AHFS Class:

• Chemotherapy antidotes/protectants 91:04.12

Generic Name(s):

• Glucarpidase

Glucarpidase (also known as carboxypeptidase G₂ [CPDG₂]) is a recombinant bacterial enzyme that is used as an antidote for methotrexate toxicity.1,7,17

Methotrexate Toxicity

Glucarpidase is used as an adjunct to leucovorin rescue1,3,4,6,9,10,11 for the treatment of toxic plasma methotrexate concentrations (exceeding 0.454 mcg/mL [1 µmol/L]) in patients with delayed methotrexate clearance due to renal impairment.1,10 Glucarpidase is designated an orphan drug by the US Food and Drug Administration (FDA) for this use.16 Because of the potential for subtherapeutic concentrations of methotrexate, glucarpidase should not be used 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

Treatment of methotrexate toxicity traditionally has included leucovorin rescue and supportive measures (IV hydration, urinary alkalinization).2,3,4,12 However, leucovorin rescue alone does not reduce systemic (i.e., extracellular) methotrexate concentrations4 and does not completely reverse toxicity when methotrexate concentrations are sustained above 10 µmol/L.11,12,13 Extracorporeal procedures (e.g., hemodialysis) have been used, although such procedures are invasive, have variable efficacy in removing systemic methotrexate, and often are associated with rebound methotrexate concentrations.3,4,6,7,11,12,13,14,15,17 Because methotrexate is excreted principally by the kidneys, high systemic concentrations of the drug (e.g., following high-dose methotrexate therapy) may cause acute renal impairment in some patients (i.e., by pH-dependent precipitation of methotrexate and its metabolites in renal tubules or by causing direct injury to the renal tubular epithelium4,7,12,13 ); this causes further delay in methotrexate clearance, resulting in subsequent severe systemic toxicities (e.g., myelosuppression, mucositis, hepatotoxicity).3,4,7,8,10,11,12,13 Glucarpidase converts circulating methotrexate to inactive metabolites that are primarily eliminated hepatically, thus providing an alternative, nonrenal route for methotrexate elimination in patients with renal impairment.1,7,8,10,12,13

The current indication for glucarpidase is based principally on data from a subset of 22 treatment-evaluable patients enrolled in a single-arm, open-label study that involved 184 patients with markedly delayed methotrexate clearance (defined as more than 2 standard deviations greater than the mean excretion curve for methotrexate) and toxic plasma methotrexate concentrations (exceeding 0.454 mcg/mL [1 µmol/L]) due to renal impairment.1,4 The primary measure of efficacy was the proportion of patients who achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration (defined as an attainment of plasma methotrexate concentration of 0.454 mcg/mL [1 µmol/L] or less within 15 minutes of glucarpidase administration that was sustained for up to 8 days).1 The median age of patients was 15.5 years (range: 5-84 years); the most common types of malignancies were osteogenic sarcoma (50%) and leukemia or lymphoma (45%).1 In this study, all patients received glucarpidase 50 units/kg by IV injection over 5 minutes; a second dose of glucarpidase was administered 48 hours after the initial dose in patients with pre-glucarpidase plasma methotrexate concentrations exceeding 45.4 mcg/mL (100 µmol/L).1 Patients continued to receive IV hydration, urinary alkalinization, and leucovorin rescue.1 Following administration of the first dose of glucarpidase, 10 of the 22 patients (45%) achieved RSCIR.1 Of the remaining 12 patients who failed to achieve RSCIR, 5 patients (23%) achieved a transient plasma methotrexate concentration of 0.454 mcg/mL (1 µmol/L) or less; in these 5 patients, the median increase in plasma methotrexate concentration from nadir was 0.636 mcg/mL (1.4 µmol/L).1 Methotrexate concentrations were reduced by at least 97% within 15 minutes in all 22 patients and were maintained at a greater than 95% reduction for up to 8 days in 20 of the 22 patients.1 Based on results of exploratory analyses, patients with lower pre-glucarpidase plasma methotrexate concentrations were more likely to achieve RSCIR compared with patients with higher pre-glucarpidase plasma methotrexate concentrations; RSCIR was achieved in 10 of 13 patients (77%) with pre-glucarpidase methotrexate concentrations of 22.7 mcg/mL (50 µmol/L) or less and in 0 of 9 patients (0%) with pre-glucarpidase methotrexate concentrations exceeding 22.7 mcg/mL (50 µmol/L).1 Despite this observation, all 9 patients with pre-glucarpidase plasma methotrexate concentrations exceeding 22.7 mcg/mL (50 µmol/L) were able to achieve a greater than 95% reduction in plasma methotrexate concentration for up to 8 days following glucarpidase administration.1

