Voraxaze

Name: Voraxaze

Uses of Voraxaze

Voraxaze is a prescription medication used to prevent harmful effects of methotrexate in patients with kidney disease.

Side Effects of Voraxaze

Common side effects of Voraxaze include the following:

  • nausea
  • vomiting
  • fever
  • chills
  • flushing or feeling hot
  • rash
  • hives
  • itching
  • throat tightness or difficulty breathing
  • feelings of numbness, tingling, pricking, burning, or creeping on the skin
  • headache

This is not a complete list of this medication’s side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Voraxaze and Lactation

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

It is not known if Voraxaze 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.

What is glucarpidase?

Glucarpidase is used in patients who develop kidney failure while receiving high doses of methotrexate (a chemotherapy drug).

Glucarpidase is an enzyme that breaks down methotrexate in the body so the drug can be easily eliminated when the kidneys are not working properly.

Glucarpidase may also be used for purposes not listed in this medication guide.

What should I avoid after receiving glucarpidase?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Uses for Voraxaze

Methotrexate Toxicity

Adjunct to leucovorin rescue1 3 4 6 9 10 11 for the treatment of toxic plasma methotrexate concentrations (>0.454 mcg/mL [1 mcmol/L]) in patients with delayed methotrexate clearance due to renal impairment (designated an orphan drug by FDA for this use16 ).1 10

Because of potential for subtherapeutic methotrexate concentrations, do not 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 methotrexate dose administered) or in those with normal or mildly impaired renal function.1

Provides an alternative, nonrenal route for methotrexate elimination (in patients with delayed methotrexate clearance due to renal impairment) by converting circulating methotrexate to inactive metabolites that are primarily eliminated hepatically.1 7 8 10 12 13

Voraxaze Pharmacokinetics

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

Advice to Patients

  • Risk of hypersensitivity reactions, including anaphylaxis.1

  • Risk of infusion reactions.1 Importance of immediately reporting signs and symptoms of such reactions (e.g., fever, chills, flushing, feeling hot, rash, hives, itching, throat tightness or breathing difficulty, tingling, numbness, headache).1

  • Importance of continued monitoring of plasma methotrexate concentrations and renal function after discharge from the hospital.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Very bad dizziness or passing out.
  • Flushing.
  • A burning, numbness, or tingling feeling that is not normal.
  • Fever or chills.
  • Feeling hot.
  • Headache.

Adverse reactions

Serious allergic reactions, including anaphylactic reactions, may occur. The most common adverse reactions (incidence >1%) with Voraxaze are paraesthesias, flushing, nausea and/or vomiting, hypotension, and headache.

    Clinical Trials Experience

Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of Voraxaze cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

The evaluation of adverse reactions in patients treated with Voraxaze is confounded by the population in which it was studied, patients with toxic plasma methotrexate levels due to impaired renal function. Adverse reactions related to toxic methotrexate levels due to prolonged methotrexate clearance include myelosuppression, mucositis, acute hepatitis, and renal dysfunction and failure.

The safety of Voraxaze is based on data from 290 patients who were treated in 2 single-arm, open-label, multicenter trials enrolling patients who had markedly delayed methotrexate clearance secondary to renal dysfunction. Patients with osteosarcoma were eligible for these studies if the plasma methotrexate concentration was greater than 50 μmol/L at 24 hours, greater that 5 μmol/L at 48 hours, or greater than 2 standard deviations above the mean methotrexate elimination curve at least 12 hours after methotrexate administration and there was a 2-fold or greater increase in serum creatinine above baseline. All other patients were eligible for these studies if the plasma methotrexate level was greater than 10 μmol/L more than 42 hours after the start of the methotrexate or the plasma level was greater than 2 standard deviations above the mean methotrexate excretion curve at least 12 hours following methotrexate and the serum creatinine was greater than 1.5 times the upper limit of normal or the creatinine clearance was less than 60 mL/min at least 12 hours following methotrexate administration.

Study 1, conducted by the National Cancer Institute (NCI), enrolled 184 patients; safety information is available for 149 patients. Voraxaze was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. Patients with pre-Voraxaze methotrexate concentrations >100 μmol/L were to receive a second dose of Voraxaze 48 hours after the first dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after Voraxaze.

