What You Need to Know About Glucarpidase Injection for Toxic Methotrexate Levels in Renal Impairment

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In January 2012, glucarpidase injection (Voraxaze) was approved for the treatment of toxic plasma methotrexate concentrations (> 1 μmol/L) in patients with delayed methotrexate clearance due to impaired renal function.1 Owing to the potential risk of subtherapeutic exposure to methotrexate, glucarpidase is not indicated for use in patients exhibiting the expected clearance of methotrexate (concentrations within 2 standard deviations of the mean methotrexate excretion curve specific for the administered dose of methotrexate) or in those with normal or mildly impaired renal function.2

Approval was based on efficacy assessment in 22 patients with delayed methotrexate clearance (more than 2 standard deviations above the average on standard nomograms) secondary to renal dysfunction.2 Evaluable patients had pre- and post-treatment plasma samples measured by high performance liquid chromatography. Patients received a single dose of glucarpidase at 50 U/kg by IV injection over 5 minutes; those with initial methotrexate concentrations > 100 μmol/L were to receive a second dose 48 hours later. Patients had a median age of 15.5 years (range, 5–84 years), 59% were male, and the most common underlying cancers were osteogenic sarcoma (50%) and leukemia/lymphoma (45%). All patients received IV hydration, urinary alkalinization, and leucovorin rescue.

Initial methotrexate concentrations were  > 1 to 50 μmol/L in 13 patients, > 50 to 100 μmol/L in 2, and > 100 μmol/L in 7. The study endpoint was achievement of a concentration ≤ 1 μmol/L within 15 minutes of glucarpidase administration that was maintained for 8 days. This response occurred in 10 patients (45%) overall, all with initial methotrexate concentrations ≤ 50 μmol. However, all patients exhibited a > 95% rapid reduction in methotrexate levels that was maintained for 8 days. A second dose of glucarpidase in 6 patients with initial methotrexate levels > 100 μmol/L did not result in response in any of the 4 patients with levels > 1 μmol/L.

How It Works

Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and such classical antifolates as methotrexate.2,3 The agent converts methotrexate to inactive metabolites, providing  an alternate non-renal pathway for methotrexate elimination.

How It Is Given

Glucarpidase is given as a single IV bolus injection of 50 U/kg over 5 minutes.

It is important to note that methotrexate concentrations within 48 hours of glucarpidase administration can be reliably measured only by a chromatographic method.2 An inactive methotrexate metabolite (DAMPA) resulting from glucarpidase treatment interferes with measurement of methotrexate by immunoassays, resulting in overestimation of methotrexate levels during this period.

Leucovorin should not be administered within 2 hours before or after a glucarpidase dose, since it is a substrate for glucarpidase.2 Otherwise, the dose of leucovorin during the first 48 hours after glucarpidase administration should be the same as that before glucarpidase administration. After 48 hours, the leucovorin dose should be based on the measured methotrexate concentration. Leucovorin should be continued for at least 3 days after the methotrexate level has dropped below the leucovorin treatment threshold, and it should not be stopped on the basis of a single methotrexate measurement below this threshold.

Safety Profile

Safety data are from 290 patients in two single-arm trials of glucarpidase in patients with markedly delayed methotrexate clearance due to renal dysfunction.2 Patients had a median age of 17 years (range, 6 months to 85 years), 64% were male, 32% had osteogenic sarcoma/sarcoma, and 63% had leukemia/lymphoma. The most common adverse reactions (incidence ≥ 1%) were paresthesias (2%), flushing (2%), nausea/vomiting (2%), hypotension (1%), and headache (1%). Of 98 patients evaluated, 16 (17%) developed antiglucarpidase antibodies after glucarpidase administration, including 12 (15%) of 78 receiving one dose and 4 (22%) of 18 receiving two doses.

Glucarpidase carries a warning/precaution for serious allergic reactions, including anaphylaxis, and a warning against use of immunoassays to measure methotrexate concentrations within 48 hours after a glucarpidase dose. ■


1. U.S. Food and Drug Administration: Glucarpidase. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm288016.htm. Accessed March 19, 2012.

2. VORAXAZE® (glucarpidase) for injection prescribing information. BTG International Inc, January 2012. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/125327lbl.pdf. Accessed March 19, 2012.

3. Patterson DM, Lee SM: Glucarpidase following high-dose methotrexate: Update on development. Expert Opin Biol Ther 10:105-111, 2010.