FDA Approves Glucarpidase Injection
Tuesday, January 17, 2012
The US Food and Drug Administration approved glucarpidase injection (Voraxaze®, BTG International Inc.) for the treatment of toxic plasma methotrexate concentrations (> 1 μmol/L) in patients with delayed methotrexate clearance due to impaired renal function.*
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 ≤1 μmol/L 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 having pre- and post-treatment plasma samples 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 >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 RCSIR [45% (95% CI: 27, 65)]. Efficacy was dependent on pre-treatment methotrexate levels. Ten of 13 patients (77%) who had baseline methotrexate levels between 1-50 μmol/L achieved an RSCIR, however, none of the 9 patients with pre-glucarpidase methotrexate concentrations > 50 μmol/L attained this endpoint. All evaluable patients exhibited more than 95% 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 (1 month to 85 years), 64% were male, 32% had osteogenic sarcoma or sarcoma and 63% had leukemia or lymphoma. The most common adverse reactions (incidence >1%) were paraesthesias, 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 a as a single intravenous injection of 50 Units/kg.
* Limitation of Use: 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.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125327lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).