Esomeprazole Sodium

1 INDICATIONS AND USAGE Esomeprazole sodium for injection is a proton pump inhibitor (PPI) indicated for the: Short-term treatment of Gastroesophageal Reflux Disease (GERD) with erosive esophagitis (EE) in adults and pediatric patients 1 month to 17 years of age, as an alternative to oral therapy when oral esomeprazole is not possible or appropriate. ( 1.1 ) Risk reduction of rebleeding of gastric or duodenal ulcers following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers in adults. ( 1.2 ) 1.1 Treatment of Gastroesophageal Reflux Disease (GERD) with Erosive Esophagitis (EE) Esomeprazole sodium for injection is indicated for the short-term treatment of GERD with EE in adults and pediatric patients 1 month to 17 years, inclusively as an alternative to oral therapy when oral esomeprazole is not possible or appropriate. 1.2 Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers following Therapeutic Endoscopy in Adults Esomeprazole sodium for injection is indicated for risk reduction of rebleeding of gastric or duodenal ulcers following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers in adults.

2 DOSAGE AND ADMINISTRATION GERD with Erosive Esophagitis. ( 2.1 ): •The recommended adult dosage is either 20 mg or 40 mg once daily by intravenous injection (no less than 3 minutes) or intravenous infusion (10 minutes to 30 minutes) for up to 10 days. •The recommended pediatric dosage is based upon age and weight. See full prescribing information. Risk Reduction of Rebleeding of Gastric and Duodenal Ulcers ( 2.2 ): •The recommended adult dosage is 80 mg administered as an intravenous infusion over 30 minutes, followed by a continuous infusion of 8 mg/hour for a total treatment duration of 72 hours. Dosage Adjustment for Hepatic Impairment ( 2.3 ): •See full prescribing information for dosage adjustment by severity of impairment and by indication. Preparation and Administration ( 2.4 , 2.5 ): •See full prescribing information for preparation and administration instructions by indication. 2.1 Dosage for GERD with EE Adult Patients The recommended adult dosage is either 20 mg or 40 mg esomeprazole sodium for injection given once daily by intravenous injection (over at least 3 minutes) or intravenous infusion (10 minutes to 30 minutes) for up to 10 days [see Dosage and Administration (2.4) ] . Pediatric Patients The recommended dosage for pediatric patients is based on age and body weight as shown in Table 1 below. Administer as an intravenous infusion over 10 to 30 minutes once daily for up to 10 days [see Dosage and Administration (2.4) ] . Table 1: Recommended Pediatric Dosage Regimen for GERD with EE Age and Body Weight Dosage Regimen 1 month to less than 1 year of age 0.5 mg/kg once daily 1 year to 17 years less than 55 kg 10 mg once daily 55 kg or greater 20 mg once daily Completion of Treatment The safety and effectiveness of esomeprazole sodium for injection for more than 10 days have not been demonstrated. As soon as oral therapy is possible or appropriate, discontinue intravenous therapy with esomeprazole sodium for injection and continue with oral esomeprazole therapy. 2.2 Dosage for Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers following Therapeutic Endoscopy in Adults The recommended adult dosage is 80 mg esomeprazole sodium for injection administered as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg/hour for a total treatment duration of 72 hours (i.e., includes initial 30-minute loading dose plus 71.5 hours of continuous infusion) [see Dosage and Administration (2.5) ] . Intravenous therapy is aimed solely at the acute initial management of bleeding gastric or duodenal ulcers and does not constitute full treatment. Administer oral acid-suppressive therapy following intravenous therapy for a full course of treatment. 2.3 Dosage Adjustment for Hepatic Impairment GERD with EE For patients with severe hepatic impairment (Child-Pugh Class C), the maximum dosage is 20 mg once daily [see Use in Specific Populations (8.6) ] . Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers following Therapeutic Endoscopy in Adults For patients with mild to moderate hepatic impairment (Child-Pugh Classes A and B, respectively), administered 80 mg as an intravenous infusion over 30 minutes, followed by a continuous infusion of 6 mg/hour for 71.5 hours. For patients with severe hepatic impairment (Child-Pugh Class C), administered 80 mg as an intravenous infusion over 30 minutes, followed by a continuous infusion of 4 mg/hour for 71.5 hours [see Use in Specific Populations (8.6) ] . 2.4 Preparation and Administration Instructions for GERD with EE Do not administer esomeprazole sodium for injection concomitantly with any other medications through the same intravenous site and/or tubing. Oral antacids may be used during treatment with esomeprazole sodium for injection. Intravenous Injection Over At Least 3 Minutes in Adult Patients Reconstitute esomeprazole sodium for injection with 5 mL of 0.9% Sodium Chloride Injection, USP. Withdraw the desired dose of the reconstituted esomeprazole…

