syringe. Rinse the oral syringe with water after each use. Giving Esomeprazole magnesium For Delayed-Release Oral Suspension with water through a nasogastric tube (NG tube) or gastric tube Esomeprazole magnesium For Delayed-Release Oral Suspension: Esomeprazole magnesium For Delayed-Release Oral Suspension comes in foil packets containing 2.5 mg or 5 mg of esomeprazole. Use only a catheter tipped syringe to give Esomeprazole magnesium for Delayed-Release Oral Suspension through a NG tube or gastric tube. If your prescribed dose is 2.5 mg or 5 mg, add 5 mL of water to a catheter tipped syringe. Add the contents of a foil packet containing the dose prescribed by your doctor. Shake the syringe well for 15 seconds and then leave it for 2 to 3 minutes to thicken. Shake the syringe and give the medicine through the NG or gastric tube (French size 6 or larger) into the stomach within 30 minutes. Refill the syringe with the same amount of water (5 mL of water). Shake the syringe and flush any remaining medicine from the NG tube or gastric tube into the stomach. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Cipla Ltd., Kurkumbh-413802, Maharashtra, India Manufactured for: Cipla USA, Inc. 10 Independence Boulevard, Suite 300 Warren, NJ 07059 Revised: 7/2023

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