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.
The efficacy of VORAXAZE was evaluated in a subset of 22 patients enrolled in Study 1 (NCT00001298), a single-arm, open-label study in patients who had markedly delayed methotrexate clearance (defined as more than 2 standard deviations greater than the mean excretion curve for methotrexate) due to impaired renal function. All patients received VORAXAZE 50 Units/kg as an intravenous injection over 5 minutes; those patients with pre-VORAXAZE methotrexate concentration >100 μmol/L were to receive a second dose of VORAXAZE 48 hours after the first dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin and that leucovorin administration be adjusted to ensure that it was not administered within 2 hours before or after VORAXAZE. These 22 patients had a pre-VORAXAZE methotrexate concentration >1 μmol/L and both pre- and post-treatment plasma samples available for determination of methotrexate concentration by a chromatographic method. The main outcome measure 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 ≤1 μmol/L at 15 minutes that was sustained for up to 8 days following the initial injection.
The median age was 15.5 years (5 to 84 years); 59% were male; and the most common underlying cancers were osteogenic sarcoma (50%) and leukemia or lymphoma (45%).
Ten of the 22 patients achieved a RSCIR [45% (95% CI: 27%, 65%)]. Of the 12 patients who failed to achieve RSCIR, 5 patients (23%) attained a transient plasma methotrexate concentration ≤1 μmol/L. In these 5 patients, the median increase of plasma methotrexate concentration from their nadir was 1.4 μmol/L (0.3 to 2.5 μmol/L).
Table 2 summarizes the results of RSCIR and exploratory analyses following the first dose of VORAXAZE. An exploratory analysis in subgroups determined by pre-VORAXAZE methotrexate concentration suggests that the likelihood of attaining a RSCIR following the first VORAXAZE dose correlates with the pre-VORAXAZE methotrexate concentration. An additional exploratory analysis showed that all 9 patients with pre-VORAXAZE methotrexate concentration >50 μmol/L achieved >95% reduction in methotrexate concentration for up to 8 days following the first VORAXAZE dose although none of them achieved a RSCIR.
| RSCIR: rapid and sustained clinically important reduction in methotrexate concentration. | |||
Pre-VORAXAZE Methotrexate Concentration (μmol/L) | Patients n | Patients Achieving RSCIR n (%) | Patients with >95% Rapid Reduction in Methotrexate Concentration and Maintained up to 8 Days n (%) |
| >1 | 22 | 10 (45%) | 20 (91%) |
| >1 to ≤50 | 13 | 10 (77%) | 11 (85%) |
| >50 to ≤100 | 2 | 0 | 2 (100%) |
| >100 | 7 | 0 | 7 (100%) |
Six of the 7 patients with pre-first dose VORAXAZE methotrexate concentration >100 μmol/L received a second VORAXAZE dose of 50 Units/kg administered 48 hours after the first dose. Among them, none of the 4 patients with pre-second dose VORAXAZE methotrexate concentration >1 μmol/L achieved a RSCIR. The remaining 2 patients achieved a RSCIR, but their pre-second dose VORAXAZE methotrexate concentration were already ≤1 μmol/L.
There are no controlled trials comparing VORAXAZE and supportive care to supportive care alone in patients with toxic plasma methotrexate concentration due to impaired renal function; therefore, there are no data regarding the effect of VORAXAZE on survival or toxic deaths due to methotrexate. VORAXAZE did not prevent fatal methotrexate toxicity in 3% of patients in the safety population.
- The recommended dosage of VORAXAZE is 50 Units per kilogram as a single intravenous injection over 5 minutes. ().
2.1 Recommended DosageThe 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.
- For the first 48 hours after the dose of VORAXAZE, administer the same leucovorin dose given prior to VORAXAZE. Administer leucovorin at least 2 hours before or 2 hours after the dose of VORAXAZE. ()
2.2 Concomitant Use with Leucovorin RescueWhen administering VORAXAZE concomitantly with leucovorin, administer leucovorin at least 2 hours before or 2 hours after the VORAXAZE dose
[see Drug Interactions ].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 ]. - Beyond 48 hours after the dose of VORAXAZE, administer leucovorin based on the measured methotrexate concentration. Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. ()
2.2 Concomitant Use with Leucovorin RescueWhen administering VORAXAZE concomitantly with leucovorin, administer leucovorin at least 2 hours before or 2 hours after the VORAXAZE dose
[see Drug Interactions ].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 ].
For Injection: 1,000 Units as a white lyophilized powder in a single-dose vial for reconstitution.
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.
None.
- Serious Hypersensitivity Reactions:Serious hypersensitivity reactions occurred. ()
5.1 Serious Hypersensitivity ReactionsSerious hypersensitivity reactions occurred in less than 1% of patients [
see Adverse Reactions]. - Monitoring Methotrexate Concentration:Measure methotrexate concentrations within 48 hours following VORAXAZE administration using a chromatographic method; immunoassays are unreliable for samples collected within 48 hours following VORAXAZE administration. ()
5.2 Interference with Immunoassay Measurements of MethotrexateDAMPA (4-deoxy-4-amino-N10- 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].When measuring methotrexate concentration following a VORAXAZE dose, a chromatographic method is preferred over an immunoassay.