Pdf glucarpidase to combat toxic levels of methotrexate in. Highdose leucovorin as sole therapy for methotrexate toxicity. Tissing2 1department of clinical pharmacology and clinical pharmacy, university medical centre, groningen, netherlands 2department of child oncology, university medical centre, groningen, netherlands. Glucarpidase voraxaze national drug monograph and considerations for use. Ml in patients with delayed methotrexate clearance due to impaired renal function. It is a homodimeric protein composed of 390 amino acids. Methotrexate inhibits dihydrofolate reductase, depleting cells. Withdrawal assessment report voraxaze glucarpidase emeahc681. Will glucarpidase after methotrexate treatment for bone.
Dec 27, 20 to investigate whether glucarpidase rescue after highdose methotrexate reduces the severity of methotrexate associated adverse effects time frame. Methotrexate mtx is a folic acid antagonist used for its antiproliferative and antiinflammatory activity, either as a standalone drug or in combination with other medications, in the treatment of neoplastic and autoimmune diseases table 1. Side effects of glucarpidase are rare and relatively mild, and include paraesthesia, flushing, nausea, vomiting, pruritus, and headache. A rapidly fatal case of lowdose methotrexate toxicity. Nov 25, 2010 highdose methotrexate chemotherapy is used to treat a variety of malignancies, including lymphoid leukemias, lymphomas and sarcomas. Dailymed voraxaze glucarpidase injection, powder, for solution. Tissing2 1department of clinical pharmacology and clinical pharmacy, university medical centre, groningen, netherlands 2department of child oncology, university medical centre, groningen, netherlands corresponding author. Glucarpidase voraxaze is an fdaapproved intravenous drug for the treatment of elevated levels of methotrexate defined as 1 micromoll during treatment of cancer patients who have impaired kidney function and thus cannot reduce the drug to safe levels sufficiently after the drug has been given. Future applications of this enzyme in chemotherapy continue to be an active area of research. Methotrexate, administered for treatment of pediatric and adult malignancies, is a direct renal toxin, which can lead to renal dysfunction, decreased methotrexate clearance, elevated methotrexate concentrations, and systemic toxicity. At present, data regarding the use of glucarpidase in lowdose methotrexate toxicity is lacking. Protection of cells from intracellular methotrexate still requires the administration of highdose leucovorin. Glucarpidase works by cleaving the methotrexate into 2 parts that are no longer toxic, she explained.
To prevent renal dysfunction and further mtx toxicity glucarpidase. Glucarpidase for methotrexate toxicity oncologic emergency. Jun 03, 20 it should be continued until the methotrexate level falls below 0. Consensus guideline for use of glucarpidase in patients with high. Voraxaze glucarpidase for injection, for intravenous use is supplied as a sterile, preservativefree, white lyophilized powder in singledose vials. Consensus guideline for use of glucarpidase in patients with.
Jun 06, 2016 methotrexate toxicity during treatment of chronic plaque psoriasis. Day 8 and 15 grading of mucositis, renal toxicity, liver toxicity, neutropaenia, thrombocytopaenia and infections. Mtx disrupts cell repair and proliferation by inhibition of folate reduction through the dihydrofolate reductase enzyme in both malignant and healthy cells. Pdf glucarpidase for the treatment of lifethreatening methotrexate. Highdose methotrexate chemotherapy is used to treat a variety of malignancies, including lymphoid leukemias, lymphomas and sarcomas. Although plasma methotrexate concentrations have been shown to decline precipitously after a single dose of. Treatment of high dose methotrexate toxicity with glucarpidase. The enzymatic action of glucarpidase carboxypeptidaseg2. Jan 01, 2017 acute kidney injury due to highdose methotrexate hdmtx is a serious, lifethreatening toxicity that can occur in pediatric and adult patients. To conclude, it cannot be emphasized enough that methotrexate, although a very useful drug in the treatment of inflammatory arthritis, even when used in the lowest dose, may prove to be fatal in the presence of renal insufficiency. Glucarpidase to combat toxic levels of methotrexate in patients. Pdf consensus guideline for use of glucarpidase in patients with. Glucarpidase is used to remove methotrexate from the body in patients whose kidneys are not working as they should.
Glucarpidase for the treatment of lifethreatening methotrexate overdose. Voraxaze glucarpidase dosing, indications, interactions. Darko mitrovic, department of clinical pharmacology and clinical. When measuring methotrexate concentration following a glucarpidase dose, a chromatographic method is preferred over an immunoassay. Voraxaze glucarpidase is a carboxypeptidase enzyme indicated for the treatment of toxic plasma methotrexate concentrations 1 micromole per liter in. Glucarpidase treatment for methotrexate intoxication. Highdose methotrexate, leucovorin and glucarpidase dosing. Essentials of glucarpidase rescue glucarpidase is a methotrexate antidote that was approved by the us food and drug administration on january 17, 2012. A 39yearold man with lymphoblastic tcell lymphoma was admitted to our intensive care unit with elevated serum creatinine and prolonged high serum mtx levels. Methotrexate toxicity methotrexate toxicity maryland poison center.