There currently are no controlled trials comparing efficacy of glucarpidase plus supportive care with supportive care alone in patients with toxic plasma methotrexate concentrations due to renal impairment.1 Therefore, effects of glucarpidase on survival or on the risk of death associated with methotrexate toxicity have not been established.1 Glucarpidase did not prevent fatal methotrexate toxicity in 3% of patients receiving the drug in clinical safety studies.1

Administration of a second dose of glucarpidase has not been shown to provide additional benefit.1,9,11,13 In the pivotal single-arm, open-label study in which patients with pre-glucarpidase methotrexate concentrations exceeding 45.4 mcg/mL (100 µmol/L) received a second dose of glucarpidase (50 units/kg administered 48 hours after the first dose), RSCIR was not achieved in any patient with pre-second-dose methotrexate concentrations exceeding 0.454 mcg/mL (1 µmol/L).1 In other studies, administration of a second dose of glucarpidase did not result in further reduction in plasma methotrexate concentrations.9,11,13 (See Methotrexate Toxicity under Dosage and Administration: Dosage.) This lack of efficacy following the second dose may be due to the presence of high concentrations of the methotrexate inactive metabolite 4-deoxy-4-amino-N¹⁰-methylpteroic acid (DAMPA), which inhibits hydrolysis of methotrexate, and/or the presence of antiglucarpidase antibodies.6,13,17 (See Antibody Formation under Cautions: Warnings/Precautions.)

General

Glucarpidase should be used only in patients who exhibit delayed methotrexate clearance (plasma methotrexate concentrations exceeding 2 standard deviations above 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 serum creatinine concentration and/or oliguria) and urgent intervention are essential to prevent development of severe methotrexate-induced toxicities.4,9

Glucarpidase should be used 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 the manufacturer of glucarpidase states that levoleucovorin may be substituted for leucovorin.4

Reconstitution and Administration

Glucarpidase is administered by direct IV injection over 5 minutes.1 The IV line should be flushed before and after administration of the drug.1

Prior to administration, glucarpidase powder for injection should be reconstituted by adding 1 mL of sterile 0.9% sodium chloride for injection to the vial labeled as containing 1000 units of glucarpidase.1 The contents should be mixed by gently rolling and tilting the vial; the vial should not be shaken.1 The reconstituted solution should be inspected visually and should be discarded if the solution is not clear, colorless, and free of particulate matter.1 Reconstituted glucarpidase solution may be used immediately or stored at 2-8°C for up to 4 hours; unused portions of the solution should be discarded.1

Unreconstituted glucarpidase powder for injection should be stored at 2-8°C and should not be frozen.1

Dosage

Dosage of glucarpidase is expressed in terms of units; a unit of glucarpidase activity is defined as the quantity of enzyme needed to catalyze the hydrolysis of 0.454 mcg/mL (1 µmol/L) of methotrexate per minute at 37°C.1,17

Methotrexate Toxicity

The recommended dosage of glucarpidase for the treatment of toxic plasma methotrexate concentrations (exceeding 0.454 mcg/mL [1 µmol/L]) in adults and pediatric patients with delayed methotrexate clearance due to renal impairment is a single IV injection of 50 units/kg.1

