FDA label d4bd9b8c-a312-463e-b6bd-45da2e3fa097

5 WARNINGS AND PRECAUTIONS Anaphylaxis and other serious allergic reactions can occur. Observe patients for one hour after administration. Discontinue Elspar in patients with serious allergic reactions. ( 5.1 ) Serious thrombotic events, including sagittal sinus thrombosis, can occur. Discontinue Elspar in patients with serious thrombotic events. ( 5.2 ) Pancreatitis, in some cases fulminant or fatal, can occur. Evaluate patients with abdominal pain for pancreatitis. Discontinue Elspar in patients with pancreatitis. ( 5.3 ) Glucose intolerance, in some cases irreversible, can occur. Monitor serum glucose. ( 5.4 ) Coagulopathy can occur. Perform appropriate monitoring. ( 5.5 ) Hepatotoxicity including hepatic failure can occur. Perform appropriate monitoring. ( 5.6 ) Posterior Reversible Encephalopathy Syndrome (PRES). ( 5.7 ) Do not interchange Elspar with Erwinia asparaginase or pegylated E. coli asparaginase [polyethylene glycol (PEG) asparaginase]. ( 5.8 ) 5.1 Anaphylaxis and Serious Allergic Reactions Serious allergic reactions can occur in patients receiving Elspar. The risk of serious allergic reactions is higher in patients with prior exposure to Elspar or other Escherichia coli -derived L-asparaginases. Observe patients for one hour after administration of Elspar in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines). Discontinue Elspar in patients with serious allergic reactions. 5.2 Thrombosis Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving Elspar. Discontinue Elspar in patients with serious thrombotic events. 5.3 Pancreatitis Pancreatitis, in some cases fulminant or fatal, can occur in patients receiving Elspar. Evaluate patients with abdominal pain for evidence of pancreatitis. Discontinue Elspar in patients with pancreatitis. 5.4 Glucose Intolerance Glucose intolerance can occur in patients receiving Elspar. In some cases, glucose intolerance is irreversible. Cases of diabetic ketoacidosis have been reported. Monitor serum glucose. 5.5 Coagulopathy Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving Elspar. CNS hemorrhages have been observed. Monitor coagulation parameters at baseline and periodically during and after treatment. Initiate treatment with fresh-frozen plasma to replace coagulation factors in patients with severe or symptomatic coagulopathy. 5.6 Hepatotoxicity and Abnormal Liver Function Fulminant hepatic failure occurs. Hepatotoxicity and abnormal liver function, including elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin (direct and indirect), and depression of serum albumin, and plasma fibrinogen can occur. Fatty changes in the liver have been documented on biopsy. Evaluate hepatic enzymes and bilirubin pretreatment and periodically during treatment. 5.7 Neurotoxicity Patients treated with Elspar, in a combination with other chemotherapeutic agents, have been reported to develop posterior reversible encephalopathy syndrome (PRES). PRES is a neurological disorder with clinical symptoms of headache, seizures, visual disturbances, altered mental status, and hypertension. Symptoms can be nonspecific, and diagnosis requires confirmation by radiological procedures. Interrupt use of Elspar if PRES is suspected or diagnosed. Control blood pressure promptly and monitor closely for seizure activity. 5.8 Risk of Medication Errors Medication errors involving Elspar have occurred. In particular, different formulations and routes of administration (intramuscular and intravenous) of asparaginase have been interchanged inappropriately, which may result in subtherapeutic blood levels of asparaginase or additional toxicity related to an overdose. Confirm the formulation of asparaginase prior to administration. Do not interchange Elspar with Erwinia asparaginase or pegylated E. coli asparaginase [polyethylene glycol (PEG) asparaginase].

6 ADVERSE REACTIONS The following serious adverse reactions occur with Elspar treatment [see Warnings and Precautions ( 5 )] : Anaphylaxis and serious allergic reactions Serious thrombosis Pancreatitis Glucose intolerance Coagulopathy Hepatotoxicity and abnormal liver function Posterior Reversible Encephalopathy Syndrome (PRES) Risk of Medication Errors The most common adverse reactions with Elspar are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Most common adverse reactions are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials and Post-Marketing Experience The adverse reactions included in this section were identified in single-arm clinical trials in which Elspar was administered as part of a multi-agent regimen or from spontaneous post-marketing reports or published literature. Because these adverse events were identified in clinical trials that were not designed to isolate the adverse effects of Elspar or were 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. Serious Adverse Reactions Anaphylaxis and serious allergic reactions. Allergic reactions have occurred with the first dose and with subsequent doses of Elspar. The risk of serious allergic reactions appears to be higher in patients with prior exposure to Elspar or other Escherichia coli -derived L-asparaginases. Serious thrombosis, including sagittal sinus thrombosis Pancreatitis, in some cases fulminant or fatal Glucose intolerance, in some cases irreversible Coagulopathy, including increased prothrombin time, increased partial thromboplastin time, and decreased fibrinogen, protein C, protein S and antithrombin III. CNS hemorrhages have been reported. Hepatotoxicity, in some cases fatal, can occur. Central Nervous System effects including coma, seizures, and hallucinations. Common Adverse Reactions Azotemia, liver function abnormalities, including hyperbilirubinemia, and elevated transaminases. Other Hyperammonemia, diabetic ketoacidosis, and hyperlipidemia including hypertriglyceridemia and hypercholesterolemia 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity, defined as development of binding and/or neutralizing antibodies to the product. Elspar is a bacterial protein and can elicit antibodies in patients treated with the drug. In 2 prospectively designed clinical trials (N=59 and 24), approximately one quarter of the patients developed antibodies that bound to Elspar as measured by enzyme-linked immunosorbent assays (ELISA). Clinical hypersensitivity reactions to Elspar in studies were common ranging from 32.5% to 75%. In these studies, concomitant medications and dosing schedules varied. Patients with hypersensitivity reactions were more likely to have antibodies than those without hypersensitivity reactions. Hypersensitivity reactions have been associated with increased clearance of Elspar. Incidence of antibody formation was lower upon first administration of Elspar than second administration. The frequency of antibody formation in adults relative to children is unknown. There is insufficient information to comment on neutralizing antibodies; however, higher levels of antibody correlated with a decrease in asparaginase activity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications and underlying disease. Therefore, comparison of the incidence of antibodies to Elspar with the incidence of antibodies to other products may be misleading.