Esomeprazole Sodium

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 appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2.1 , 2.2) , Adverse Reactions (6.2) ]. 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2) ] . Discontinue esomeprazole sodium for injection at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including esomeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving esomeprazole sodium for injection, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.7 Interaction with Clopidogrel Avoid concomitant use of esomeprazole sodium for injection with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel. When using esomeprazole sodium for injection consider alternative anti-platelet therapy [see Drug Interactions (7) ]. 5.8 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2) ] . Consider monitoring magnesium and calcium levels prior to initiation of esomeprazole sodium for injection and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI. 5.9 Interaction with St. John's Wort or Rifampin Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s Wort or rifampin) can substantially decrease esomeprazole concentrations [see Drug Interactions (7) ]. Avoid concomitant use of esomeprazole sodium for injection with St. John’s Wort or rifampin. 5.10 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop esomeprazole treatment 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 [see Drug Interactions (7) ]. 5.11 Interaction with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7) ]. 5.12 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

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, swelling, inflammation, pruritus, phlebitis, thrombophlebitis and superficial phlebitis. % of patients Esomeprazole sodium for injection (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 With the exception of injection site reactions described above, intravenous treatment with esomeprazole sodium for injection 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; Hepatobiliary Disorders: hepatic failure, hepatitis with or without jaundice; Immune 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.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 3: Adverse Reactions¹ in the Esomeprazole Sodium for Injection Group in Active Controlled Trials of Symptomatic GERD with or without EE </caption><colgroup><col width="50%"/><col width="50%"/></colgroup><tfoot><tr><td colspan="22">¹ Incidence of at least 1% in the Esomeprazole sodium for injection group </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Adverse Reactions</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">% of patients</content> <content styleCode="bold">Esomeprazole sodium for injection</content> <content styleCode="bold">(n=359)</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Headache<content styleCode="bold"/> </td><td styleCode="Rrule" align="center" valign="middle">11 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Flatulence<content styleCode="bold"/> </td><td styleCode="Rrule" align="center" valign="middle">10 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Nausea<content styleCode="bold"/> </td><td styleCode="Rrule" align="center" valign="middle">6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Abdominal pain </td><td styleCode="Rrule" align="center" valign="middle">6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Diarrhea </td><td styleCode="Rrule" align="center" valign="middle">4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Mouth dry </td><td styleCode="Rrule" align="center" valign="middle">4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Dizziness/vertigo </td><td styleCode="Rrule" align="center" valign="middle">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Constipation </td><td styleCode="Rrule" align="center" valign="middle">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Injection site reaction </td><td styleCode="Rrule" align="center" valign="middle">2 </td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Pruritus </td><td styleCode="Rrule" align="center" valign="middle">1 </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 4: Adverse Reactions¹ Occurring within 72 Hours after Start of Treatment in Patients with Endoscopically Confirmed Bleeding Ulcers </caption><colgroup><col width="33.34%"/><col width="33.34%"/><col width="33.34%"/></colgroup><tfoot><tr><td colspan="20">^1. Incidence &#x2265;1% in the esomeprazole sodium for injection group and greater than placebo group ^2. Injection site reactions included erythema, swelling, inflammation, pruritus, phlebitis, thrombophlebitis and superficial phlebitis. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" align="center" valign="middle"/><td styleCode="Rrule" colspan="2" align="center" valign="middle"><content styleCode="bold">% of patients</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"><content styleCode="bold">Esomeprazole sodium for injection</content> <content styleCode="bold">(n=375) </content> </td><td styleCode="Rrule" align="center" valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">(n=389) </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Duodenal ulcer hemorrhage </td><td styleCode="Rrule" align="center" valign="top">4 </td><td styleCode="Rrule" align="center" valign="top">4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Injection site reaction<content styleCode="italics">²</content> </td><td styleCode="Rrule" align="center" valign="top">4 </td><td styleCode="Rrule" align="center" valign="top">1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Pyrexia </td><td styleCode="Rrule" align="center" valign="top">4 </td><td styleCode="Rrule" align="center" valign="top">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Cough </td><td styleCode="Rrule" align="center" valign="top">1 </td><td styleCode="Rrule" align="center" valign="top">0.3 </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top">Dizziness </td><td styleCode="Rrule" align="center" valign="top">1 </td><td styleCode="Rrule" align="center" valign="top">1 </td></tr></tbody></table>