Medically reviewed by Drugs.com. Last updated on Jul 15, 2019.
(gloo KAR pid ase)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Voraxaze: 1000 units (1 ea)
Brand Names: U.S.
Glucarpidase is a recombinant enzyme which rapidly hydrolyzes the carboxyl-terminal glutamate residue from extracellular methotrexate into inactive metabolites (DAMPA and glutamate), resulting in a rapid reduction of methotrexate concentrations independent of renal function
Vd: IV: 3.6 L; distribution restricted to plasma volume
Clearance: 7.5 mL/minute
Onset of Action
Methotrexate toxicity: Reduces methotrexate concentrations by ≥97% within 15 minutes of IV administration
Duration of Action
Methotrexate toxicity: Maintains a >95% reduction of methotrexate concentrations for up to 8 days
IV: Normal renal function: Serum glucarpidase activity levels: 5.6 hours; Serum total glucarpidase: ~9 hours. Impaired renal function (CrCl <30 mL/minute): 8 to 10 hours (Phillips 2008)
Special Populations: Renal Function Impairment
The pharmacokinetics of glucarpidase in subjects with severe renal impairment (CrCl <30 mL/minute) were similar to those observed in healthy subjects except for a longer half-life of 8.2 hours compared with 5.6 hours in healthy subjects.
Use: Labeled Indications
Methotrexate toxicity: Management of toxic methotrexate plasma concentrations (>1 micromole/L) in adult and pediatric patients with delayed methotrexate clearance (methotrexate plasma concentration >2 standard deviations of the mean methotrexate excretion curve specific for methotrexate dose administered) due to impaired renal function.
Limitations of use: Due to the risk of subtherapeutic methotrexate exposure, glucarpidase is NOT recommended when methotrexate clearance and methotrexate plasma concentrations are within the expected range.
Off Label Uses
Intrathecal methotrexate overdose
Data from a limited number of patients studied suggest that glucarpidase may be beneficial for the treatment of accidental intrathecal methotrexate overdose [O’Marcaigh 1996], [Widemann 2004]. Additional data may be necessary to further define the role of glucarpidase in this condition. Consensus guidelines also suggest the utility of glucarpidase in managing accidental intrathecal methotrexate overdose [Ramsey 2018].
There are no contraindications listed in the manufacturer's labeling.
Note: Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites; when administering glucarpidase concomitantly with leucovorin calcium, administer leucovorin calcium at least 2 hours before or 2 hours after the glucarpidase dose.
Methotrexate toxicity: IV: 50 units/kg as a single dose (Buchen 2005; Widemann 1997; Widemann 2010).
Note: Consensus guidelines suggest that optimal glucarpidase administration is within 48 to 60 hours from the start of the high-dose methotrexate infusion (beyond this point, life-threatening toxicities may not be preventable). A repeat glucarpidase dose within 48 hours of the first dose is not recommended (during the same methotrexate course) due to decreased efficacy. If less than the 50 units/kg dose is available, administer the glucarpidase amount available as lower doses may be effective (Ramsey 2018).
Intrathecal methotrexate overdose (off-label route/use; based on limited data): Intrathecal: 2,000 units as soon as possible after accidental methotrexate overdose (Widemann 2004).
Refer to adult dosing.
Note: Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites; do not administer leucovorin calcium within 2 hours before or after glucarpidase.
Methotrexate toxicity: Infants, Children, and Adolescents: IV: 50 units/kg as a single dose (Buchen 2005; Widemann 1997; Widemann 2010)
Intrathecal methotrexate overdose: Limited data available: Children ≥5 years and Adolescents: Intrathecal: 2,000 units as soon as possible after accidental exposure (O’Marcaigh 1996; Widemann 2004)
IV: Reconstitute each vial (1,000 units/vial) with 1 mL normal saline. Mix gently by rolling or tilting vial; do not shake. Upon reconstitution, solution should be clear, colorless and free of particulate matter.
Intrathecal (off-label route/use): Reconstitute 2,000 units with 12 mL preservative-free normal saline (Widemann 2004)
IV: Infuse over 5 minutes; flush IV line before and after glucarpidase administration. Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites; when administering glucarpidase concomitantly with leucovorin calcium, administer leucovorin calcium at least 2 hours before or 2 hours after the glucarpidase dose.
Intrathecal (for intrathecal methotrexate overdose; off-label route/use): Glucarpidase was administered within 3 to 9 hours of accidental intrathecal methotrexate overdose in conjunction with lumbar drainage or ventriculolumbar perfusion (Widemann 2004). Administered over 5 minutes via lumbar route, ventriculostomy, Ommaya reservoir, or lumbar and ventriculostomy (O'Marcaigh 1996; Widemann 2004). In one case report, 1,000 units were administered through the ventricular catheter over 5 minutes and another 1,000 units were administered through the lumbar catheter (O'Marcaigh 1996).
Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Reconstituted solutions should be used immediately or may be stored for up to 4 hours under refrigeration.
Leucovorin Calcium-Levoleucovorin: Glucarpidase may decrease serum concentrations of the active metabolite(s) of Leucovorin Calcium-Levoleucovorin. Specifically, 6S-5-methyltetrahydrofolateconcentrations may be reduced. Glucarpidase may decrease the serum concentration of Leucovorin Calcium-Levoleucovorin. Management: Avoid leucovorin administration within 2 hours of glucarpidase dosing. Continue to administer the pre-glucarpidase leucovorin dose for at least the first 48 hours after glucarpidase administration, and dose based on methotrexate concentration thereafter. Consider therapy modification
Methotrexate levels: For up to 48 hours following glucarpidase administration, the preferred method of measuring methotrexate concentrations is the chromatographic method. DAMPA, an inactive methotrexate metabolite with a half-life of ~9 hours, interferes with immunoassays and may result in the overestimation of the methotrexate concentration.
>10%: Immunologic: Antibody development (21%; neutralizing: 44%)
1% to 10%:
Cardiovascular: Flushing (2%), hypotension (1%)
Central nervous system: Headache (1%)
Gastrointestinal: Nausea (≤2%), vomiting (≤2)
Neuromuscular & skeletal: Paresthesia (2%)
<1%, postmarketing, and/or case reports: Blurred vision, diarrhea, hypersensitivity reaction, hypertension, pharyngeal edema, skin rash, throat irritation, tremor
Concerns related to adverse effects:
• Hypersensitivity: Serious hypersensitivity reactions have been reported (rarely).
Concurrent drug therapy issues:
• Leucovorin calcium: Leucovorin calcium administration should be continued after glucarpidase; the same dose as was given prior to glucarpidase should be continued for the first 48 hours after glucarpidase; after 48 hours, leucovorin doses should be based on methotrexate concentrations (Ramsey 2018). A single methotrexate concentration below the threshold should not determine when leucovorin should be discontinued; continue leucovorin until the methotrexate concentration remains below the threshold for leucovorin rescue for a minimum of 3 days. Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites; when administering glucarpidase concomitantly with leucovorin calcium, administer leucovorin calcium at least 2 hours before or 2 hours after the glucarpidase dose.
• Hydration/alkalinization: In addition to leucovorin, glucarpidase use should be accompanied with adequate IV hydration and urinary alkalinization (Vohra 2018). Continue alkalinization and IV hydration as clinically indicated.
• Intrathecal methotrexate overdose: Glucarpidase for intrathecal methotrexate overdose (off-label route/use) should be used in conjunction with immediate lumbar drainage; concurrent dexamethasone (4 mg IV every 6 hours for 4 doses) may minimize methotrexate-induced chemical arachnoiditis; leucovorin calcium (100 mg IV every 6 hours for 4 doses) may prevent systemic methotrexate toxicity (Widemann 2004).
• Monitoring methotrexate: For up to 48 hours following glucarpidase administration, the preferred method of measuring methotrexate concentrations is the chromatographic method. DAMPA, an inactive methotrexate metabolite with a half-life of ~9 hours, interferes with immunoassays and may result in the overestimation of the methotrexate concentration (Mulder 2018; Ramsey 2018).
• Multiple doses: The utility of more than one glucarpidase dose in reducing plasma methotrexate levels was evaluated in a study of 100 patients with high-dose methotrexate-induced nephrotoxicity (Widemann 2010). Glucarpidase 50 units/kg IV was administered either as a single dose (n = 65), 2 doses given 24 hours apart (n = 28), or 3 doses given at 4 hour intervals (n = 7). Six of the 65 patients randomized to a single dose also received a second delayed glucarpidase dose (>24 hours later) due to persistent methotrexate concentrations ≥1 micromole/L in spite of a ≥90% decrease in the plasma methotrexate concentration after the initial dose. The use of scheduled second and third glucarpidase doses did not result in additional methotrexate concentration decreases; and only 2 of the 6 patients who received a second delayed glucarpidase dose (>24 hours later) experienced a ≥50% methotrexate concentration reduction. Consensus guidelines suggest a repeat glucarpidase dose within 48 hours of the first dose is not recommended (during the same methotrexate course) due to decreased efficacy (Ramsey 2018).
Serum methotrexate levels: Use chromatographic method if ≤48 hours from glucarpidase administration (DAMPA interferes with immunoassay results until >48 hours)
CBC with differential, bilirubin, ALT, AST, serum creatinine; evaluate for signs/symptoms of methotrexate toxicity
Animal reproduction studies have not been conducted. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea or vomiting. Have patient report immediately to prescriber severe dizziness, passing out, flushing, chills, headache, sensation of warmth, or burning or numbness feeling (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
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More about glucarpidase
Other brands: Voraxaze