Glucarpidase is an intravenous carboxypeptidase enzyme approved to reduce toxic plasma methotrexate concentrations (greater than 1 micromol/L) in adults and pediatric patients with delayed methotrexate clearance (greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function. The drug is not indicated for use in patients who exhibit the expected clearance of methotrexate or in patients with normal or mildly impaired renal function. The likelihood of achieving a plasma methotrexate concentration of 1 micromol/L or less 15 minutes after glucarpidase receipt and maintained for up to 8 days appears to be correlated with the methotrexate concentration before glucarpidase receipt. For example, the endpoint was reached in 77% of patients (n = 13) with a baseline methotrexate concentration greater than 1 but less than 50 micromol/L as compared with 0% of patients (n = 9) with a higher baseline plasma concentration. However, all patients with a baseline methotrexate concentration greater than 50 micromol/L had more than a 95% rapid reduction in methotrexate concentration that was maintained up to 8 days after glucarpidase receipt.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard if the solution is not clear, colorless, and free of particulate matter.
Intravenous Administration
Reconstitution:
-Add 1 mL of 0.9% Sodium Chloride Injection, USP to the glucarpidase vial.
-Roll and tilt the vial gently to mix; do not shake.
-Store the reconstituted solution at 36 to 46 degrees F (2 to 8 degrees C) for up to 4 hours. Discard any unused product; no preservative is present.
Intravenous injection:
-Flush the intravenous line then inject as a bolus injection over 5 minutes. Flush the intravenous line after glucarpidase administration.
Of 290 glucarpidase recipients, flushing or a hot, burning sensation was noted in 2% of patients; the event was of Grade 3 severity in less than 1% of patients. Paresthesias were noted in 2% of patients, hypotension and headache were each noted in 1% of patients, and rash, throat irritation or tightness, hypertension, hypersensitivity, and serious allergic reactions were each noted in less than 1% of patients. Serious allergic reactions such as anaphylactic shock or anaphylactoid reactions may occur. Advise patients to immediately report any signs and symptoms of infusion-related reactions such as fever, chills, flushing, feeling hot, rash, hives, itching, throat tightness or breathing problems, tingling, numbness, or headache.
Of 290 glucarpidase recipients, 2% had nausea or vomiting, and less than 1% had diarrhea.
Of 290 glucarpidase recipients, less than 1% had blurred vision or tremor.
Of 121 patients, 21% had antibody formation against glucarpidase after glucarpidase receipt. Nineteen of the 25 patients who developed anti-glucarpidase antibodies had received a single glucarpidase dose, and 6 of the patients had received 2 doses. Neutralizing antibodies were detected in 11 of the 25 patients who tested positive for anti-glucarpidase binding antibodies.
Methotrexate concentrations within 48 hours of glucarpidase administration can only be reliably measured by a chromatographic method. Administration of glucarpidase causes methotrexate to be broken down into inactive metabolites including 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA), which interferes with the measurement of methotrexate concentration using immunoassays. The half-life of DAMPA is approximately 9 hours, so measurement of methotrexate using immunoassays is unreliable for samples collected within 48 hours of glucarpidase administration. If an immunoassay is used to determine methotrexate concentrations within 48 hours of glucarpidase receipt, an overestimation of the methotrexate concentration will occur.
No adequate and well-controlled studies have been conducted regarding the use of glucarpidase during pregnancy. It is unknown if the drug is associated with an increased risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. However, glucarpidase is administered in combination with methotrexate, which can cause embryo-fetal harm. Only administer glucarpidase to a pregnant woman if clearly needed.
Excretion of glucarpidase in human milk is unknown. The manufacturer recommends caution if the drug is administered to a woman who is breast-feeding a child because many drugs are excreted in human milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of methotrexate toxicity (methotrexate plasma concentration greater than 1 micromole/liter) in patients with delayed methotrexate clearance due to impaired renal function:
NOTE: Glucarpidase is not indicated for use in patients who exhibit the expected clearance of methotrexate defined as plasma methotrexate concentrations within 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered.
NOTE: Glucarpidase is not indicated for use in patients with normal or mildly impaired renal function because of the potential risk of subtherapeutic exposure to methotrexate.
Intravenous dosage:
Adults: 50 units/kg as a single IV bolus over 5 minutes. After the bolus injection, monitor methotrexate blood concentrations using a chromatographic method and continue intravenous hydration and urinary alkalinization as indicated. In patients requiring treatment with leucovorin, administer leucovorin at least 2 hours before or 2 hours after the glucarpidase dose. Leucovorin receipt is needed until the methotrexate concentration has been maintained below the leucovorin rescue threshold for a minimum of 3 days.