Following administration of glucarpidase, rescue therapy with leucovorin (or levoleucovorin4 ) should be continued.1,4 During the first 48 hours after glucarpidase administration, leucovorin (or levoleucovorin) should be administered at the same dosage administered prior to glucarpidase administration; beyond 48 hours, dosage should be based on the measured methotrexate concentration.1,4 (See Drug Interactions: Reduced Folates and also see Leucovorin Calcium 92:12.) Therapy with leucovorin (or levoleucovorin) should be continued until the methotrexate concentration has been maintained below the threshold for such treatment for at least 3 days.1,4

Because of the lack of efficacy observed with the second dose, use of more than one dose of glucarpidase is not recommended.1,4 (See Uses: Methotrexate Toxicity.)

Special Populations

There are no special population dosage recommendations at this time.1 (See Specific Populations under Cautions: Warnings/Precautions.)

Contraindications

The manufacturer states there are no known contraindications to the use of glucarpidase.1

Warnings/Precautions

Sensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, may occur.1 In clinical studies, serious hypersensitivity reactions occurred in less than 1% of patients receiving glucarpidase.1

Monitoring of Methotrexate Concentrations and Assay Interference

Glucarpidase converts methotrexate to 4-deoxy-4-amino-N¹⁰-methylpteroic acid (DAMPA), an inactive metabolite that interferes with immunoassays and causes an overestimation of plasma methotrexate concentrations.1 Because of the long half-life of DAMPA (approximately 9 hours), plasma methotrexate concentrations measured by immunoassay within 48 hours following glucarpidase administration are unreliable.1 Therefore, the manufacturer recommends using a chromatographic method to obtain reliable measurements of plasma methotrexate concentrations within 48 hours following glucarpidase administration.1

Continuation of Adjunctive Therapy

Following administration of glucarpidase, rescue therapy with leucovorin (or levoleucovorin4 ) should be continued until the methotrexate concentration has been maintained below the threshold for such treatment for at least 3 days.1,4 (See Methotrexate Toxicity under Dosage and Administration: Dosage and also see Drug Interactions: Reduced Folates.) IV hydration and urinary alkalinization should be continued as indicated.1

Antibody Formation

Antiglucarpidase antibodies have been detected in 16 of 96 (17%) patients receiving the drug in clinical studies.1,17 Antiglucarpidase antibodies were detected between 7 days to 7 months following exposure to glucarpidase.17 The incidence of antiglucarpidase antibody formation appeared to be similar in patients receiving either 1 or 2 doses of glucarpidase (12 of 78 patients [15%] or 4 of 18 patients [22%], respectively).17

The development of antiglucarpidase antibodies is 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 (See Users Guide.)

Lactation

It is not known whether glucarpidase is distributed into human milk.1 Caution is advised when glucarpidase is administered in nursing women.1

Pediatric Use

Efficacy of glucarpidase as adjunctive therapy for the treatment of toxic plasma methotrexate concentrations (exceeding 0.454 mcg/mL [1 µmol/L]) in pediatric patients with delayed methotrexate clearance due to renal impairment has been established in one study that included 12 patients 5-16 years of age.1 In this study, 3 of the 6 pediatric patients with pre-glucarpidase plasma methotrexate concentrations of 0.454-22.7 mcg/mL (1-50 µmol/L) achieved rapid and sustained clinically important reductions (RSCIR) in plasma methotrexate concentrations, while none of the remaining 6 patients with pre-glucarpidase plasma methotrexate concentrations exceeding 22.7 mcg/mL (50 µmol/L) achieved RSCIR.1

In an analysis of pooled clinical safety data in 147 patients 1 month to 17 years of age, no overall difference in safety was observed between pediatric and adult patients.1

Geriatric Use

In clinical studies, 15% of patients were 65 years of age or older and 4% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between geriatric patients and younger adults.1

