Glucarpidase

Description

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).

What Is Glucarpidase Used For?

1 INDICATIONS AND USAGE VORAXAZE is indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per liter) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function. Limitations of Use: VORAXAZE is not recommended for use in patients who exhibit the expected clearance and expected plasma methotrexate concentration. Reducing plasma methotrexate concentration in these patients may result in subtherapeutic exposure to methotrexate [see Clinical Studies ( 14 )] . VORAXAZE is a carboxypeptidase indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per liter) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function. ( 1 ) Limitations of Use: VORAXAZE is not recommended for use in patients who exhibit the expected clearance and expected plasma methotrexate concentration. Reducing plasma methotrexate concentration in these patients may result in subtherapeutic exposure to methotrexate. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION The recommended dosage of VORAXAZE is 50 Units per kilogram as a single intravenous injection over 5 minutes. ( 2.1 ). For the first 48 hours after the dose of VORAXAZE, administer the same leucovorin dose given prior to VORAXAZE. Administer leucovorin at least 2 hours before or 2 hours after the dose of VORAXAZE. ( 2.2 ) Beyond 48 hours after the dose of VORAXAZE, administer leucovorin based on the measured methotrexate concentration. Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. ( 2.2 ) 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.

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Hypersensitivity Reactions [Warnings and Precautions ( 5.1 )]. The most common related adverse events (>1%) were paresthesia, flushing, nausea and/or vomiting, hypotension and headache. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact BTG at 877-377-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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....

Drug Interactions

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.

Contraindications

4 CONTRAINDICATIONS None. None.

Pregnancy and Breastfeeding

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.

How Supplied

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.