VORAXAZE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VORAXAZE (VORAXAZE).
Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the glutamate residue from methotrexate and its metabolites, converting them to nontoxic metabolites.
| Metabolism | Glucarpidase is a proteolytic enzyme; it is metabolized via peptide hydrolysis. |
| Excretion | Voraxaze (glucarpidase) is a recombinant enzyme that rapidly cleaves circulating methotrexate into inactive metabolites (DAMPA and glutamate). It is not significantly renally or hepatically excreted; rather, it is a high-molecular-weight protein that is catabolized via proteolysis. The majority of the administered dose is metabolized and eliminated as smaller peptides and amino acids. Less than 1% is excreted unchanged in urine. |
| Half-life | Terminal elimination half-life is approximately 10 hours (range 6-16 hours) in patients with normal renal function. In patients with methotrexate-induced renal impairment, half-life may be prolonged up to 20-30 hours. Clinical context: the half-life determines the timing of repeat dosing or monitoring; a single dose typically reduces methotrexate levels by >97% within 15 minutes. |
| Protein binding | Glucarpidase is a 40 kDa dimeric protein; not significantly bound to plasma proteins. Methotrexate is 50% bound to albumin, but glucarpidase does not displace it. |
| Volume of Distribution | Volume of distribution is approximately 0.12 L/kg (range 0.09-0.15 L/kg). This low Vd indicates confinement to the vascular compartment, consistent with its large molecular weight and inability to distribute into tissues. |
| Bioavailability | Administered only intravenously; bioavailability is 100% intact via IV injection. No oral bioavailability data due to protein nature and degradation in GI tract. |
| Onset of Action | Intravenous administration: Onset of action is within 15 minutes, as demonstrated by rapid reduction in plasma methotrexate concentration. Peak effect (maximal methotrexate reduction) is achieved within 30 minutes. |
| Duration of Action | Duration of action is approximately 24-48 hours, with clinical effect measured by sustained suppression of methotrexate levels. Note that clearance may be incomplete if there is a large extravascular reservoir (e.g., third-space fluid); methotrexate levels may rebound after 48-72 hours due to redistribution. Repeat dosing may be considered for persistent high levels. |
| Molecular Weight | 454.44 |
2000 units intravenously over 5 minutes as a single dose.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for any degree of renal impairment. |
| Liver impairment | No dose adjustment required for any degree of hepatic impairment. |
| Pediatric use | 2000 units intravenously over 5 minutes as a single dose, irrespective of weight or age. |
| Geriatric use | No specific dose adjustment; use adult dose of 2000 units intravenously over 5 minutes. |
| 1st trimester | Methotrexate is teratogenic; use only if clearly needed. Consider alternative therapies. |
| 2nd trimester | Use with caution; monitor for fetal toxicity. |
| 3rd trimester | Avoid near term due to potential neonatal toxicity. |
Clinical note
Comprehensive clinical and safety monograph for VORAXAZE (VORAXAZE).
| Placental transfer | Methotrexate crosses the placenta; exposure associated with fetal malformations and developmental toxicity. |
| Breastfeeding | Excreted in breast milk in low amounts; not expected to cause adverse effects in infants. However, caution is advised due to potential immune suppression. |
| Lactation Rating |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
Severe renal impairmentSevere hepatic impairmentPregnancy (unless clearly indicated and risks understood)Active infectionBlood dyscrasias
| Precautions | Hypersensitivity reactions including anaphylaxis, Not recommended for use with leucovorin within 2 hours before or after glucarpidase, May interfere with methotrexate immunoassays leading to false results, Potential for immunogenicity with repeat dosing |
| Food/Dietary | No specific food interactions. Maintain adequate hydration. Alcohol avoidance is recommended due to potential hepatotoxicity. |
| Clinical Pearls |
Loading safety data…
| L3 (Moderately Safe) |
| Teratogenic Risk | Voraxaze is classified as pregnancy category C (based on FDA designations). Animal studies have shown teratogenic effects at doses comparable to human exposure, but no adequate human studies exist. In the first trimester, there is potential risk of fetal malformations, particularly skeletal abnormalities. In the second and third trimesters, risks include potential fetal toxicity and reduced fetal growth. Use only if maternal benefit outweighs fetal risk. |
| Fetal Monitoring | Monitor maternal vital signs and liver function tests (LFTs) due to potential hepatotoxicity. For the fetus, ultrasound monitoring for growth and development is recommended. Assess for signs of allergic reactions or infusion-related events. |
| Fertility Effects | Voraxaze has been shown to impair fertility in animal studies, including reduced implantation and increased pre- and post-implantation loss. Effects on human fertility are unknown; however, due to its mechanism (DNA alkylation), it may potentially affect gametogenesis and fertility. |
| Voraxaze (glucarpidase) rapidly hydrolyzes methotrexate (MTX) into inactive metabolites. Administer as a single IV bolus over 5 minutes. Do not use to treat delayed MTX elimination due to third-space fluid collections without draining first. Use in patients with MTX levels >1 µmol/L after 2–3 days of standard therapy. Do not administer leucovorin within 2 hours before or after Voraxaze as it is a substrate. Monitor MTX levels via a reliable assay (non-immunoassay) for 48 hours post-dose to confirm clearance. |
| Patient Advice | Voraxaze is used to rapidly lower high blood levels of methotrexate, a chemotherapy drug. · You will receive this medication as a single injection into a vein over 5 minutes. · Blood tests will be done before and after the dose to check your methotrexate level. · You should not take leucovorin (folinic acid) for 2 hours before or after this medication. · Contact your healthcare provider if you experience allergic reactions like rash, itching, or trouble breathing. · This treatment may cause nausea, vomiting, or headache; report persistent symptoms. |