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Voraxaze

Generic Name: Glucarpidase
Class: Antidotes
Chemical Name: Recombinant glutamate carboxypeptidase (carboxypeptidase G2)
Molecular Formula: C1950H3157N543O599S7
CAS Number: 9074-87-7

Introduction

Antidote for methotrexate toxicity; recombinant bacterial enzyme.1 7 17

Uses for Voraxaze

Methotrexate Toxicity

Adjunct to leucovorin rescue1 3 4 6 9 10 11 for the treatment of toxic plasma methotrexate concentrations (>0.454 mcg/mL [1 mcmol/L]) in patients with delayed methotrexate clearance due to renal impairment (designated an orphan drug by FDA for this use16 ).1 10

Because of potential for subtherapeutic methotrexate concentrations, do not 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 methotrexate dose administered) or in those with normal or mildly impaired renal function.1

Provides an alternative, nonrenal route for methotrexate elimination (in patients with delayed methotrexate clearance due to renal impairment) by converting circulating methotrexate to inactive metabolites that are primarily eliminated hepatically.1 7 8 10 12 13

Voraxaze Dosage and Administration

General

Methotrexate Toxicity

  • Use only in patients who exhibit delayed methotrexate clearance (plasma methotrexate concentrations >2 standard deviations greater than the mean methotrexate excretion curve specific for the methotrexate dose administered) due to renal impairment.4 Early recognition of delayed methotrexate clearance and renal impairment (i.e., an increase in Scr and/or oliguria) and urgent intervention are essential to prevent development of severe methotrexate-induced toxicities.4

  • Use in conjunction with leucovorin rescue and supportive measures (i.e., IV hydration, urinary alkalinization with sodium bicarbonate).1 4 11 Because the pharmacokinetics of leucovorin and levoleucovorin are similar,5 manufacturer of glucarpidase states may substitute levoleucovorin for leucovorin.4

Administration

IV Administration

Administer by direct IV injection; flush IV line before and after administration of drug.1

Reconstitution

Use strict aseptic technique since drug product contains no preservative.1

Add 1 mL of 0.9% sodium chloride injection to vial containing 1000 units of glucarpidase.1 Gently roll and tilt vial to ensure dissolution; do not shake.1

Rate of Administration

Administer by direct IV injection over 5 minutes.1

Dosage

Dosage expressed in terms of units; a unit of activity is the quantity of enzyme needed to catalyze hydrolysis of 1 mcmol/L of methotrexate per minute at 37°C.1 17

Pediatric Patients

Methotrexate Toxicity
IV

50 units/kg as a single dose.1 Second dose not shown to produce further reduction in methotrexate concentrations.1 9 11 13

Continue leucovorin (or levoleucovorin4 ) rescue.1 4 (See Specific Drugs under Interactions.) During first 48 hours after glucarpidase administration, administer leucovorin (or levoleucovorin) at same dosage administered prior to glucarpidase; beyond 48 hours, base dosage on methotrexate concentration.1 4 Continue leucovorin (or levoleucovorin) rescue until methotrexate concentration has been maintained below the leucovorin (or levoleucovorin) treatment threshold for ≥3 days.1 4

Adults

Methotrexate Toxicity
IV

50 units/kg as a single dose.1 Second dose not shown to produce further reduction in methotrexate concentrations.1 9 11 13

Continue leucovorin (or levoleucovorin4 ) rescue.1 4 (See Specific Drugs under Interactions.) For first 48 hours after glucarpidase administration, administer leucovorin (or levoleucovorin) at same dosage administered prior to glucarpidase; beyond 48 hours, base dosage on methotrexate concentration.1 4 Continue leucovorin (or levoleucovorin) rescue until methotrexate concentration has been maintained below the leucovorin (or levoleucovorin) treatment threshold for ≥3 days.1 4

Prescribing Limits

Pediatric Patients

Methotrexate Toxicity
IV

Single 50-unit/kg dose.1 4

Adults

Methotrexate Toxicity
IV

Single 50-unit/kg dose.1 4

Special Populations

No special population dosage recommendations at this time.1

Cautions for Voraxaze

Contraindications

  • No known contraindications.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Risk of serious sensitivity reactions, including anaphylaxis.1

Monitoring of Methotrexate Concentrations and Assay Interference

Plasma methotrexate concentrations measured by immunoassay within 48 hours following glucarpidase administration are unreliable.1

During first 48 hours after glucarpidase administration, use chromatographic method to obtain reliable measurements of plasma methotrexate concentrations.1

Continuation of Adjunctive Therapy

Following glucarpidase administration, continue leucovorin (or levoleucovorin4 ) rescue until methotrexate concentration has been maintained below the leucovorin (or levoleucovorin) treatment threshold for ≥3 days.1 4 (See Methotrexate Toxicity under Dosage and Administration and also see Specific Drugs under Interactions.)

Continue IV hydration and urinary alkalinization as indicated.1

Antibody Formation

Development of antiglucarpidase antibodies reported.1 17 Detected between 7 days to 7 months following exposure to glucarpidase.17 Incidence appeared to be similar between patients receiving either 1 or 2 doses of glucarpidase.17

Development of antiglucarpidase antibodies not expected to be clinically important considering the rapid time to maximum pharmacodynamic effect (15 minutes) and the recommended dosage regimen (i.e., single dose).17

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether glucarpidase is distributed into milk.1 Use with caution.1

Pediatric Use

Efficacy established for treatment of toxic plasma methotrexate concentrations (>0.454 mcg/mL [1 mcmol/L]) in pediatric patients with delayed methotrexate clearance due to renal impairment.1

No overall differences in safety observed between pediatric patients (1 month to 17 years of age) and adults.1

Geriatric Use

No overall differences in safety or efficacy in geriatric patients (≥65 years of age) compared with younger adults.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1

Renal Impairment

Half-life is prolonged in patients with severe renal impairment.1 8 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Paresthesia,1 2 flushing,1 2 nausea and/or vomiting,1 hypotension,1 headache.1 2

Interactions for Voraxaze

Substrates of Glucarpidase

Possible decreased peak concentrations and AUC of the glucarpidase substrate.1 (See Specific Drugs under Interactions.)

