Glucarpidase

Glucarpidase comes as a powder to be mixed with liquid and injected intravenously (into a vein). It is usually given over 5 minutes as a one-time dose. Glucarpidase is given along with leucovorin (another medication used to prevent harmful effects of methotrexate) until laboratory tests show treatment is no longer needed.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some people receiving a glucarpidase injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you have:

• severe dizziness or weakness;
• severe nausea, feeling like you might pass out;
• cold sweat, itching, numbness or tingly feeling;
• sudden headache;
• fast heartbeats, chest tightness; or
• trouble breathing.

Common side effects may include:

• mild nausea;
• mild headache; or
• mild numbness or tingling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if glucarpidase crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using this medication.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

The recommended dose is a single intravenous (into the vein) injection of 50 Units per kilograms of body weight.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some people receiving a glucarpidase injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you have:

• severe dizziness or weakness;

• severe nausea, feeling like you might pass out;

• cold sweat, itching, numbness or tingly feeling;

• sudden headache;

• fast heartbeats, chest tightness; or

• trouble breathing.

Common side effects may include:

• mild nausea;

• mild headache; or

• mild numbness or tingling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Substrates of Glucarpidase

Possible decreased peak concentrations and AUC of the glucarpidase substrate.1 (See Specific Drugs under Interactions.)

Specific Drugs

Absorption

Onset

Following a single 50-unit/kg dose, plasma methotrexate concentrations (measured by chromatographic method) decreased by ≥97% within 15 minutes.1

Duration

Following a single 50-unit/kg dose, reductions in plasma methotrexate concentrations were maintained at >95% for up to 8 days.1

Distribution

Extent

Distributed primarily in intravascular (i.e., extracellular) compartment;4 7 11 does not cross blood-brain barrier.7

Not known whether glucarpidase is distributed into human milk.1

Elimination

Half-life

5.6 hours (by enzymatic assay) or 9 hours (by enzyme-linked immunosorbent assay [ELISA]).1 17

Special Populations

In patients with severe renal impairment (Clcr <30 mL/minute), half-life is prolonged (8.2 hours).1 8

• Recombinant bacterial enzyme produced in Escherichia coli.1 7 17

• Rapidly hydrolyzes methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate.1 7 17

• Because DAMPA and glutamate are principally metabolized hepatically, glucarpidase provides an alternative, nonrenal route for methotrexate elimination in patients with delayed methotrexate clearance due to renal impairment.1 7 8 10 12 13

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If you need to store glucarpidase at home, talk with your doctor, nurse, or pharmacist about how to store it.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take glucarpidase or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to glucarpidase. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Methotrexate toxicity: Maintains a >95% reduction of methotrexate concentrations for up to 8 days

Half-Life Elimination

IV: Normal renal function: Serum glucarpidase activity levels: 5.6 hours; Serum total glucarpidase: ~9 hours. Impaired renal function (CrCl <30 mL/minute): 8 to 10 hours (Phillips 2008)

Concerns related to adverse effects:

• Hypersensitivity: Serious allergic reactions have been reported.

Concurrent drug therapy issues:

• Leucovorin calcium: Leucovorin calcium administration should be continued after glucarpidase; the same dose as was given prior to glucarpidase should be continued for the first 48 hours after glucarpidase; after 48 hours, leucovorin doses should be based on methotrexate concentrations. A single methotrexate concentration should not determine when leucovorin should be discontinued; continue leucovorin until the methotrexate concentration remains below the threshold for leucovorin treatment for ≥3 days. Leucovorin calcium is a substrate for glucarpidase and may compete with methotrexate for binding sites; do not administer leucovorin calcium within 2 hours before or after glucarpidase.

Other warnings/precautions:

• Hydration/alkalinization: In addition to leucovorin, glucarpidase use should be accompanied with adequate hydration and urinary alkalinization.

• Intrathecal methotrexate overdose: Glucarpidase for intrathecal methotrexate overdose (off-label route/use) should be used in conjunction with immediate lumbar drainage; concurrent dexamethasone (4 mg IV every 6 hours for 4 doses) may minimize methotrexate-induced chemical arachnoiditis; leucovorin calcium (100 mg IV every 6 hours for 4 doses) may prevent systemic methotrexate toxicity (Widemann, 2004).

• Monitoring methotrexate: During the first 48 hours after glucarpidase administration, the only reliable method of measuring methotrexate concentrations is the chromatographic method. DAMPA, an inactive methotrexate metabolite with a half-life of 9 hours, may interfere with immunoassay and result in the overestimation of the methotrexate concentration (when collected within 48 hours of glucarpidase administration).

• Multiple doses: The utility of more than one glucarpidase dose in reducing plasma methotrexate levels was evaluated in a study of 100 patients with high-dose methotrexate-induced nephrotoxicity (Widemann 2010). Glucarpidase 50 units/kg IV was administered either as a single dose (n=65), 2 doses given 24 hours apart (n=28), or 3 doses given at 4 hour intervals (n=7). Six of the 65 patients randomized to a single dose also received a second delayed glucarpidase dose (>24 hours later) due to persistent methotrexate concentrations ≥1 micromole/L in spite of a ≥90% decrease in the plasma methotrexate concentration after the initial dose. The use of scheduled second and third glucarpidase doses did not result in additional methotrexate concentration decreases; and only 2 of the 6 patients who received a second delayed glucarpidase dose (>24 hours later) experienced a ≥50% methotrexate concentration reduction.

Animal studies have not been conducted. There are no controlled data in human pregnancy. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should be used during pregnancy only if clearly needed. US FDA pregnancy category: C

Caution is recommended. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comments: The effects in the nursing infant are unknown.