Drug Interaction:
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
Indication:
For Injection, for intravenous use
Initial U.S. Approval: 2012
Drug Name- Voraxaze
Active Ingredient - Glucarpidase
To treat patients with toxic levels of methotrexate in their blood due to
kidney failure
Indication-
Ttreat patients with toxic levels of methotrexate in their blood due to
kidney failure
Approved by FDA on 17-1-2012 (Ref- FDA Approved List- 2012)
Adverse Reaction:
In clinical trials, the most common related adverse events (occurring in >1% of patients)
were paraesthesia, flushing, nausea and/or vomiting, hypotension and headache.
Contra-Indications:
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Serious allergic reactions, including anaphylactic reactions, may occur.
Measurement of methotrexate using immunoassays is unreliable for samples
collected within 48 hours following VORAXAZE administration.
Continue therapy with leucovorin until the methotrexate concentration has been
maintained below the leucovorin treatment threshold for a minimum of 3 days.
Do not administer leucovorin within 2 hours before or after a dose of VORAXAZE.
For 48 hours after VORAXAZE administration, determine the leucovorin dose based
on the patient¡¦s pre-VORAXAZE methotrexate concentration.
Continue hydration and alkalinization of the urine as indicated.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
VORAXAZE (glucarpidase) is a carboxypeptidase enzyme indicated for the
treatment of toxic plasma methotrexate concentrations (>1 micromole per liter)
in patients with delayed methotrexate clearance due to impaired renal function.
Limitation of use:
VORAXAZE is not indicated for use in patients who exhibit the expected clearance
of methotrexate (plasma methotrexate concentrations within 2 standard deviations
of the mean methotrexate excretion curve specific for the dose of methotrexate
administered) or those with normal or mildly impaired renal function because
of the potential risk of subtherapeutic exposure
to methotrexate.
DOSAGE AND ADMINISTRATION
Administer VORAXAZE as a single intravenous injection of 50 Units per kg.
DOSAGE FORMS AND STRENGTHS
Lyophilized powder 1,000 Units per vial
Patient Information:
PATIENT COUNSELING INFORMATION
Inform patients that allergic reactions, including potentially serious reactions,
may occur during VORAXAZE treatment.
Advise patients to immediately report any signs and symptoms of infusion
reactions such as fever, chills, flushing, feeling hot, rash, hives, itching,
throat tightness or breathing problems, tingling, numbness, or headache.
Inform patients of the importance of continued monitoring of methotrexate blood
concentrations and renal status at the appropriate times after discharge from the hospital.
Pharmacology/ Pharmacokinetics:
1. 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
2. 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 (t1/2)
of 5.6 hours. The mean Cmax was 3.3 ìg/mL and the mean area under the curve (AUC-inf)
was 23.3 ìg·h/mL. The mean systemic clearance (CL) was 7.5 mL/min.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Pregnancy category C.
There are no adequate and well controlled studies with VORAXAZE in pregnant women
and animal reproduction studies have not been conducted with VORAXAZE.
Therefore, it is not known whether VORAXAZE can cause fetal harm when
administered to a pregnant woman. VORAXAZE should be given to a pregnant
woman only if clearly needed.
2. Nursing Mothers
It is not known if VORAXAZE is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when VORAXAZE
is administered to a nursing woman.
3. Pediatric Use
The effectiveness of VORAXAZE in pediatric patients was established in Study 1.
Of the 22 patients in the efficacy dataset in Study 1, 12 were pediatric patients
with ages ranging from 5 to 16 years. Three of the six pediatric patients with
a pre-VORAXAZE methotrexate concentration of 1-50 mol/L achieved a rapid
and sustained clinically important reduction (RSCIR) in plasma methotrexate
concentration, while none of the six pediatric patients with a pre-VORAXAZE
methotrexate concentration >50 mol/L achieved a RSCIR
The pooled clinical safety database for VORAXAZE included data for 147
patients from 1 month up to 17 years of age. No overall differences in safety
were observed between these patients and adult patients.
4. 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 patients.
Manufacturer Details