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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Gastric Malignancy: In adults, symptomatic response to therapy with esomeprazole sodium does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. (5.1) • Acute Interstitial Nephritis: Observed in patients taking PPIs. (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) • Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue esomeprazole sodium and refer to specialist for evaluation. (5.5) • Interaction with Clopidogrel: Avoid concomitant use of esomeprazole. (5.6) • Hypomagnesemia: Reported rarely with prolonged treatment with PPIs. (5.7) • Interaction with St. John’s Wort or Rifampin: Avoid concomitant use of esomeprazole sodium. (5.8, 7.2) • Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Increased chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors; temporarily stop esomeprazole sodium at least 14 days before assessing CgA levels. (5.9, 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 a temporary withdrawal of esomeprazole sodium. (5.10, 7.3) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with esomeprazole sodium does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adults 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 Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including esomeprazole sodium for injection. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue esomeprazole sodium for injection if acute interstitial nephritis develops [ see Contraindications (4) ]. 5.3 Clostridium-difficile Associated Diarrhea Published observational studies suggest that PPI therapy like esomeprazole sodium 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 ), Adverse Reactions ( 6.2 ) ]. 5.5 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, 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. 5.6 Interaction with Clopidogrel Avoid concomitant use of esomeprazole sodium 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 consider alternative anti-platelet therapy [see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )]. 5.7 Hypomagnesemia 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. 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 ) ]. 5.8 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 with St. John’s Wort or rifampin. 5.9 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 Clinical Pharmacology ( 12.2 )]. 5.10 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 (7.3) ].
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Acute Interstitial 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) ] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.5) ] Hypomagnesemia [see Warnings and Precautions (5.7) ] 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 Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience with Intravenous Esomeprazole Sodium 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 intravenous esomeprazole is based on results from clinical trials conducted in three different populations including patients having symptomatic GERD with or without a history of erosive esophagitis (n=199), patients with erosive esophagitis (n=160), and healthy subjects (n=204). Symptomatic GERD and Erosive Esophagitis Trials The data described below reflect exposure to esomeprazole sodium for injection in 359 patients. Esomeprazole sodium for injection was studied only in actively-controlled trials. The population was 18 to 77 years of age; 45% Male, 52% Caucasian, 17% Black, 3% Asian, 28% Other, and had either erosive reflux esophagitis (44%) or GERD (56%). Most patients received doses of either 20 mg or 40 mg either as an infusion or an injection. Adverse reactions occurring in ≥ 1% of patients treated with intravenous esomeprazole (n=359) in clinical trials are listed below: Table 2 Adverse Reactions Occurring at an Incidence ≥ 1% in the Esomeprazole sodium for injection Group Adverse Reactions % of patients Esomeprazole Intravenous (n=359) Headache 10.9 Flatulence 10.3 Nausea 6.4 Abdominal pain 5.8 Diarrhea 3.9 Mouth dry 3.9 Dizziness/vertigo 2.8 Constipation 2.5 Injection site reaction 1.7 Pruritus 1.1 Intravenous treatment with esomeprazole 20 mg and 40 mg-administered as an injection or as an infusion was found to have a safety profile similar to that of oral administration of esomeprazole. Pediatric 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. The safety results are consistent with the known safety profile of esomeprazole and no unexpected safety signals were identified [s ee Clinical Pharmacology (12.3) ]. 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. Postmarketing Reports - There have been spontaneous reports of adverse events with postmarketing use of esomeprazole. These reports occurred rarely and are listed below by body system: Blood And Lymphatic System Disorders : agranulocytosis, pancytopenia; Eye Disorders: blurred vision; Gastrointestinal Disorders: pancreatitis; stomatitis; microscopic colitis; 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 with or without hypocalcemia and/or hypokalemia; 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; 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), cutaneous lupus erythematosus. Other adverse events not observed with esomeprazole, but occurring with omeprazole can be found in the omeprazole package insert, ADVERSE REACTIONS section.