High dose IV calcium folinate (Leucovorin®) rescue is commonly used for elevated plasma methotrexate levels, however it is less effective at high methotrexate concentrations. There have also been reports of chemotherapy treatment failure as a result of competitive cellular uptake and reduced methotrexate efficacy.r
Glucarpidase (formally known as carboxypeptidase G2) is a carboxypeptidase enzyme which converts plasma methotrexate into inactive metabolites, providing an alternative rapid non-renal route of elimination. Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations 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 or those with normal or mildly impaired renal function because of the potential risk of subtherapeutic exposure to methotrexate.r
In Australia, at present, glucarpidase (Voraxaze®) is on the life saving drug register and can be obtained via the Special Access Scheme (cost approximately $25,000 per 1000 unit vial). Consignment stock is held at:
- The Children’s Hospital Westmead (NSW):
- Business hours (Mon – Fri 0830 – 1700h): Oncology Pharmacy 02 9845 2061 (if unavailable- 02 9845 2696)
- Evenings (Mon – Fri 1700 – 2000h): Pharmacy department 02 9845 2696
- After hours: switchboard 02 9845 0000 for on-call pharmacist
- Peter MacCallum Cancer Centre (VIC):
- Business hours (Mon – Fri 0830 – 1700h): Pharmacy department 03 8559 5200
- After hours: switchboard 03 8559 5000 for on-call pharmacist
Access criteria may vary depending on institution guidelines.
Administration of glucarpidase
- Treatment should be initiated within 48 to 60 hours (up to 96 hours) from the start of methotrexate infusion, as life threatening toxicities may not be preventable beyond this time.r,r
- Dose is 50 units/kg (cap at 2000 units) IV bolus over 5 minutes as a single dose.
- Reconstitute each glucarpidase vial with 1mL sodium chloride 0.9%.
- Consider treatment if:
- methotrexate level elevated (see flowchart below) OR
- serum creatinine > 1.5 x ULN OR
- serum creatinine ≥ 2 x baseline (pre methotrexate), associated with elevated methotrexate level.
Flowchart for use of glucarpidase
Adapted from ©The Oncologist 2018 and ©Journal of Clinical Oncology 2015r
- Continue fluid hydration and urinary alkalinisation as per treatment protocol and for at least 48 hours after glucarpidase dose.
- Calcium folinate (Leucovorin®) is a substrate of glucarpidase, therefore do not administer within 2 hours before or after a dose of glucarpidase (glucarpidase should not be delayed for this reason).
- Calcium folinate (Leucovorin®) should be administered until glucarpidase is available, and continued until the methotrexate concentration has been maintained below the calcium folinate (Leucovorin®) treatment threshold for a minimum of 48 hours due to potential for a rebound effect.
- Measurement of methotrexate concentration using immunoassays is unreliable for samples collected within 48 hours following glucarpidase administration. During this period, calcium folinate (Leucovorin®) dose should be based on the pre-glucarpidase methotrexate concentration.r
- Consider dialysis if glucarpidase is unavailable.