glucarpidase 1000 UNT Injection [Voraxaze]

INDICATIONS AND USAGE VORAXAZE is indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per liter) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function. Limitations of Use: VORAXAZE is not recommended for use in patients who exhibit the expected clearance and expected plasma methotrexate concentration. Reducing plasma methotrexate concentration in these patients may result in subtherapeutic exposure to methotrexate [see Clinical Studies ( 14 )] . VORAXAZE is a carboxypeptidase indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per liter) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function. ( 1 ) Limitations of Use: VORAXAZE is not recommended for use in patients who exhibit the expected clearance and expected plasma methotrexate concentration. Reducing plasma methotrexate concentration in these patients may result in subtherapeutic exposure to methotrexate. ( 1 )

DOSAGE AND ADMINISTRATION The recommended dosage of VORAXAZE is 50 Units per kilogram as a single intravenous injection over 5 minutes. ( 2.1 ). For the first 48 hours after the dose of VORAXAZE, administer the same leucovorin dose given prior to VORAXAZE. Administer leucovorin at least 2 hours before or 2 hours after the dose of VORAXAZE. ( 2.2 ) Beyond 48 hours after the dose of VORAXAZE, administer leucovorin based on the measured methotrexate concentration. Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of VORAXAZE is 50 Units per kilogram (kg) as a single intravenous injection administered over 5 minutes. Flush intravenous line before and after administration. 2.2 Concomitant Use with Leucovorin Rescue When administering VORAXAZE concomitantly with leucovorin, administer leucovorin at least 2 hours before or 2 hours after the VORAXAZE dose [see Drug Interactions ( 7.1 )] . For the first 48 hours after a dose of VORAXAZE: Administer the same leucovorin dosage given prior to the VORAXAZE dose. Beyond 48 hours after a dose of VORAXAZE : Determine the leucovorin dosage based on the measured methotrexate concentration. Do not discontinue leucovorin based on the determination of a single methotrexate concentration below the leucovorin rescue threshold. Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin rescue threshold for a minimum of 3 days. Continue intravenous hydration and urinary alkalinization as indicated. When measuring methotrexate concentrations following a VORAXAZE dose, a chromatographic method is preferred over an immunoassay [see Warnings and Precautions ( 5.2 )] . 2.3 Preparation Reconstitute the contents of the vial with 1 mL of 0.9% Sodium Chloride Injection, USP. Roll and tilt the vial gently to mix. Do not shake. Inspect the vial and discard VORAXAZE if the solution is not clear, colorless, and free of particulate matter. Use reconstituted VORAXAZE immediately or store under refrigeration at 36° to 46°F (2° to 8°C) for up to 4 hours if not used immediately. VORAXAZE contains no preservative and is supplied as a single-dose vial. Discard any unused product.

WARNINGS AND PRECAUTIONS Serious Hypersensitivity Reactions: Serious hypersensitivity reactions occurred. ( 5.1 ) Monitoring Methotrexate Concentration: Measure methotrexate concentrations within 48 hours following VORAXAZE administration using a chromatographic method; immunoassays are unreliable for samples collected within 48 hours following VORAXAZE administration. ( 5.2 ) 5.1 Serious Hypersensitivity Reactions Serious hypersensitivity reactions occurred in less than 1% of patients [ see Adverse Reactions ( 6.1 ) ]. 5.2 Interference with Immunoassay Measurements of Methotrexate DAMPA (4-deoxy-4-amino-N 10 - methylpteroic acid), an inactive metabolite of methotrexate formed following VORAXAZE administration, interferes with the measurement of methotrexate concentration using immunoassays. This interference results in an overestimation of the methotrexate concentration. Based on the half-life of DAMPA (about 9 hours), VORAXAZE may interfere with the measurement of methotrexate concentration for up to 48 hours following a VORAXAZE dose [see Clinical Pharmacology ( 12.1 ) ]. When measuring methotrexate concentration following a VORAXAZE dose, a chromatographic method is preferred over an immunoassay.

CONTRAINDICATIONS None. None.

Mechanism of Action Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl- terminal glutamate residue from folic acid and classical antifolates such as methotrexate. Glucarpidase converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N 10 - methylpteroic acid (DAMPA) and glutamate. VORAXAZE provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.