FDA Approval for Glucarpidase
Brand name: Voraxaze®
- Treatment of toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance due to impaired kidney function
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
On January 17, 2012, the Food and Drug Administration (FDA) approved glucarpidase injection (Voraxaze®, made by BTG International Inc.) for the treatment of toxic plasma methotrexate concentrations (more than 1 μmol/L) in patients with delayed methotrexate clearance due to impaired renal function. Glucarpidase is not indicated for use in patients who exhibit the expected clearance of methotrexate (plasma methotrexate concentrations within 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) or those with normal or mildly impaired renal function because of the potential risk of subtherapeutic exposure to methotrexate.
The approval was based on the pharmacodynamic endpoint of a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, defined as an attainment of plasma methotrexate concentration of 1 μmol/L or less within 15 minutes following glucarpidase administration and sustained for up to 8 days.
Efficacy was established in 22 patients with delayed methotrexate clearance (more than 2 standard deviations above the average indicated on standard nomograms) secondary to renal dysfunction. The efficacy assessment was limited to patients from whom pre- and post-treatment plasma samples were collected and handled according to a validated procedure to yield reliable methotrexate measurements by HPLC.
All patients received glucarpidase, 50 Units/kg, as an intravenous injection over 5 minutes. Patients with pre-glucarpidase methotrexate concentrations higher than 100 μmol/ L were to receive a second dose of glucarpidase 48 hours after the initial dose. All patients received vigorous intravenous hydration, urinary alkalinization, and leucovorin rescue.
Ten of the 22 patients met the criteria for RSCIR in plasma methotrexate concentration [45 percent (95 percent CI: 27 percent, 65 percent)]. Efficacy was dependent on pre-treatment methotrexate levels. Ten of 13 patients (77 percent) who had baseline methotrexate levels of between 1 and 50 μmol/L achieved an RSCIR, whereas none of the 9 patients with pre-glucarpidase methotrexate concentrations higher than 50 μmol/L attained this endpoint. All evaluable patients exhibited more than 95 percent reduction in methotrexate concentration from pre-treatment baseline levels that was maintained for up to 8 days following glucarpidase therapy.
Safety data were evaluated in 290 patients treated in two single-arm open-label multicenter trials. These trials enrolled patients who had markedly delayed methotrexate clearance secondary to renal dysfunction. The median age was 17 years (range, 1 month to 85 years), 64 percent were male, 32 percent had osteogenic sarcoma or sarcoma, and 63 percent had leukemia or lymphoma. The most common adverse reactions (incidence more than 1 percent) were paresthesias, flushing, nausea and/or vomiting, hypotension, and headache.
Healthcare providers should note that:
- Methotrexate concentrations within 48 hours following glucarpidase administration can only be reliably measured by a chromatographic method due to interference from metabolites [4-deoxy-4-amino-N10-methylpteroic acid (DAMPA)]. Measurement of methotrexate concentrations within 48 hours of glucarpidase administration using immunoassays can overestimate the methotrexate concentration.
- Leucovorin should not be administered within 2 hours before or after a glucarpidase dose because leucovorin is a substrate for glucarpidase.
The recommended dose and schedule for glucarpidase is as a single intravenous injection of 50 Units/kg.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.