2.1    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.

2.2    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)] .

2.3    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.

5.1     Serious Hypersensitivity Reactions

Serious hypersensitivity reactions occurred in less than 1% of patients [ see Adverse Reactions ( 6.1) ].

5.2   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.

6.1     Clinical Trials Experience

Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of VORAXAZE cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

The evaluation of adverse reactions in patients who received VORAXAZE was confounded, because patients had toxic plasma methotrexate concentration due to prolonged methotrexate clearance, which is associated with myelosuppression, mucositis, acute hepatitis, and renal dysfunction and failure.

The safety of VORAXAZE is based on data from 290 patients who were enrolled in Study 1 or Study 2, two single-arm, open-label, multicenter studies conducted in patients who had markedly delayed methotrexate clearance due to impaired renal function. Patients with osteosarcoma were eligible for these studies if the plasma methotrexate concentration was >50 µmol/L at 24 hours, >5 µmol/L at 48 hours, or >2 standard deviations above the mean methotrexate elimination curve at least 12 hours after methotrexate administration; and there was a ≥2-fold increase in serum creatinine above baseline. All other patients were eligible for these studies if the plasma methotrexate concentration was >10 µmol/L more than 42 hours after the start of the methotrexate or the plasma methotrexate concentration was >2 standard deviations above the mean methotrexate excretion curve at least 12 hours following methotrexate; and the serum creatinine was >1.5 times the upper limit of normal (ULN) or the creatinine clearance (CLcr) was <60 mL/min at least 12 hours following methotrexate administration.

Safety data was available for 149 patients enrolled in Study 1. The protocol specified that patients with pre-VORAXAZE methotrexate concentration >100 μmol/L were to receive a second VORAXAZE dose 48 hours after the first dose; 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 a VORAXAZE dose. VORAXAZE-related adverse reactions were collected on a flow sheet with a daily log of adverse reactions characterized as “glucarpidase toxicity”. Additional safety information was collected from clinical records submitted by treating physicians. This safety information was abstracted and categorized using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3. One (n=106) or 2 (n= 30) doses of VORAXAZE were administered; the number of doses was not specified for 13 patients. Doses ranged from 18 Units/kg to 98 Units/kg, with a median dose of 49 Units/kg. The median age was 18 years (1 month to 85 years); 63% were male; and the underlying malignancies were osteosarcoma/sarcomas in 32% and leukemia or lymphoma in 63% of patients.

Safety data was available for 141 patients enrolled in Study 2. The protocol did not specify the criterion for allowing patients to receive a second VORAXAZE 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. VORAXAZE-related adverse reactions were collected and severity was graded according to NCI CTCAE version 3. One (n=122) or 2 (n= 18) doses of VORAXAZE were administered; the number of doses was not specified for 1 patient. Doses ranged from 6 Units/kg to 189 Units/kg, with a median dose of 50 Units/kg. The median age was 17 years (6 months to 85 years); 64% were male; and the underlying malignancies were osteogenic sarcoma in 32% and leukemia or lymphoma in 62% of patients.

Among the 290 patients, 8 deaths occurred within 30 days of VORAXAZE exposure that were not related to progressive disease.

The most common adverse reactions (reported in >1%) were paresthesia, flushing, and nausea and/or vomiting. Table 1summarizes select adverse reactions; adverse reactions likely associated with toxic methotrexate plasma concentrations, such as hematological, renal and hepatic adverse reactions, were not included in this table.

6.2     Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other glucarpidase products may be misleading.

In clinical trials, 121 patients who received one (n=99), 2 (n=21), or 3 (n=1) doses of VORAXAZE were evaluated for anti-glucarpidase antibodies. Twenty-five of these 121 patients (21%) had detectable anti-glucarpidase antibodies following VORAXAZE administration, of which 19 received 1 dose of VORAXAZE and 6 received 2 doses of VORAXAZE. Antibody titers were determined using a bridging enzyme-linked immunosorbent assay (ELISA) for anti- glucarpidase antibodies.

Neutralizing antibodies were detected in 11 of the 25 patients who tested positive for anti- glucarpidase binding antibodies. Eight of these 11 patients had received a single dose of VORAXAZE; however, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.

7.1 Effects of VORAXAZE on Leucovorin

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.

7.2 Effect of VORAXAZE on Measurement of Methotrexate Concentration

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.

8.1     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.

8.2 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.

8.4     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.

8.5     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.

8.6     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)].

12.1     Mechanism of Action

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-N 10- 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.

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 C maxwas 3.3 μg/mL and the mean area under the curve (AUC 0-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 (V d) was 3.6 L.

Elimination

Serum glucarpidase activity levels declined with a mean elimination half-life (t 1/2) 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/m 2) and leucovorin rescue, a VORAXAZE dose of 50 Units/kg administered intravenously 2 hours before leucovorin, reduced (6S)-leucovorin AUC 0-3hby 33% and C maxby 52% and reduced its active metabolite (6S)-5-methyltetrahydrofolate AUC 0-3hby 92% and C maxby 93% [see Drug Interactions ( 7.1)] .

13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

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