5 WARNINGS AND PRECAUTIONS Gastric Malignancy : In adults, symptomatic response to therapy with esomeprazole sodium for injection 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 sodium for injection and refer to specialist for evaluation. ( 5.6 ) Interaction with Clopidogrel : Avoid concomitant use of esomeprazole sodium for injection. ( 5.7 , 7 ) Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.8 ) Interaction with St. John’s Wort or Rifampin : Avoid concomitant use of esomeprazole sodium for injection. ( 5.9 , 7 ) Interactions with Diagnostic Investigations for Neuroendocrine Tumors : Increased chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors; temporarily stop esomeprazole sodium for injection at least 14 days before assessing CgA levels. ( 5.10 , 7 ) Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider a temporary withdrawal of esomeprazole sodium for injection. ( 5.11 , 7 ) Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.12 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with esomeprazole sodium for injection does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients also consider an endoscopy. 5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue esomeprazole sodium for injection and evaluate patients with suspected acute TIN [see Contraindications (4) ] . 5.3 Clostridium difficile- Associated Diarrhea Published observational studies suggest that PPI therapy like esomeprazole sodium for injection may be associated with an increased risk of Clostridium difficile- associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2) ]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 5.4 Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appro…

4 CONTRAINDICATIONS Esomeprazole sodium for injection is contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.2) , Adverse Reactions (6.2) ]. Proton pump inhibitors (PPIs), including esomeprazole sodium for injection, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7) ]. Patients with known hypersensitivity to any component of the formulation or to substituted benzimidazoles. ( 4 ) Patients receiving rilpivirine-containing products. ( 4 , 7 )

7 DRUG INTERACTIONS Tables 5 and 6 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 5: Clinically Relevant Interactions Affecting Drugs Co-Administered with Esomeprazole and Interaction with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.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) ]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole may increase toxicity [see Clinical Pharmacology (12.3) ]. There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole. Intervention: Rilpivirine-containing products: Concomitant use with esomeprazole sodium for injection is contraindicated [see Contraindications (4) ] . Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with esomeprazole sodium for injection. 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 (5.11) ]. Intervention: A temporary withdrawal of esomeprazole sodium for injection may be considered in some patients receiving high-dose methotrexate. 2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, diazepam) 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 sodium for injection. 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 prescr…

8.1 Pregnancy 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. 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 H 2 -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 99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero 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 H 2 -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 H 2 -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 h…

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.2) ] Clostridium difficile -Associated Diarrhea [see Warnings and Precautions (5.3) ] Bone Fracture [see Warnings and Precautions (5.4) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6) ] Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.8) ] Fundic Gland Polyps [see Warnings and Precautions (5.12) ] Most common adverse reactions (≥1%) are: headache, flatulence, nausea, abdominal pain, injection site reaction, diarrhea, dry mouth, dizziness/vertigo, constipation and pruritus. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. Symptomatic GERD and EE Adults The safety of esomeprazole sodium for injection is based on results from clinical trials conducted in four different populations including healthy subjects (n=204) and patients with bleeding gastric or duodenal ulcers (n=375). The data described below reflect exposure to esomeprazole sodium for injection in 359 patients in actively-controlled trials: symptomatic GERD with or without a history of EE (n=199) and patients with EE (n=160). The population was 18 to 77 years of age; 45% Male, 52% Caucasian, 17% Black, 3% Asian, and 28% other race. Most patients received doses of either 20 or 40 mg either as an infusion or an injection. Adverse reactions occurring in at least 1% of patients are listed below in Table 3: Table 3: Adverse Reactions 1 in the Esomeprazole Sodium for Injection Group in Active Controlled Trials of Symptomatic GERD with or without EE 1 Incidence of at least 1% in the Esomeprazole sodium for injection group Adverse Reactions % of patients Esomeprazole sodium for injection (n=359) Headache 11 Flatulence 10 Nausea 6 Abdominal pain 6 Diarrhea 4 Mouth dry 4 Dizziness/vertigo 3 Constipation 3 Injection site reaction 2 Pruritus 1 Intravenous treatment with esomeprazole sodium for injection 20 and 40 mg-administered as an injection or as an infusion was found to have a safety profile similar to that of oral esomeprazole. Pediatrics A randomized, open-label, multi-national study to evaluate the pharmacokinetics of repeated intravenous doses of once daily esomeprazole sodium for injection in pediatric patients 1 month to 17 years old, inclusive was performed [see Clinical Pharmacology (12.3) ] . The safety results are consistent with the known safety profile of esomeprazole and no unexpected safety signals were identified. Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers in Adults The data described in Table 4 below reflect exposure to esomeprazole sodium for injection in 375 patients who presented with endoscopically confirmed gastric or duodenal ulcer bleeding in a placebo-controlled trial. The population was 18 to 98 years old; 68% Male, 87% Caucasian, 1% Black, 7% Asian, and 4% other race. Following endoscopic hemostasis, patients received either placebo or 80 mg esomeprazole sodium for injection as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg/hour for a total treatment duration of 72 hours. After the initial 72-hour period, all patients received an oral PPI for 27 days. Table 4: Adverse Reactions 1 Occurring within 72 Hours after Start of Treatment in Patients with Endoscopically Confirmed Bleeding Ulcers 1. Incidence ≥1% in the esomeprazole sodium for injection group and greater than placebo group 2. Injection site reactions included erythema, swel…