Infants, Children, and Adolescents: 50 units/kg as a single IV bolus over 5 minutes. After the bolus injection, monitor methotrexate blood concentrations using a chromatographic method and continue intravenous hydration and urinary alkalinization as indicated. In patients requiring treatment with leucovorin, administer leucovorin at least 2 hours before or 2 hours after the glucarpidase dose. Leucovorin receipt is needed until the methotrexate concentration has been maintained below the leucovorin rescue threshold for a minimum of 3 days.
Maximum Dosage Limits:
-Adults
50 units/kg/dose IV.
-Geriatric
50 units/kg/dose IV.
-Adolescents
50 units/kg/dose IV.
-Children
50 units/kg/dose IV.
-Infants
50 units/kg/dose IV.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
No dosage adjustment is necessary.
*non-FDA-approved indication
Leucovorin: (Major) Continue to administer leucovorin after glucarpidase, but do not administer leucovorin within 2 hours before or after a glucarpidase dose because leucovorin is a substrate for glucarpidase. For example, intravenous administration of 50 Units/kg glucarpidase 2 hours before leucovorin reduced (6S)-leucovorin AUC0-3h by 33% and Cmax by 52% and also reduced its active metabolite, (6S)-5-methyltetrahydrofolate, AUC0-3h by 92% and Cmax by 93%. For the first 48 hours after glucarpidase administration, administer the same leucovorin dose as given before 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. Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days; use of a chromatographic method to determine methotrextae concentrations is needed for the first 48 hours after glucarpidase receipt. Also, continue hydration and alkalinization of the urine as indicated. Levoleucovorin is the l-isomer of leucovorin and a similar interaction is expected.
Levoleucovorin: (Major) Continue to administer leucovorin after glucarpidase, but do not administer leucovorin within 2 hours before or after a glucarpidase dose because leucovorin is a substrate for glucarpidase. For example, intravenous administration of 50 Units/kg glucarpidase 2 hours before leucovorin reduced (6S)-leucovorin AUC0-3h by 33% and Cmax by 52% and also reduced its active metabolite, (6S)-5-methyltetrahydrofolate, AUC0-3h by 92% and Cmax by 93%. For the first 48 hours after glucarpidase administration, administer the same leucovorin dose as given before 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. Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days; use of a chromatographic method to determine methotrextae concentrations is needed for the first 48 hours after glucarpidase receipt. Also, continue hydration and alkalinization of the urine as indicated. Levoleucovorin is the l-isomer of leucovorin and a similar interaction is expected.
Pemetrexed: (Moderate) Potential exogenous substrates of glucarpidase include reduced folates and folate antimetabolites. Thus, administration of pemetrexed with glucarpidase may be inadvisable because reduced concentrations of pemetrexed may occur.
Pralatrexate: (Moderate) Potential exogenous substrates of glucarpidase include reduced folates and folate antimetabolites. Thus, administration of pralatrexate with glucarpidase may be inadvisable because reduced concentrations of pralatrexate may occur.
Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from methotrexate and, thus, provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment. As a result of its enzymatic action, glucarpidase converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate.
Glucarpidase is administered intravenously. After receipt of 50 units/kg IV over 5 minutes to healthy patients, the mean systemic clearance was 7.5 mL/minute. Serum glucarpidase activity levels declined with a mean elimination half-life of 5.6 hours. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for a longer half-life of 9 hours. After receipt of glucarpidase 50 units/kg to 22 patients with methotrexate toxicity, the methotrexate concentration measured by a chromatographic method was reduced by at least 97% within 15 minutes in everyone and was maintained at a more than 95% reduction up to 8 days in 20 of the patients.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Intravenous Route
Glucarpidase distribution appears to be restricted to plasma volume. After administration of 50 units/kg IV to healthy patients, the mean volume of distribution was 3.6 L. The mean Cmax for serum glucarpidase activity levels was 3.3 microgram/mL, and the mean systemic exposure was 23.3 microgram hour/mL.
-Special Populations
Renal Impairment
After receipt of 50 units/kg IV glucarpidase in 4 patients with a CrCl less than 30 mL/min in the absence of methotrexate, the mean pharmacokinetic parameters of glucarpidase were similar to those observed in patients with normal renal function with the exception of a longer half-life of serum glucarpidase activity levels: 8.2 hours as compared with 5.6 hours.