a) In a single-arm, open-label trial, glucarpidase reduced toxic plasma methotrexate concentrations in 3 of 12 pediatric patients with delayed methotrexate clearance due to renal dysfunction. Within another study assessing safety and efficacy of glucarpidase (n=22), 12 pediatric patients were identified (ages 5 to 16 years old) who had a methotrexate plasma level greater than 1 mcmol/L. All patients received glucarpidase 50 units/kg as a bolus intravenous injection over 5 minutes along with IV hydration, urinary alkalinization, and leucovorin therapy (not given within 2 hours before or after glucarpidase). Among 6 pediatric patients with a pre-glucarpidase methotrexate concentration between 1 to 50 mcmol/L, 3 achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration (primary outcome, defined as plasma methotrexate concentration 1 mcmol/L or less at 15 minutes, sustained for up to 8 days). However, none of the 6 pediatric patients with a pre-glucarpidase methotrexate concentration greater than 50 mcmol/L achieved a RSCIR (Prod Info VORAXAZE(R) IV injection, 2012).
b) In one study, early intervention with leucovorin and glucarpidase was highly effective in patients with high-dose methotrexate-induced renal dysfunction. Patients (n=100; median age, 17 years; range, 0.3 to 82 years) with methotrexate-induced nephrotoxicity and delayed methotrexate excretion received glucarpidase 50 Units/kg/dose for 5 minutes given by one of three regimens: a single dose, 2 doses 24 hours apart, or 3 doses every 4 hours. Patients had to meet either of the two eligibility criteria: plasma methotrexate concentration of at least 10 mcmol/L at least 42 hours after the start of high-dose methotrexate infusion OR serum creatinine of at least 1.5 times the upper limit of normal or creatinine clearance of 60 mL/min/m(2) or less and plasma methotrexate concentration of at least 2 standard deviations above the mean at 12 hours or greater after methotrexate administration. Leucovorin doses 1 g/m(2) IV every 6 hours (or per institutional guidelines) before glucarpidase and 250 mg/m(2) IV every 6 hours after the last dose of glucarpidase was given. In the first 35 patients, thymidine (8 g/m(2)/day) IV continuous infusion was administered for at least 48 hours after the last dose of glucarpidase. In patients receiving thymidine, glucarpidase was administered at a median of 96 hours (range, 22 to 294 hours) after the start of methotrexate infusion. Overall, glucarpidase was given at a median of 96 hours (range, 22 to 294 hours; receiving thymidine, n=44) and 66 hours (range, 22 to 192 hours; not receiving thymidine, n=56). Within 15 minutes after the first dose of glucarpidase, plasma methotrexate concentration decreased by 98.7% (range, 84% to 99.5%). Patients who received glucarpidase more than 96 hours after the start of the methotrexate developed more grade 4 and 5 toxicity compared with those patients who received glucarpidase earlier (Widemann et al, 2010).
c) CASE REPORT: A 13-year-old girl with osteosarcoma developed severe methotrexate toxicity (plasma methotrexate concentration 446 mcmol/L at 48 hours; target, less than 0.5 mcmol/L), including encephalopathy, liver failure, and renal failure after receiving high-dose methotrexate 12 g/m(2) over 4 hours with standard prehydration, alkalinization, and leucovorin rescue. Initially, she was treated with continuous venovenous hemodialysis (CVVHD) for 9 hours and then with single-pass albumin dialysis (SPAD) for 23.9 hours. Despite an immediate decline in concentration and half-life (before: 14.8 hours; after: 6.5 hours with CVVHD and 7.4 hours with SPAD) with the start of both therapies, glucarpidase therapy (2000 Units IV infusion) and then continuous venovenous hemodiafiltration (CVVHDF) were required. CVVHDF achieved the highest clearance rate with an effluent rate of 4950 mL/hr. Glucarpidase therapy resulted in the most rapid percentage (86%) decline in methotrexate concentrations. The patient's condition improved gradually (Vilay et al, 2010).
d) In a study of 43 adult cancer patients (median age 54; range 18 to 78 years) with delayed methotrexate elimination, the effects of glucarpidase were evaluated. Patients with a methotrexate concentration of 1 to 1,187 micromol/L received glucarpidase, leucovorin rescue, daily monitoring and supportive care. Although glucarpidase was well tolerated and produced a rapid reduction of circulating methotrexate, 10 (23%) patients died of complications (ie, infection (n=7), uremia and seizures (n=1), methotrexate neurotoxicity (n=1), and peritonitis with multiorgan failure (n=1)) associated with high dose methotrexate therapy. Of note, all the patients in this study had evidence of delayed elimination of methotrexate, which may have contributed to the high case fatality rate, as compared to two previous trials with rates </= to 7%; the authors suggested that a higher median age may have been a contributing factor (Schwartz et al, 2007).
e) CASE REPORT: A 16-year-old girl with a non-metastatic osteosarcoma developed severe acute toxicity after receiving the first course of high-dose methotrexate (HD-methotrexate) (12 g/m(2) IV infusion over 4 hours). She recovered gradually after receiving two doses of glucarpidase (CPDG2) (50 Units/kg). On day 47, she received a methotrexate test-dose (50 mg/m(2) IV infusion over 30 min) to determine her elimination pharmacokinetic parameters. She received 16 more courses of HD-methotrexate (10 g or 12 g each course) without any toxicity. In this case, fluorescence polarization immunoassay (FPIA) was found unreliable for determining methotrexate concentration after the first dose of CPDG2, due to a cross-reaction between methotrexate and its non-toxic metabolite, 2,4-diamino-N10-methylpteroic acid (DAMPA). However, HPLC was effective in determining the true remaining serum methotrexate level and to evaluate the necessity for a second dose of CPDG2 (Esteve et al, 2007).
f) CASE REPORT/GLUCARPIDASE and AMINOPHYLLINE: A 14-year-old boy with nonmetastatic osteosarcoma of the tibia developed acute renal failure after the sixth cycle of high-dose methotrexate and was initially treated with leucovorin and urine alkalinization. CPDG2 (50 units/kilogram) and aminophylline were started later as a second-intention rescue strategy. Sixteen hours after the first infusion of CPDG2, the methotrexate plasma concentration decreased from 614 to 24.1 mcmol/L. A second dose of CPDG2 was given approximately 5 days later for persistent renal failure. Aminophylline, an adenosine antagonist, was also given to minimize renal dysfunction. Within 2 weeks, the patient had complete recovery of clinical signs and symptoms and went on to have limb salvage surgery (Peyriere et al, 2004).
g) CASE SERIES: In one study, cancer patients were treated with methotrexate-induced renal dysfunction with a combination therapy of glucarpidase, thymidine, and leucovorin. Of note, patients who had adequate urine output continued to receive IV hydration undergo alkalinization. Glucarpidase 50 units/kilogram was reconstituted in normal saline and given intravenously over 5 minutes for a total of 3 doses at 4 hour intervals. Thymidine was given as a 24 hour continuous infusion at a dose of 8 grams/square meter/day for a minimum of 48 hours after glucarpidase administration and until the methotrexate concentration was less than 1 micromole/liter. Leucovorin was administered based on plasma methotrexate concentration. Several patients experienced feelings of warmth, tingling in fingers, shaking, and minimal burning of the face and extremities which was relieved with diphenhydramine. Glucarpidase resulted in a rapid 95.6% to 99.6% decrease in plasma methotrexate concentrations in all patients. Following this dramatic reduction in the plasma methotrexate concentration from CPDG2, methotrexate was eliminated slowly in all patients; half-life of methotrexate ranged from 26.8 to 211.9 hours (median 86.6 hours); 18 of 20 patients experienced only mild to moderate methotrexate-related toxicity. Creatinine gradually decreased and reached normal values 6 to 70 days (median 22) after the start of methotrexate infusion (Widemann et al, 1997).

