Methotrexate is an immunosuppressive agent used to treat cancer, dermatology-, and rheumatology-related issues.
Organ system toxicities from methotrexate can lead to acute hepatitis, myelosuppression, mucositis, and further nephrotoxicity. Glucarpidase (Voraxaze) is for adult and pediatric patients with delayed methotrexate clearance due to impaired renal function.1
Glucarpidase reduces toxic plasma methotrexate concentrations. Patients who demonstrate the expected clearance and plasma methotrexate concentration should not take glucarpidase. The FDA approved the use of glucarpidase in 2012.
Methotrexate is an immunosuppressive agent used to treat cancer, dermatology-, and rheumatology-related issues.2 In some cases, patients with impaired renal function may have reduced methotrexate clearance. This causes a methotrexate buildup that leads to toxicity.
Symptoms include diarrhea, nausea, vomiting, acute renal failure, and other adverse effects (AEs). This toxicity can eventually be fatal, which is why it is important to use glucarpidase when needed.
Clinical trials studying the efficacy of glucarpidase examined patients who had significantly delayed methotrexate clearance due to impaired renal function. After a significant study, researchers concluded that glucarpidase caused a clinically important 99% or greater sustained reduction of serum methotrexate levels.
It also provided noninvasive rescue from methotrexate toxicity in renally impaired patients.3 If providers administer glucarpidase upon discovery of toxicity, morbidity risk is significantly lowered. Additionally, patients may experience reductions in plasma methotrexate concentrations within as early as 15 minutes
In some cases, intrathecal administration of glucarpidase was successful in lowering toxicity after clinicians accidentally administering methotrexate intrathecally.4 This is only for emergency situations and glucarpidase is not FDA-approved for intrathecal use.
Mechanism of Action
Glucarpidase is a carboxypeptidase enzyme that rapidly metabolizes circulating methotrexate into glutamate and 2,4-diamino-N-10-methylpteroic acid (DAMPA).4 Also known as carboxypeptidase-G2 (CPDG2), glucarpidase is a modified form of Escherichia coli.
Glucarpidase is a zinc peptidase, so it hydrolyzes the amide linkage on circulating (not intracellular) methotrexate to form glutamate and DAMPA. The liver then metabolizes these metabolites.
Dosage and Administration
Glucarpidase is an intravenous injection. The recommended dosage is 50 units per kilogram as a single injection. Providers should administer it over 5 minutes. It is available as 1000 units of a white lyophilized powder in a single dose vial for reconstitution.
Health care providers should reconstitute the contents of the vial with 1 mL of 0.9% sodium chloride injection, USP. After reconstitution, providers should roll and tilt the vial gently to mix but should not shake it.
Health care providers should administer glucarpidase immediately once reconstituted, or store under refrigeration for up to 4 hours if not used immediately. Patients with renal impairment do not need dose adjustments.
Pharmacists should counsel patients regarding the importance of continuous monitoring of plasma methotrexate concentration and renal functions throughout therapy.
Pediatric patients can safely and effectively use glucarpidase. Clinical trials studied the use of glucarpidase in patients 5 years of age and older. There are also additional safety data in patients 1-17 years of age and older.
Warnings and Contraindications
There are no contraindications for glucarpidase. If patients are to receive glucarpidase concomitantly with leucovorin, providers should administer leucovorin at least 2 hours before or 2 hours after the glucarpidase dose. Serious hypersensitivity reactions occurred in less than 1% of patients.1
AEs to glucarpidase include headache, hypotension, nausea and/or vomiting, and paresthesia.1
Pregnancy and Lactation
Data are not available regarding the use of glucarpidase during pregnancy, however patients would only receive glucarpidase if also receiving methotrexate, which can cause embryo-fetal harm.1
Patients should consult their physician regarding the use of methotrexate or glucarpidase during pregnancy. There is additionally no information relating to the presence of glucarpidase in human milk.
About the Author
Greta Staubly is a 2024 PharmD candidate at the University of Connecticut