Voraxaze
(glucarpidase)Dosage & Administration
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Voraxaze Prescribing Information
VORAXAZE is indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per liter) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function.
Limitations of Use:VORAXAZE is not recommended for use in patients who exhibit the expected clearance and expected plasma methotrexate concentration. Reducing plasma methotrexate concentration in these patients may result in subtherapeutic exposure to methotrexate [see Clinical Studies ( 14)] .
Recommended Dosage
The recommended dosage of VORAXAZE is 50 Units per kilogram (kg) as a single intravenous injection administered over 5 minutes. Flush intravenous line before and after administration.
Concomitant Use with Leucovorin Rescue
When administering VORAXAZE concomitantly with leucovorin, administer leucovorin at least 2 hours before or 2 hours after the VORAXAZE dose [see Drug Interactions ( 7.1)] .
For the first 48 hours after a dose of VORAXAZE:
- Administer the same leucovorin dosage given prior to the VORAXAZE dose.
Beyond 48 hours after a dose of VORAXAZE:
- Determine the leucovorin dosage based on the measured methotrexate concentration. Do not discontinue leucovorin based on the determination of a single methotrexate concentration below the leucovorin rescue threshold.
- Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin rescue threshold for a minimum of 3 days.
Continue intravenous hydration and urinary alkalinization as indicated.
When measuring methotrexate concentrations following a VORAXAZE dose, a chromatographic method is preferred over an immunoassay [see Warnings and Precautions ( 5.2)] .
Preparation
Reconstitute the contents of the vial with 1 mL of 0.9% Sodium Chloride Injection, USP.
Roll and tilt the vial gently to mix. Do not shake.
Inspect the vial and discard VORAXAZE if the solution is not clear, colorless, and free of particulate matter.
Use reconstituted VORAXAZE immediately or store under refrigeration at 36° to 46°F (2° to 8°C) for up to 4 hours if not used immediately. VORAXAZE contains no preservative and is supplied as a single-dose vial. Discard any unused product.
For Injection: 1,000 Units as a white lyophilized powder in a single-dose vial for reconstitution.
Pregnancy
Risk Summary
There are no available data on VORAXAZE 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.
VORAXAZE is administered in combination with methotrexate, which can cause embryo-fetal harm. Refer to methotrexate prescribing information for additional information.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Lactation
Risk Summary
There are no data on the presence of glucarpidase in human milk or its effects on the breastfed infant or on milk production.
VORAXAZE is administered in combination with methotrexate. Refer to methotrexate prescribing information for additional information.
Pediatric Use
The safety and effectiveness of VORAXAZE have been established in pediatric patients. Use of VORAXAZE for this indication is supported by evidence from a single-arm, open-label study in adult and pediatric patients 5 years of age and older with additional safety data in pediatric patients 1 to 17 years of age as described below.
Of the 22 patients in the efficacy dataset in Study 1, 12 were pediatric patients with ages ranging from 5 years to 16 years. Three of the 6 pediatric patients with a pre-VORAXAZE methotrexate concentration of 1 μmol/L to 50 μmol/L achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, while none of the 6 pediatric patients with a pre-VORAXAZE methotrexate concentration >50 μmol/L achieved a RSCIR [see Clinical Studies ( 14)] .
One-hundred forty-seven pediatric patients from 1 month to 17 years received VORAXAZE in Study 1 and Study 2 [see Adverse Reactions ( 6.1)] . No overall differences in safety were observed between these patients and adult patients.
Geriatric Use
Of the total number of 290 patients in clinical studies of VORAXAZE, 15% were 65 and over, while 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger adult patients.
Renal Impairment
A study of the pharmacokinetics of glucarpidase in the absence of methotrexate in 4 subjects with severe renal impairment (CLcr <30 mL/min) showed that the mean pharmacokinetic parameters were similar to those observed in healthy subjects.
On this basis, no dose adjustment of VORAXAZE is recommended for patients with renal impairment [see Clinical Pharmacology ( 12.3)].
None.
Serious Hypersensitivity Reactions
Serious hypersensitivity reactions occurred in less than 1% of patients [ see Adverse Reactions ( 6.1) ].
Interference with Immunoassay Measurements of Methotrexate
DAMPA (4-deoxy-4-amino-N 10- methylpteroic acid), an inactive metabolite of methotrexate formed following VORAXAZE administration, interferes with the measurement of methotrexate concentration using immunoassays. This interference results in an overestimation of the methotrexate concentration. Based on the half-life of DAMPA (about 9 hours), VORAXAZE may interfere with the measurement of methotrexate concentration for up to 48 hours following a VORAXAZE dose [see Clinical Pharmacology ( 12.1) ].
When measuring methotrexate concentration following a VORAXAZE dose, a chromatographic method is preferred over an immunoassay.