Glucarpidase

Glucarpidase is used for: Methotrexate Toxicity

Methotrexate Toxicity Indicated for treatment of toxic plasma methotrexate concentrations (>1 micromole/L) in patients with delayed methotrexate clearance due to impaired renal function 50 units/kg as a single IV injection over 5 minutes

Methotrexate Toxicity Indicated for treatment of toxic plasma methotrexate concentrations (>1 micromole/L) in patients with delaye methotrexate clearance due to impaired renal function 50 units/kg as a single IV injection over 5 minutes Clinical trials in children Effectiveness in pediatric patients was established in 22 patients in the efficacy dataset; 12 were pediatric patients with ages ranging from 5-16 years The pooled clinical safety database included data for 147 patients from 1 month up to 17 years; no overall differences in safety were observed between pediatrics and adult patients

Renal Impairment Renal impairment: No dose adjustment is recommended

IV Preparation Reconstitute the lyophilized powder in the vial with 1 mL of sterile saline for injection, USP Do not shake Roll and tilt the vial gently to mix Inspect the vial and discard if the solution is not clear, colorless, and free of particulate matter Use reconstituted solution immediately or store under refrigeration at 36-46°F (2-8°C) for up to 4 hr if not used immediately Contains no preservative and is supplied as a single-use vial Discard any unused product IV Administration Administer IV as a bolus over 5 minutes Flush IV line before and after administration

Serious allergic reactions (occurred in <1% of patients) Leucovorin is a substrate for glucarpidase; other potential substrates of glucarpidase include reduced folates and folate antimetabolites (eg, folic acid, L-methylfolate, pemetrexed, pralatrexate, trimethoprim, pentamidine) Immunogenicity: 17% (n=16) of patients developed anti-glucarpidase antibodies; 12 of the 16 patients had received 1 dose and the other 4 patients had received 2 doses Monitoring methotrexate serum concentrations Methotrexate concentrations within 48 hours following administration of glucarpidase can only be reliably measured by a chromatographic method DAMPA (4-deoxy-4-amino-N10-methylpteroic acid) is an inactive metabolite of methotrexate resulting from treatment with glucarpidase that interferes with the measurement of methotrexate concentration using immunoassays (ie, immunoassays overestimates the methotrexate concentration) Due to the long half-life of DAMPA (~9 hours), measurement of methotrexate using immunoassays is unreliable for samples collected within 48 hours following glucarpidase administration Continuation and timing of leucovorin rescue Leucovorin is a substrate for glucarpidase Do not administer leucovorin within 2 hr before or after glucarpidase No dose adjustment is recommended for the continuing leucovorin regimen because the leucovorin dose is based on the patient’s pre-glucarpidase methotrexate concentration For the first 48 hours after glucarpidase, administer the same leucovorin dose as given prior to glucarpidase Beyond 48 hours after glucarpidase, administer leucovorin based on the measured methotrexate concentration Do not discontinue therapy with leucovorin based on the determination of a single methotrexate concentration below the leucovorin treatment threshold Therapy with leucovorin should be continued until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days Continue hydration and alkalinization of the urine as indicated

Pregnancy There are no available data on use in pregnant women or animal reproduction studies to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes Therapy is administered in combination with methotrexate, which can cause embryo-fetal harm; refer to methotrexate prescribing information for additional information Lactation There are no data on presence of glucarpidase in human milk or effects on breastfed infant or on milk production Therapy administered in combination with methotrexate; refer to methotrexate prescribing information for additional information

Side effects of Glucarpidase : 1-10% Paresthesias (2%) Flushing (2%) Nausea/vomiting (2%) Headache (1%) Hypotension (1%) <1% Blurred vision Diarrhea Hypersensitivity Hypertension Rash Throat irritation/throat tightness Tremor Frequency Not Defined Antibody formation

Recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate Converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate Provides an alternate nonrenal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment