VORAXAZE

Voraxaze( glucarpidase):

Date of Approval: 17^th january 2012.

Mechanism of Action

VORAXAZE (glucarpidase) is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. VORAXAZE 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.

Pharmacodynamics

Plasma methotrexate concentrations within 48 hours following administration of VORAXAZE can only be reliably measured by a chromatographic method because DAMPA interferes with the immunoassays. 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.

Pharmacokinetics

The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in eight healthy subjects following an intravenous injection of VORAXAZE 50 Units/kg over 5 minutes. Serum glucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidase concentrations were measured by ELISA.

Serum glucarpidase activity levels declined with a mean elimination half-life (t_1/2) of 5.6 hours. The mean Cmax was 3.3 µg/mL and the mean area under the curve (AUC_0-inf) was 23.3 µg·h/mL. The mean systemic clearance (CL) was 7.5 mL/min. The mean volume of distribution (V_d) was 3.6 L, suggesting that glucarpidase distribution is restricted to plasma volume. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for a longer t_1/2 of 9 hours.

Among the 290 patients included in the safety evaluation of VORAXAZE, there were 8 deaths within 30 days of VORAXAZE exposure that were not related to progressive disease. Twenty-one of 290 patients (7%) experienced adverse reactions that were assessed as related to VORAXAZE. Most were Grade 1 or 2 events. One patient experienced related Grade 3 flushing. The most common related adverse reactions that were not hematologic, hepatic or renal events were paresthesia, flushing, and nausea and/or vomiting, which each occurred in 2% of patients (Table 1).

Table 1: Per Patient Incidence of Grade 1 and 2 Adverse Reactions Assessed as Possibly, Probably, or Definitely Related to VORAXAZE Excluding Hematologic, Hepatic, or Renal Adverse Reactions

Adverse Reaction	N= 290 n (%)
Paresthesias	7 (2%)
Flushing1,2	5 (2%)
Nausea/Vomiting	5 (2%)
Headache	2 (1%)
Hypotension	2 (1%)
Blurred Vision	1 ( < 1%)
Diarrhea	1 ( < 1%)
Hypersensitivity	1 ( < 1%)
Hypertension	1 ( < 1%)
Rash	1 ( < 1%)
Throat irritation/Throat tightness	1 ( < 1%)
Tremor	1 ( < 1%)
1 This incidence includes the following terms: flushing, feeling hot, burning sensation. 2 One of these reactions was classified as Grade 3 in severity.

Immunogenicity

In clinical studies, 96 patients were evaluated for anti-glucarpidase antibodies. One (n=78) or two (n=18) doses of VORAXAZE were administered intravenously to these patients. Sixteen patients (17%) developed anti-glucarpidase antibodies following VORAXAZE administration. Antibody titers were determined using a validated bridging enzyme-linked immunosorbent assay (ELISA) for anti-glucarpidase antibodies. Twelve of the 16 patients who developed anti-glucarpidase antibodies had received a single dose of VORAXAZE, and four of the patients had received two doses of VORAXAZE.

Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to VORAXAZE with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

Use of VORAXAZE with Leucovorin

Leucovorin is a substrate for VORAXAZE. Do not administer leucovorin within 2 hours before or after a dose of VORAXAZE. No dose adjustment is recommended for the continuing leucovorin regimen because the leucovorin dose is based on the patient¡¦s pre-VORAXAZE methotrexate concentration

CONTRAINDICATIONS

None

FDA APPROVED USES:

The U.S. Food and Drug Administration today approved Voraxaze (glucarpidase) to treat patients with toxic levels of methotrexate in their blood due to kidney fa