N2 highdose methotrexate hdmtx is widely and safely used in oncology, with adequate measures including vigorous hydration, urine alkalinization and leucovorin rescue. Glucarpidase is an orphan medicine, not licensed in the uk. Using a lower dose of glucarpidase to reduce plasma levels of. Of 476 patients with renal toxicity and delayed methotrexate elimination who were treated with intravenous glucarpidase for rescue after highdose methotrexate. Glucarpidase is a 390amino acid homodimer protein with a molecular weight of 83 kda. Pdf glucarpidase to combat toxic levels of methotrexate. It was licensed in the us in early 2012 for the treatment of patients with toxic levels of methotrexate in their blood due to kidney failure.
The rationale for use of glucarpidase in methotrexate toxicity is based on its ability to hydrolyze the carboxyl terminal glutamate residue from compounds such as methotrexate, producing glutamate and 2,4diaminon10methylpteroic acid dampa. Smith, md, facep, facmt 36 th i nternational c ongress of the e uropean a ssociation of p oisons c entres and c linical t oxicologists p recongress. Treatment of methotrexate intoxication with various. Future applications of this enzyme in chemotherapy continue to be an active area. These patients received glucarpidase in doses ranging from 1031 unitskg, with no different effect on mtx toxicity or pharmacokinetics compared to patients who received the full dose. Highdose methotrexate mtx induced acute kidney injury can lead to sustained high systemic mtx levels and severe toxicity. Each potency unit corresponds to the enzymatic cleavage of 1 moll of methotrexate per minute at 37c. Glucarpidase has no impact on intracellular concentrations of methotrexate or on reversing methotrexate induced renal toxicity. Call the specialists at the maryland poison center for assistance in obtaining glucarpidase for methotrexate toxicity. Glucarpidase voraxaze, a carboxypeptidase enzyme for. Glucarpidase is a recombinant bacterial enzyme carboxypeptidase that converts methotrexate mtx to its inactive metabolite dampa, providing an alternate nonrenal pathway for elimination. Treatment of high dose methotrexate toxicity with glucarpidase darko mitrovic1, daan j. The product is a recombinant form of the bacterial enzyme carboxypeptidase g2, and works by.
After receipt of glucarpidase 50 unitskg to 22 patients with methotrexate toxicity, the methotrexate concentration measured by a chromatographic method was reduced by at least 97% within 15 minutes in everyone and was maintained at a more than 95% reduction up to 8 days in 20 of the patients. Consensus guideline for use of glucarpidase in patients. The amount needed to reverse toxicity is proportional to the methotrexate concentration. Glucarpidase for the urgent treatment of methotrexate induced renal.
Glucarpidase voraxaze, a carboxypeptidase enzyme for methotrexate toxicity. Following glucarpidase administration, continue leucovorin or levoleucovorin 4 rescue until methotrexate concentration has been maintained below the leucovorin or levoleucovorin treatment threshold for. Glucarpidase is a recombinant form of the cpdg2 enzyme, produced via modi fied escherichia coli. Nov 22, 2012 side effects of glucarpidase are rare and relatively mild, and include paraesthesia, flushing, nausea, vomiting, pruritus, and headache. Toxic blood levels of the anticancer drug methotrexate. Glucarpidase, methotrexate, toxicity introduction methotrexate mtx is an important chemotherapeutic agent for many oncological indications.
Acute kidney injury due to highdose methotrexate hdmtx is. Standard supportive care was complemented by the addition of a relatively novel agent, glucarpidase, which. Acute kidney injury due to highdose methotrexate hdmtx is a serious, lifethreatening toxicity that can occur in pediatric and adult patients. 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. Request pdf glucarpidase voraxaze, a carboxypeptidase enzyme for methotrexate toxicity glucarpidase voraxaze for methotrexate toxicity. Methotrexate toxicity treated with continuous venovenous. Cost of glucarpidase is an important factor to consider, as emphasized by the authors. Glucarpidase is a treatment approved by the food and drug administration for high methotrexate concentrations in the context of kidney dysfunction, but the guidelines for when to use it are unclear. Glucarpidase has seen limited use in intrathecal treatment of methotrexate toxicity for which it is also effective.
There are three antidotes that have been used for mtx toxicity. Methotrexate mtx is an antimetabolite chemotherapeutic used to treat malignancies and rheumatologic conditions, such as nonhodgkins lymphoma, osteosarcoma and rheumatoid arthritis. Definition from the nci drug dictionary detailed scientific definition and other names for this drug. Glucarpidase to combat toxic levels of methotrexate in. T1 glucarpidase for the treatment of lifethreatening methotrexate overdose. Glucarpidase has recently been approved for the treatment of toxic plasma mtx concentrations in patients with delayed mtx clearance due to impaired renal.
Voraxaze glucarpidase dose, indications, adverse effects. The fdaapproved glucarpidase in 2012 as an antidote to methotrexate toxicity secondary to renal impairment. Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites. The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides. Glucarpidase for the management of elevated methotrexate. It is only available under an openlabel treatment protocol for compassionate use in patients with high serum methotrexate levels or in patients with intrathecal methotrexate overdoses.
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