Voraxaze: Package Insert and Label Information (Page 2 of 2)

12.2 Pharmacodynamics

Following administration of VORAXAZE 50 Units/kg to patients in Study 1, methotrexate concentration measured by a chromatographic method was reduced by ≥ 97% within 15 minutes in all 22 treatment-evaluable patients and was maintained at a > 95% reduction up to 8 days in 20 of the 22 patients [see Clinical Studies (14)].

12.3 Pharmacokinetics

The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in 8 healthy subjects following VORAXAZE 50 Units/kg administered as an intravenous injection over 5 minutes. Serum glucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidase concentrations were measured by ELISA. The mean Cmax was 3.3 μg/mL and the mean area under the curve (AUC0-INF ) was 23.3 μg·h/mL. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for elimination half-life as described below.

Distribution

The mean volume of distribution (Vd ) was 3.6 L.

Elimination

Serum glucarpidase activity levels declined with a mean elimination half-life (t1/2 ) of 5.6 hours and serum total glucarpidase concentration declined with a mean elimination half-life of 9 hours. The mean systemic clearance (CL) was 7.5 mL/min.

Specific Populations

Patients with Renal Impairment

The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in 4 subjects with severe renal impairment (CLcr <30 mL/min). Following a dose of VORAXAZE of 50 Units/kg, the mean pharmacokinetic parameters were similar to those observed in healthy subjects except for a longer half-life of 8.2 hours in subjects with severe renal impairment as compared to 5.6 hours in healthy subjects using an enzymatic assay to measure serum glucarpidase activity levels.

Drug Interaction Studies

In patients with cancer receiving high-dose methotrexate (≥1 g/m2) and leucovorin rescue, a VORAXAZE dose of 50 Units/kg administered intravenously 2 hours before leucovorin, reduced (6S)-leucovorin AUC0-3h by 33% and Cmax by 52% and reduced its active metabolite (6S)-5-methyltetrahydrofolate AUC0-3h by 92% and Cmax by 93% [see Drug Interactions (7.1)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Glucarpidase has not been evaluated in animals for carcinogenic or mutagenic potential or for impairment of fertility.

14 CLINICAL STUDIES

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.

Table 2: Efficacy Results Following the First VORAXAZE Dose in Study 1
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%)

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

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.

17 PATIENT COUNSELING INFORMATION

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)].

Administration

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

International Ltd.

P21011D

Package Label — Principal Display Panel — VORAXAZE Vial

Package Label -- Principal Display Panel -- VORAXAZE Vial
(click image for full-size original)

Package Label — Principal Display Panel — VORAXAZE Carton

Package Label -- Principal Display Panel -- VORAXAZE Carton
(click image for full-size original)
VORAXAZE
glucarpidase injection, powder, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50633-210
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
GLUCARPIDASE (GLUCARPIDASE) GLUCARPIDASE 1000 [USP’U]
Inactive Ingredients
Ingredient Name Strength
LACTOSE MONOHYDRATE 10 mg
ZINC ACETATE 0.002 mg
TROMETHAMINE HYDROCHLORIDE 0.6 mg
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:50633-210-11 1 VIAL in 1 CARTON contains a VIAL
1 1 INJECTION, POWDER, FOR SOLUTION in 1 VIAL This package is contained within the CARTON (50633-210-11)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125327 04/01/2012
Labeler — BTG International Inc. (617382395)
Registrant — BTG International Inc. (617382395)

Revised: 11/2022 BTG International Inc.

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