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 …

3 DOSAGE FORMS AND STRENGTHS For Injection: 40 mg of esomeprazole as a sterile, freeze-dried, white to off-white, porous cake or lyophilized powder in a single-dose vial for reconstitution. For Injection: 40 mg of esomeprazole as a sterile, freeze-dried, white to off-white, porous cake or lyophilized powder in a single-dose vial for reconstitution. ( 3 )

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 )

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 Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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 Incidence of at least 1% in the esomeprazole sodium for injection group in the Esomeprazole Sodium for Injection Group in Active Controlled Trials of Symptomatic GERD with or without EE 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 Incidence ≥1% in the esomeprazole sodium for injection group and greater than placebo group. Occurring within 72 Hours after Start of Treatment in Patients with Endoscopically Confirmed Bleeding Ulcers % of patients Esomeprazole Sodium for Inj …

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 pres …

8 USE IN SPECIFIC POPULATIONS 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 …

12.1 Mechanism of Action Esomeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H + /K + ATPase enzyme system at the secretory surface of the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.

11 DESCRIPTION The active ingredient in esomeprazole sodium for injection is ( S )-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1 H -benzimidazole sodium, a PPI. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R-isomers. Its molecular formula is C 17 H 18 N 3 O 3 SNa with molecular weight of 367.4 g/mol (sodium salt) and 345.4 g/mol (parent compound). Esomeprazole sodium is a white or almost white, hygroscopic powder. It is very soluble in water and freely soluble in ethanol (95%). The structural formula is: Esomeprazole sodium for injection is supplied as a sterile, freeze-dried, white to off-white, porous cake or powder in a 5 mL single-dose vial, intended for intravenous administration after reconstitution with 0.9% Sodium Chloride Injection, USP; Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP. Esomeprazole sodium for injection contains 40 mg esomeprazole (equivalent to 42.5 mg esomeprazole sodium), edetate disodium 1.5 mg and sodium hydroxide q.s. for pH adjustment. The pH of reconstituted solution of esomeprazole sodium for injection depends on the reconstitution volume and is in the pH range of 9 to 11. The stability of esomeprazole sodium in aqueous solution is strongly pH dependent. The rate of degradation increases with decreasing pH. Esomeprazole Sodium Chemical Structure

10 OVERDOSAGE The symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient. Reports of overdosage with omeprazole in humans may also be relevant. Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen at recommended dosages. See the full prescribing information for oral omeprazole for complete safety information. No specific antidote for esomeprazole is known. Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive. If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING Esomeprazole sodium for injection is supplied in a single-dose vial as a as a white to off-white lyophilized powder for reconstitution containing 40 mg of esomeprazole. Esomeprazole sodium for injection is available as follows: NDC Number Strength Package Size 70436-190-82 40 mg esomeprazole 10 vials Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Protect from light. Store in carton until time of use. Following reconstitution and administration, discard any unused portion of esomeprazole solution [see Dosage and Administration (2.4 , 2.5) ] .