Voraxaze (Page 2 of 3)

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 DRUG INTERACTIONS

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 USE IN SPECIFIC POPULATIONS

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)].

11 DESCRIPTION

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).

12 CLINICAL PHARMACOLOGY

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-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.

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)].

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