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Glucarpidase: Drug information

Glucarpidase: Drug information
(For additional information see "Glucarpidase: Patient drug information" and see "Glucarpidase: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Voraxaze
Pharmacologic Category
  • Antidote;
  • Enzyme
Dosing: Adult

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

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). Also administer adequate supportive care.

Glucarpidase Administration Recommendations for High-Dose Methotrexate Rescuea

Methotrexate infusion duration

Indication for glucarpidase administration

aRamsey 2018

≤6 hours

Serum creatinine is significantly elevated relative to baseline and

24-hour plasma methotrexate level >50 micromolar, or

36-hour plasma methotrexate level >30 micromolar, or

42-hour plasma methotrexate level >10 micromolar, or

48-hour methotrexate level >5 micromolar

24 hours

Serum creatinine is significantly elevated relative to baseline and

36-hour plasma methotrexate level >30 micromolar, or

42-hour plasma methotrexate level >10 micromolar, or

48-hour plasma methotrexate level >5 micromolar

36 to 42 hours

48-hour plasma methotrexate level >5 micromolar

Intrathecal methotrexate overdose

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).

Dosing: Kidney Impairment: Adult

No dosage adjustment necessary.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Glucarpidase: Pediatric drug information")

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 glucarpidase.

Methotrexate toxicity

Methotrexate toxicity: Infants, Children, and Adolescents: 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). Refer to study protocols for specific details for clinical criteria for initiation of therapy, timing, and administration.

Glucarpidase Administration Recommendations for High-Dose Methotrexate Rescuea

Methotrexate infusion duration

Indication for glucarpidase administration

aRamsey 2018

≤6 hours

Serum creatinine is significantly elevated relative to baseline and

24-hour plasma methotrexate level >50 micromolar, or

36-hour plasma methotrexate level >30 micromolar, or

42-hour plasma methotrexate level >10 micromolar, or

48-hour methotrexate level >5 micromolar

24 hours

Serum creatinine is significantly elevated relative to baseline and

36-hour plasma methotrexate level >30 micromolar, or

42-hour plasma methotrexate level >10 micromolar, or

48-hour plasma methotrexate level >5 micromolar

36 to 42 hours

48-hour plasma methotrexate level >5 micromolar

Intrathecal methotrexate overdose

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).

Dosing: Kidney Impairment: Pediatric

Infants, Children, and Adolescents: No dosage adjustments necessary

Dosing: Hepatic Impairment: Pediatric

Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>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

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Warnings/Precautions

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.

Other warnings/precautions:

• 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 (age range: ≤1 to 82 years; median: 17 years) 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).

Warnings: Additional Pediatric Considerations

In children, upon resolution of renal dysfunction following glucarpidase therapy, rechallenge with high-dose methotrexate therapy has been successfully completed; monitor renal function and serum methotrexate concentrations closely in these patients (Christensen 2012). Glucarpidase for intrathecal methotrexate overdose should be used in conjunction with immediate lumbar drainage; in a case series of seven patients including four children (5 to 9 years of age) 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).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Voraxaze: 1000 units (1 ea)

Generic Equivalent Available: US

No

Pricing: US

Solution (reconstituted) (Voraxaze Intravenous)

1000 unit (per each): $46,176.00

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Prescribing and Access Restrictions

Voraxaze is distributed through ASD Healthcare; procurement information is available (24 hours a day; 365 days a year) at 1-855-786-7292. Voraxaze may also be obtained through certain pharmacy wholesalers on a drop-ship basis; orders will only be processed during business hours for overnight delivery. For additional information, refer to https://www.voraxaze.com/Order-Voraxaze.

Administration: Adult

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).

Administration: Pediatric

IV: Prior to administration, flush IV line; infuse glucarpidase over 5 minutes; flush IV line after 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: In clinical reports, the 2,000 unit dose was administered over 5 minutes via lumbar route, ventriculostomy, Ommaya reservoir, or lumbar and ventriculostomy (O'Marcaigh 1996; Widemann 2004); other reports of lower doses (1,000 units) have been administered through ventricular or lumbar catheter over 5 minutes (O'Marcaigh 1996).

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.

Use: Off-Label: Adult

Intrathecal methotrexate overdose

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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. Risk D: Consider therapy modification

Pregnancy Considerations

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 a pregnant patient if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).

Breastfeeding Considerations

It is not known if glucarpidase is present in breast milk.

Monitoring Parameters

Monitor serum methotrexate levels (use chromatographic method if ≤48 hours from glucarpidase administration [DAMPA interferes with immunoassay results until >48 hours]). Monitor CBC with differential, bilirubin, ALT, AST, and serum creatinine. Evaluate for signs/symptoms of methotrexate toxicity.