Specific Drugs

Drug

Interaction

Comments

Folic acid antagonists (e.g., pyrimethamine, trimethoprim)

Possible decreased peak concentrations and AUC of folic acid antagonist1

Reduced folates (e.g., leucovorin, levoleucovorin)

Administration of glucarpidase 2 hours before leucovorin reduces peak concentrations and AUC of leucovorin (by 52 and 33%, respectively) and of its active metabolite 5-methyl-THF (by 93 and 92%, respectively);1 similar effects expected with levoleucovorin4

Do not administer within 2 hours before or after glucarpidase1 4 (see Dosage under Dosage and Administration)

Voraxaze Pharmacokinetics

Absorption

Onset

Following a single 50-unit/kg dose, plasma methotrexate concentrations (measured by chromatographic method) decreased by ≥97% within 15 minutes.1

Duration

Following a single 50-unit/kg dose, reductions in plasma methotrexate concentrations were maintained at >95% for up to 8 days.1

Distribution

Extent

Distributed primarily in intravascular (i.e., extracellular) compartment;4 7 11 does not cross blood-brain barrier.7

Not known whether glucarpidase is distributed into human milk.1

Elimination

Half-life

5.6 hours (by enzymatic assay) or 9 hours (by enzyme-linked immunosorbent assay [ELISA]).1 17

Special Populations

In patients with severe renal impairment (Clcr <30 mL/minute), half-life is prolonged (8.2 hours).1 8

Stability

Storage

Parenteral

Powder for Injection

2–8°C.1 Do not freeze.1

Following reconstitution, use immediately or store at 2–8°C for up to 4 hours; discard unused portions.1

Actions

  • Recombinant bacterial enzyme produced in Escherichia coli.1 7 17

  • Rapidly hydrolyzes methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate.1 7 17

  • Because DAMPA and glutamate are principally metabolized hepatically, glucarpidase provides an alternative, nonrenal route for methotrexate elimination in patients with delayed methotrexate clearance due to renal impairment.1 7 8 10 12 13

Advice to Patients

  • Risk of hypersensitivity reactions, including anaphylaxis.1

  • Risk of infusion reactions.1 Importance of immediately reporting signs and symptoms of such reactions (e.g., fever, chills, flushing, feeling hot, rash, hives, itching, throat tightness or breathing difficulty, tingling, numbness, headache).1

  • Importance of continued monitoring of plasma methotrexate concentrations and renal function after discharge from the hospital.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Glucarpidase

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

1000 units

Voraxaze

BTG

AHFS DI Essentials. © Copyright 2016, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. BTG International Inc. Voraxaze (glucarpidase) for injection prescribing information. West Conshohocken, PA; 2012 Jan.

2. Widemann BC, Jayaprakash N, Howard SC et al. Clinical trial and compassionate use experience with glucarpidase for methotrexate toxicity. J Clin Oncol. 2012; 30 (American Society of Clinical Oncology Annual Meeting Abstracts): Abstract No. 6530.

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; 118:4321-30. [PubMed 22252903]

4. BTG International Inc., West Conshohocken, PA: Personal communication.

5. Zittoun J, Tonelli AP, Marquet J et al. Pharmacokinetic comparison of leucovorin and levoleucovorin. Eur J Clin Pharmacol. 1993; 44:569-73. [PubMed 8405015]

6. Schwartz S, Borner K, Müller 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; 12:1299-308. [PubMed 18055849]

7. Patterson DM, Lee SM. Glucarpidase following high-dose methotrexate: update on development. Expert Opin Biol Ther. 2010; 10:105-11. [PubMed 19925307]

8. Phillips M, Smith W, Balan G et al. Pharmacokinetics of glucarpidase in subjects with normal and impaired renal function. J Clin Pharmacol. 2008; 48:279-84. [PubMed 18192538]

9. 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; 28:3979-86. [PubMed 20679598]

10. Anon. Glucarpidase (Voraxaze) for methotrexate toxicity. Med Lett Drugs Ther. 2012; 54:19-20. [PubMed 22382581]

11. Buchen S, Ngampolo D, Melton RG et al. Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer. 2005; 92:480-7. [PubMed 15668713]

12. Tuffaha HW, Al Omar S. Glucarpidase rescue in a patient with high-dose methotrexate-induced nephrotoxicity. J Oncol Pharm Pract. 2011; 17:136-40. [PubMed 19833686]

13. 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; 15:2125-34. [PubMed 9164227]

14. Bedford Laboratories. Methotrexate injection and for injection prescribing information. Bedford, OH; 2012 Apr.

15. Wall SM, Johansen MJ, Molony DA et al. Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis. 1996; 28:846-54. [IDIS 377816] [PubMed 8957036]

16. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website (http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm). Accessed 2012 Sep 14.

17. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 125327Orig1s000: Summary review. From FDA website. 2012 Jan 12.

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