In Study 1, Voraxaze-related adverse reactions were collected on a flow sheet with a daily log of adverse reactions characterized as "glucarpidase toxicity." Additional safety information was collected from clinical records submitted by treating physicians. This information was abstracted and categorized using the National Cancer Institute (NCI) "Common Terminology Criteria for Adverse Events" (CTCAE) version 3 scale.

The Study 1 population enrolled patients with a median age of 18 years (1 month to 85 years); 63% were male, and the underlying malignancies were osteosarcoma/sarcomas in 32%, and leukemia or lymphoma in 63% of patients. One (n=106) or 2 (n= 30) doses of Voraxaze were administered intravenously; the number of doses was not specified in 13 patients. Doses ranged from 18 to 98 Units/kg, with a median dose of 49 Units/kg.

Study 2 is an ongoing expanded access program. At the time of data cut-off, 243 patients were enrolled and safety data was available for 141 patients. Voraxaze was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. The criterion for allowing patients to receive a second glucarpidase dose was not specified in the protocol. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after Voraxaze.

Study 2 enrolled patients with a median age of 17 years (6 months to 85 years); 64% were male, and the underlying malignancies were osteogenic sarcoma in 32%, and leukemia or lymphoma in 62% of patients. One (n=122) or 2 (n= 18) doses of Voraxaze were administered intravenously; the number of doses was not specified for 1 patient. Doses ranged from 6 to 189 Units/kg, with a median dose of 50 Units/kg.

In Study 2 only Voraxaze-related adverse reactions were collected and severity was graded according to NCI CTCAE version 3.

Among the 290 patients included in the safety evaluation of Voraxaze, there were 8 deaths within 30 days of Voraxaze exposure that were not related to progressive disease. Twenty-one of 290 patients (7%) experienced adverse reactions that were assessed as related to Voraxaze. Most were Grade 1 or 2 events. One patient experienced related Grade 3 flushing. The most common related adverse reactions that were not hematologic, hepatic or renal events were paresthesia, flushing, and nausea and/or vomiting, which each occurred in 2% of patients (Table 1).

Table 1: Per Patient Incidence of Grade 1 and 2 Adverse Reactions Assessed as Possibly, Probably, or Definitely Related to Voraxaze Excluding Hematologic, Hepatic, or Renal Adverse Reactions
1 This incidence includes the following terms: flushing, feeling hot, burning sensation.
2 One of these reactions was classified as Grade 3 in severity.
Adverse Reaction N= 290
n (%)
Paresthesias 7 (2%)
Flushing1,2 5 (2%)
Nausea/Vomiting 5 (2%)
Headache 2 (1%)
Hypotension 2 (1%)
Blurred Vision 1 (<1%)
Diarrhea 1 (<1%)
Hypersensitivity 1 (<1%)
Hypertension 1 (<1%)
Rash 1 (<1%)
Throat irritation/Throat tightness 1 (<1%)
Tremor 1 (<1%)

    Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials, 121 patients who received one (n=99), two (n=21), or three (n=1) doses of Voraxaze were evaluated for anti-glucarpidase antibodies. Twenty-five of these 121 patients (21%) had detectable anti-glucarpidase antibodies following Voraxaze administration, of which 19 received a single dose of Voraxaze and 6 received two doses of Voraxaze. Antibody titers were determined using a bridging enzyme-linked immunosorbent assay (ELISA) for anti-glucarpidase antibodies.

Neutralizing antibodies were detected in 11 of the 25 patients who tested positive for anti-glucarpidase binding antibodies. Eight of these 11 patients had received a single dose of Voraxaze. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors , including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Voraxaze with the incidence of antibodies to other products may be misleading.

Before receiving Voraxaze

If possible before you receive Voraxaze, tell your doctor if you are also being treated with leucovorin.

FDA pregnancy category C. It is not known whether Voraxaze will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether glucarpidase passes into breast milk or if it could harm a nursing baby. Do not use Voraxaze without telling your doctor if you are breast-feeding a baby.

In an emergency situation it may not be possible to tell your caregivers if you are pregnant or breast feeding. Make sure any doctor caring for your pregnancy or your baby knows you have received this medication.

Voraxaze side effects

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

What other drugs will affect Voraxaze?

Other drugs may interact with Voraxaze, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use, especially leucovorin.

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