a) Seven patients were treated with intrathecal glucarpidase after inadvertent intrathecal methotrexate overdose (median methotrexate dose 364 mg; range 155 to 600 mg). Intrathecal glucarpidase caused a rapid and profound (greater than 98%) decrease in CSF methotrexate concentrations, and all patients recovered. These patients were also treated with CSF drainage and some received ventriculolumbar perfusion (Widemann et al, 2004).
b) CASE REPORT: A 6-year-old boy inadvertently received 600 milligrams of intrathecal methotrexate (intended dose 12 milligrams). Severe toxicity including seizures, severe headache, apnea, coma, and ventricular premature beats occurred within 20 minutes of administration. Lumbar puncture with drainage of 15 milliliters of CSF was performed 2 hours after administration, and resulted in removal of 32% of the administered drug. Ventriculolumbar perfusion with 240 milliliters of warmed isotonic saline was then performed over 3 hours, removing another 58% of the administered dose. The patient also received dexamethasone (4 mg/m(2) every 6 hours) and leucovorin calcium (1000 mg/m(2) then 100 mg/m(2) every 3 hours with therapy) while the ventricular and lumbar catheters were being placed. At this point approximately 1% of the administered dose remained in the CSF and 9% had entered the systemic circulation. Immediately after ventriculolumbar perfusion, 1000 units of carboxypeptidase G2 was administered through the ventricular catheter over 5 minutes and another 1000 units were administered through the lumbar catheter. This was associated with a decrease in CSF methotrexate levels from 128 micromolar to 0.8 micromolar over 16 hours. The patient had gradual complete neurologic recovery over 10 days. This is the largest intrathecal overdose with neurologic recovery (O'Marcaigh et al, 1996).

