Overview
11 DESCRIPTION Glucarpidase is a carboxypeptidase produced by recombinant DNA technology in genetically modified Escherichia coli. Glucarpidase is a 390-amino acid homodimer protein with a molecular weight of 83 kDa. Each potency Unit corresponds to the enzymatic cleavage of 1 µmol/L of methotrexate per minute at 37°C.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 Pharmacodynamics Following administration of VORAXAZE 50 Units/kg to patients in Study 1, methotrexate concentration measured by a chromatographic method was reduced by ≥ 97% within 15 minutes in all 22 treatment-evaluable patients and was maintained at a > 95% reduction up to 8 days in 20 of...
Indications
- 1 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.
Common Doses
- 1 mL
Dosage
2 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.
Contraindications
- 4 CONTRAINDICATIONS None. None.
Side Effects
- 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Hypersensitivity Reactions [Warnings and Precautions ( 5.1 )]. The most common related adverse events (>1%) were paresthesia, flushing, nausea and/or vomiting, hypotension and headache. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact BTG at 877-377-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.
Interactions
- 7 DRUG INTERACTIONS 7.1 Effects of VORAXAZE on Leucovorin VORAXAZE can decrease leucovorin concentration, which may decrease the effect of leucovorin rescue unless leucovorin is dosed as recommended [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )] . VORAXAZE may also reduce the concentrations other folate analogs or folate analog metabolic inhibitors. 7.2 Effect of VORAXAZE on Measurement of Methotrexate Concentration DAMPA (4-deoxy-4-amino-N10- methylpteroic acid), an inactive metabolite of methotrexate formed following VORAXAZE administration, interferes with the...