Mechanism of Action

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

Pharmacokinetics (Adult Data Unless Noted)

Onset of action: Methotrexate toxicity: Reduces methotrexate concentrations by ≥97% within 15 minutes of IV administration

Duration: Methotrexate toxicity: Maintains a >95% reduction of methotrexate concentrations for up to 8 days

Distribution: Vd: IV: 3.6 L; distribution restricted to plasma volume

Half-life elimination: 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)

Excretion: Clearance: 7.5 mL/minute

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: 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.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (EE) Estonia: Voraxaze;
  • (FI) Finland: Voraxaze;
  • (FR) France: Voraxaze;
  • (GB) United Kingdom: Voraxaze;
  • (IT) Italy: Voraxaze;
  • (NL) Netherlands: Voraxaze;
  • (NO) Norway: Voraxaze;
  • (PT) Portugal: Voraxaze;
  • (SK) Slovakia: Voraxaze
  1. Bailey B. Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women? Birth Defects Res A Clin Mol Teratol. 2003;67(2):133-140. doi: 10.1002/bdra.10007. [PubMed 12769509]
  2. Buchen S, Ngampolo D, Melton RG, et al, “Carboxypeptidase G2 Rescue in Patients With Methotrexate Intoxication and Renal Failure,” Br J Cancer, 2005, 92(3):480-7. [PubMed 15668713]
  3. Christensen AM, Pauley JL, Molinelli AR, et al, “Resumption of High-Dose Methotrexate After Acute Kidney Injury and Glucarpidase Use in Pediatric Oncology Patients,” Cancer, 2012, 118(17):4321-30. [PubMed 22252903]
  4. Dart RC, Goldfrank LR, Erstad BL, et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Ann Emerg Med. 2018;71(3):314-325.e1. doi:10.1016/j.annemergmed.2017.05.021 [PubMed 28669553]
  5. Fermiano M, Bergsbaken J, Kolesar JM. Glucarpidase for the management of elevated methotrexate levels in patients with impaired renalfunction. Am J Health Syst Pharm. 2014;71(10):793-798. [PubMed 24780487]
  6. Krause AS, Weihrauch MR, Bode U, et al, “Carboxypeptidase-G2 Rescue in Cancer Patients With Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy,” Leuk Lymphoma, 2002, 43(11):2139-43. [PubMed 12533039]
  7. Mitrovic D, Touw DJ, Tissing W. Treatment of High Dose Methotrexate Toxicity with Glucarpidase. J Clin Toxicol. 2016;6(2). Available at: https://www.omicsonline.org/open-access/treatment-of-high-dose-methotrexate-toxicity-with-glucarpidase-2161-0495-1000293.php?aid=72591. Accessed May 3, 2017.
  8. Mulder MB, Huisman R, Engels FK, van der Sluis IM, Koch BCP. Therapeutic drug monitoring of methotrexate in plasma using ultra high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: necessary after administration of glucarpidase in methotrexate intoxications. Ther Drug Monit. 2018;40(4):383-385. [PubMed 29994985]
  9. O'Marcaigh AS, Johnson CM, Smithson WA, et al, "Successful Treatment of Intrathecal Methotrexate Overdose by Using Ventriculolumbar Perfusion and Intrathecal Instillation of Carboxypeptidase G2," Mayo Clin Proc, 1996, 71(2):161-5. [PubMed 8577190]
  10. Phillips M, Smith W, Balan G, et al, “Pharmacokinetics of Glucarpidase in Subjects With Normal and Impaired Renal Function,” J Clin Pharmacol, 2008, 48(3):279-84. [PubMed 18192538]
  11. Ramsey LB, Balis FM, O'Brien MM, et al. Consensus guideline for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance. Oncologist. 2018;23(1):52-61. doi: 10.1634/theoncologist.2017-0243. [PubMed 29079637]
  12. Schwartz S, Borner K, Muller K, et al, “Glucarpidase (Carboxypeptidase G2) Intervention in Adult and Elderly Cancer Patients With Renal Dysfunction and Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy,” Oncologist, 2007 12(11):1299-308. [PubMed 18055849]
  13. Scott JR, Zhou Y, Cheng C, et al. Comparable efficacy with varying dosages of glucarpidase in pediatric oncology patients. Pediatr Blood Cancer. 2015;62(9):1518-1522. [PubMed 25631103]
  14. Smith SW and Nelson LS, “Case Files of the New York City Poison Control Center: Antidotal Strategies for the Management of Methotrexate Toxicity,” J Med Toxicol, 2008, 4(2):132-40. [PubMed 18570175]
  15. Vohra R, Vohra SS, Grock A, Mason J. Working through the paradox of methotrexate toxicity. Ann Emerg Med. 2018;72(2):129-132. [PubMed 30031507]
  16. Voraxaze (glucarpidase) [prescribing information]. West Conshohocken, PA: BTG International Inc; August 2019.
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  18. Widemann BC. Using a lower dose of glucarpidase to reduce plasma levels of methotrexate. Clin Adv Hematol Oncol. 2013;11(5):324-325. [PubMed 23880720]
  19. Widemann BC, Balis FM, Kim A, et al, “Glucarpidase, Leucovorin, and Thymidine for High-Dose Methotrexate-Induced Renal Dysfunction: Clinical and Pharmacologic Factors Affecting Outcome,” J Clin Oncol, 2010, 28(25):3979-86. [PubMed 20679598]
  20. Widemann BC, Balis FM, Murphy RF, et al, “Carboxypeptidase-G2, Thymidine, and Leucovorin Rescue in Cancer Patients With Methotrexate-Induced Renal Dysfunction,” J Clin Oncol, 1997, 15(5):2125-34. [PubMed 9164227]
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