1) In studies, the most common adverse effects (greater than 1%) following glucarpidase use were paresthesia, flushing, nausea and/or vomiting, hypotension, and headache.

1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Severe toxicity from glucarpidase overdose is not expected.

1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with vomiting or diarrhea.

1) Treatment is symptomatic and supportive. Severe toxicity is not expected after overdose of glucarpidase. NOTE: Severe toxicity symptoms may be due to methotrexate overdose. Refer to "METHOTREXATE AND RELATED AGENTS" document for more information.

1) HOSPITAL: Gastrointestinal decontamination is not recommended; administered via the parenteral route.

1) Should not be required in patients with glucarpidase overdose; however, may be required in patients with symptoms of severe methotrexate toxicity (eg, CNS and cardiac toxicity).

1) None.

1) IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine.

1) Hemodialysis is not required in patients after an inadvertent glucarpidase overdose. However, this agent is used in patients with methotrexate overdose. These patients may already be treated with enhanced elimination methods (eg, high flux hemodialysis and charcoal hemoperfusion).

1) HOME CRITERIA: Glucarpidase is administered in an inpatient medical setting; patients with inadvertent overdose should be observed in a medical setting.
2) OBSERVATION CRITERIA: Symptomatic patients need to be monitored for several hours to assess electrolyte and fluid balance.
3) ADMISSION CRITERIA: Patients receiving glucarpidase are generally already admitted for high methotrexate concentrations or overdose.
4) CONSULT CRITERIA: Consult a poison center, medical toxicologist, or oncologist for assistance in managing patients with severe toxicity (may be due to methotrexate toxicity) or in whom the diagnosis is not clear.

1) When managing a suspected glucarpidase overdose, the possibility of multidrug involvement should be considered.

1) Following the administration of single dose glucarpidase 50 units/kg IV in 8 healthy individuals, the mean Cmax and systemic clearance were 3.3 mcg/mL and 7.5 mL/minute, respectively, in the absence of methotrexate. Vd: 3.6 L. Elimination half-life: 5.6 hours.

1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers).

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) There are no adequate or well controlled studies of glucarpidase in human pregnancy. Animal studies have not been conducted. It is currently unknown if glucarpidase use during pregnancy can result in fetal harm. As a result, the manufacturer recommends the use of glucarpidase during pregnancy only if clearly needed (Prod Info VORAXAZE(R) intravenous injection, 2013).

1) Glucarpidase is classified as FDA pregnancy category C (Prod Info VORAXAZE(R) intravenous injection, 2013).

1) Lactation studies have not been conducted with glucarpidase. Because many drugs are known to be excreted in breast milk, the manufacturer recommends using caution when administering glucarpidase to lactating women (Prod Info VORAXAZE(R) intravenous injection, 2013).

1) No animal carcinogenicity studies have been performed (Prod Info VORAXAZE(R) IV injection, 2012).

A) Patients receiving glucarpidase are generally already admitted for high methotrexate concentrations or overdose.

A) Glucarpidase is administered in an inpatient medical setting, patients with inadvertent overdose should be observed in a medical setting.

A) Consult a poison center, medical toxicologist, or oncologist for assistance in managing patients with severe toxicity (may be due to methotrexate toxicity) or in whom the diagnosis is not clear.

A) Symptomatic patients need to be monitored for several hours to assess electrolyte and fluid balance.

1) Monitor vital signs in symptomatic patients.
2) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
3) Following glucarpidase treatment, DAMPA, the inactive metabolite of methotrexate, interferes with immunoassays for methotrexate measurement. This measurement will be unreliable for samples collected within 48 hours of glucarpidase administration because of the long half-life of DAMPA (approximately 9 hours).

1) SUMMARY
2) DOPAMINE
3) NOREPINEPHRINE

1) UNITED STATES
2) EUROPE (except for Greece, Italy, and Scandinavia)
3) REST OF THE WORLD (including Greece, Italy, and Scandinavia)

1) UNITED STATES
2) EUROPE (except for Greece, Italy, and Scandinavia)
3) REST OF THE WORLD (including Greece, Italy, and Scandinavia)