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 sodium 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 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. I ntravenous Injection Over At Least 3 Minutes in Adult Patients 1. Reconstitute esomeprazole sodium for injection with 5 mL of 0.9% Sodium Chloride Injection, USP. 2. Withdraw the desired dose of the reconstituted esomeprazole sodium solution for a 20 mg or 40 mg dose. 3. Discard any unused portion of esomeprazole sodium for injection solution remaining in the vial. 4. Inspect the reconstituted esomeprazole sodium for injection solution visually for particulate matter and discoloration prior to and during administration. 5. Administer as an intravenous injection over no less than 3 minutes. 6. Flush the intravenous line with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of esomeprazole sodium for injection. Intravenous Infusion Over 10 Minutes to 30 Minutes in Adult and Pediatric Patients 1. Reconstitute the contents of one vial of esomeprazole sodium for injection with 5 mL of 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP. 2. Further dilute the resulting solution with 45 mL of 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP to a final concentration of 0.8 mg/mL. 3. Withdraw the desired dose of the reconstituted esomeprazole sodium for injection solution for an adult or pediatric dose. 4. Discard any unused portion of esomeprazole sodium for injection solution remaining in the vial. 5. Inspect the reconstituted esomeprazole sodium for injection solution visually for particulate matter and discoloration prior to and during administration. 6. Administer intravenously over 10 minutes to 30 minutes. 7. Flush the intravenous line with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of esomeprazole sodium for injection. Storage Store the final (diluted) esomeprazole sodium for injection solution at room temperature up to 30°C (86°F) and administer within the designated time period as listed in Table 2 below. Table 2: Storage Time for Final (diluted) Esomeprazole Sodium for Injection Solution Diluent Administer within: 0.9% Sodium Chloride Injection, USP 12 hours Lactated Ringer’s Injection, USP 12 hours 5% Dextrose Injection, USP 6 hours 2.5 Preparation and Administration Instructions for Risk Reduction of Rebleeding of Gastric or Duodenal Ulcers in Adults 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. Loading Dose (80 mg) 1. Reconstitute each of two 40 mg vials of esomeprazole sodium for injection with 5 mL of 0.9% Sodium Chloride Injection, USP. 2. Further dilute the resulting solution in 100 mL 0.9% Sodium Chloride Injection, USP. 3. Inspect the reconstituted esomeprazole sodium for injection solution visually for particulate matter and discoloration prior to and during administration. 4. Administer intravenously over 30 minutes. 5. Flush the intravenous line with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of esomeprazole sodium for injection. Continuous Infusion 1. Reconstitute each of two 40 mg vials of esomeprazole sodium for injection with 5 mL of 0.9% Sodium Chloride Injection, USP. 2. Further dilute the reconstituted esomeprazole sodium for injection solution in 100 mL 0.9% Sodium Chloride Injection, USP. 3. Inspect the reconstituted esomeprazole sodium for injection solution visually for particulate matter and discoloration prior to and during administration. 4. Administer intravenously as a continuous infusion at a rate of 8 mg/hour for 71.5 hours. 5. Flush the intravenous line with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of esomeprazole sodium for injection. Storage • Store the final (diluted) esomeprazole sodium for injection solution at room temperature up to 30°C (86°F) and administer within 12 hours.

4 CONTRAINDICATIONS • Esomeprazole sodium 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 )

Not available.

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 Gland Pharma at 864-879-9994 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 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 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 Group in Active Controlled Trials of Symptomatic GERD with or without EE Adverse Reactions % of patients Esomeprazole Sodium (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 1 Incidence of at least 1% in the esomeprazole sodium group Intravenous treatment with esomeprazole 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 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 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 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 % of patients Esomeprazole Sodium (n=375) Placebo (n=389) Duodenal ulcer hemorrhage 4 4 Injection site reaction 2 4 1 Pyrexia 4 3 Cough 1 0.3 Dizziness 1 1 1. Incidence ≥1% in the esomeprazole group and greater than placebo group 2. Injection site reactions included erythema, swelling, inflammation, pruritus, phlebitis, thrombophlebitis and superficial phlebitis. With the exception of injection site reactions described above, intravenous treatment with esomeprazole administered as an injection or as an infusion was found to have a safety profile similar to that of oral esomeprazole. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of esomeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: agranulocytosis, pancytopenia; Eye Disorders: blurred vision; Gastrointestinal Disorders: pancreatitis; stomatitis; microscopic colitis; fundic gland polyps; H epatobiliary Disorders: hepatic failure, hepatitis with or without jaundice; I mmune System Disorders: anaphylactic reaction/shock; systemic lupus erythematosus; Infections and Infestations: GI candidiasis; Metabolism and nutritional disorders: hypomagnesemia (may lead to hypocalcemia and/or hypokalemia) [see Warnings and Precautions (5.8) ], hyponatremia; Musculoskeletal and Connective Tissue Disorders: muscular weakness, myalgia, bone fracture; Nervous System Disorders: hepatic encephalopathy, taste disturbance; Psychiatric Disorders: aggression, agitation, depression, hallucination; Renal and Urinary Disorders: interstitial nephritis; Reproductive System and Breast Disorders: gynecomastia, erectile dysfunction; Respiratory, Thoracic and Mediastinal Disorders: bronchospasm; Skin and Subcutaneous Tissue Disorders: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN, some fatal), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), cutaneous lupus erythematosus. Adverse reactions associated with omeprazole may also be expected to occur with esomeprazole sodium for injection. See the full prescribing information for oral omeprazole for complete safety information.