VORAXAZE can decrease leucovorin concentration, which may decrease the effect of leucovorin rescue unless leucovorin is dosed as recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
VORAXAZE may also reduce the concentrations other folate analogs or folate analog metabolic inhibitors.
DAMPA (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, VORAXAZE may interfere with the measurement of methotrexate concentrations for approximately 48 hours following a VORAXAZE dose [see Warnings and Precautions (5.2)].
When measuring methotrexate concentration following a VORAXAZE dose, a chromatographic method is preferred over an immunoassay.
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.
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.
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.
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.
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)].
Glucarpidase is a carboxypeptidase produced by recombinant DNA technology in genetically modified Escherichia coli. Glucarpidase is a 390-amino acid homodimer protein with a molecular weight of 83 kDa. Each potency Unit corresponds to the enzymatic cleavage of 1 µmol/L of methotrexate per minute at 37°C.
VORAXAZE (glucarpidase) for injection, for intravenous use is supplied as a sterile, preservative-free, white lyophilized powder in single-dose vials. Each vial contains 1,000 Units of glucarpidase, lactose monohydrate (10 mg), Tris-HCl (0.6 mg) and zinc acetate dihydrate (0.002 mg).
Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl- terminal glutamate residue from folic acid and classical antifolates such as methotrexate.
Glucarpidase converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10 — methylpteroic acid (DAMPA) and glutamate. VORAXAZE provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.
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)].
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.
The mean volume of distribution (Vd ) was 3.6 L.
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.
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)].
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.
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