Hepatic Impairment

Glucarpidase has not been studied in patients with hepatic impairment.1

Renal Impairment

Following IV administration of glucarpidase 50 units/kg in 4 patients with severe renal impairment (creatinine clearance less than 30 mL/minute), mean pharmacokinetic parameters of glucarpidase (as assessed by enzymatic assay) were similar to those observed in healthy individuals except for a prolonged half-life (8.2 hours compared with 5.6 hours in healthy individuals).1,8

Common Adverse Effects

Adverse effects reported in 1% or more of patients receiving glucarpidase include paresthesia,1,2 flushing,1,2 nausea and/or vomiting,1 hypotension,1 and headache.1,2

Reduced Folates

Leucovorin is a substrate of glucarpidase.1 In patients receiving high-dose methotrexate therapy with leucovorin rescue, administration of glucarpidase 2 hours before a leucovorin dose reduced peak plasma concentrations and area under the plasma concentration-time curve (AUC) of leucovorin by 52 and 33%, respectively, and of its active metabolite (5-methyltetrahydrofolate) by 93 and 92%, respectively.1 Similar effects would be expected with levoleucovorin.4 Therefore, leucovorin or levoleucovorin should not be administered within 2 hours before or after glucarpidase administration.1,4 During the first 48 hours after glucarpidase administration, dosage adjustment of the continuing leucovorin or levoleucovorin regimen is not necessary since dosage is based on the patient's methotrexate concentration prior to glucarpidase administration.1,4 (See Methotrexate Toxicity under Dosage and Administration: Dosage.)

Other Substrates of Glucarpidase

Concomitant use with other drugs that are substrates of glucarpidase (including folic acid antagonists [e.g., pyrimethamine, trimethoprim]) may result in decreased peak plasma concentrations and AUC of the glucarpidase substrate.1

Description

Glucarpidase (also known as carboxypeptidase G₂ [CPDG₂]) is a bacterial enzyme produced by recombinant DNA technology.1,7,17 Glucarpidase was isolated from the Pseudomonas strain RS-16 and cloned, purified, and sequenced in genetically modified Escherichia coli .7,17 Glucarpidase rapidly hydrolyzes the carboxyl-terminal glutamate residue of folic acid, folic acid derivatives, and classic antifolates (e.g., methotrexate, leucovorin); the drug converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N¹⁰-methylpteroic acid (DAMPA) and glutamate, which are metabolized principally by the liver.1,7,17 Following administration of glucarpidase (50 units/kg) in the pivotal single-arm, open-label study, plasma methotrexate concentrations (measured by chromatographic method) were reduced by at least 97% within 15 minutes in all 22 treatment-evaluable patients and were maintained at a greater than 95% reduction for up to 8 days in 20 of the 22 patients.1

Because of the large molecular size of glucarpidase, the drug is distributed primarily in the intravascular (i.e., extracellular) compartment and does not directly reduce intracellular concentrations (or interfere with intracellular antineoplastic effects) of methotrexate;4,7,11 therefore, rescue therapy with leucovorin must be continued following administration of glucarpidase.6,10,11 (See Methotrexate Toxicity under Dosage and Administration: Dosage and also see Drug Interactions: Reduced Folates.) Reductions in plasma methotrexate concentrations produced by glucarpidase are expected to cause redistribution (i.e., efflux) of intracellular methotrexate back into plasma, resulting in a rise in plasma methotrexate concentrations;11,13 as such, small rebound increases in plasma methotrexate concentrations have been observed in patients receiving glucarpidase in clinical studies.4,6,9,13

The mean elimination half-life of glucarpidase is 5.6 hours (as assessed by enzymatic assay) or 9 hours (as assessed by enzyme-linked immunosorbent assay [ELISA]).1,17

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, including fever, chills, flushing, feeling hot, rash, hives, itching, throat tightness or breathing difficulty, tingling, numbness, or 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.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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][PubMedCentral]

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][PubMedCentral]

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][PubMedCentral]

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. [PubMed 8957036]

16. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website ([Web]). Accessed 2012 Sep 14. [Web]

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