VORAXAZE

Antidotes, Systemic
Cytoprotectant Agents

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.

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.[48304]
 
Intravenous injection:
Flush the intravenous line then inject as a bolus injection over 5 minutes. Flush the intravenous line after glucarpidase administration.[48304]

flushing / Rapid / 0-1.0
anaphylactic shock / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

antibody formation / Delayed / 21.0-21.0
hypotension / Rapid / 1.0-1.0
hypertension / Early / 0-1.0
blurred vision / Early / 0-1.0
infusion-related reactions / Rapid / Incidence not known

paresthesias / Delayed / 2.0-2.0
nausea / Early / 2.0-2.0
vomiting / Early / 2.0-2.0
throat irritation / Early / 0-1.0
headache / Early / 1.0-1.0
rash / Early / 0-1.0
diarrhea / Early / 0-1.0
tremor / Early / 0-1.0

VORAXAZE

Rx

IV carboxypeptidase enzyme that converts methotrexate to inactive metabolites
Used for toxic methotrexate concentrations in patients with delayed clearance due to impaired renal function
Not for use in patients with expected methotrexate clearanc

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.[48304]

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.[48304]

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

No dosage adjustment is necessary.

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.

VORAXAZE Intravenous Inj Pwd F/Sol: 1000IU

50 units/kg/dose IV.

50 units/kg/dose IV.

50 units/kg/dose IV.

50 units/kg/dose IV.

50 units/kg/dose IV.

Safety and efficacy have not been established.

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

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.

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.[48304]

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.