Glucarpidase has not been evaluated in animals for carcinogenic or mutagenic potential or for impairment of fertility.
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 |
|Patients n|| Patients Achieving |
| Patients with >95% Rapid Reduction in |
Methotrexate Concentration and
Maintained up to 8 Days
|>1||22||10 (45%)||20 (91%)|
|>1 to ≤50||13||10 (77%)||11 (85%)|
|>50 to ≤100||2||0||2 (100%)|
Lack of Efficacy with a Second Dose of VORAXAZE
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.
Deaths Attributable to Methotrexate Toxicity
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.
VORAXAZE (glucarpidase) for injection is supplied as a sterile, preservative-free white lyophilized powder in an individually packaged glass single-dose vial closed with a bromo butyl elastomeric stopper and blue flip-off seal.
1,000 Units of glucarpidase per vial (1 vial per carton) NDC 50633-210-11
Store VORAXAZE refrigerated at 36°F to 46°F (2°C to 8°C). Do not freeze. Do not use VORAXAZE after the expiration date on the vial.
Serious Hypersensitivity Reactions
Inform patients that hypersensitivity reactions, including potentially serious reactions, may occur following a dose of VORAXAZE and to immediately report any signs and symptoms of infusion reactions [see Warnings and Precautions (5.1)].
Inform patients of the importance of continued monitoring of plasma methotrexate concentration and renal function at the appropriate times after discharge from the hospital [see Warnings and Precautions (5.2)].
Manufactured and distributed by:
BTG International Inc.
West Conshohocken, PA 19428
U.S. license 1861
VORAXAZE® is a registered trademark of Protherics Medicines Development
Ltd. BTG and the BTG roundel logo are registered trademarks of BTG
Package Label — Principal Display Panel — VORAXAZE Vial
Package Label — Principal Display Panel — VORAXAZE Carton
| VORAXAZE |
glucarpidase injection, powder, for solution
|Labeler — BTG International Inc. (617382395)|
|Registrant — BTG International Inc. (617382395)|
Revised: 11/2022 BTG International Inc.
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