Voraxaze

IV Preparation

Reconstitute the lyophilized powder in the vial with 1 mL of sterile saline for injection, USP

Do not shake

Roll and tilt the vial gently to mix

Inspect the vial and discard if the solution is not clear, colorless, and free of particulate matter

Use reconstituted solution immediately or store under refrigeration at 36-46°F (2-8°C) for up to 4 hr if not used immediately

Contains no preservative and is supplied as a single-use vial

Discard any unused product

IV Administration

Administer IV as a bolus over 5 minutes

Flush IV line before and after administration

Storage

Unopened vials are stable until date indicated on package when stored at refrigerated 36-46°F (2-8°C)

Reconstituted solution: May store under refrigeration at 36-46°F (2-8°C) for up to 4 hr if not used immediately

Do not freeze

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

FDA pregnancy category C. It is not known whether glucarpidase 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 this medication 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.

Antidote for methotrexate toxicity; recombinant bacterial enzyme.1 7 17

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of glucarpidase injection in children. However, safety and efficacy have not been established in children younger than 1 month of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of glucarpidase injection in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Leucovorin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Your doctor will check your progress closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it. Blood and urine tests may be needed to check for unwanted effects. Be sure to keep all appointments.

Serious allergic reactions may occur during treatment with glucarpidase. Check with your doctor right away if you have a fever; chills; flushing of the face; headache; hives; itching; rash; tightness of the throat; tingling or numbness sensation; troubled breathing; rash; swelling of the face, tongue, and throat; or chest pain after you receive the medicine.

• Tell all of your health care providers that you take Voraxaze. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If you are also taking another drug called leucovorin, keep taking it as you were told by your doctor. Do not take leucovorin within 2 hours before or after a dose of this medicine. Talk with your doctor.
• You may need to do other things to help treat high methotrexate levels. Talk with your doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Voraxaze while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach or throwing up.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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

    Mechanism of Action

Voraxaze (glucarpidase) is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. Voraxaze converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. Voraxaze provides an alternative non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.

    Pharmacodynamics

Plasma methotrexate concentrations within 48 hours following administration of Voraxaze can only be reliably measured by a chromatographic method because DAMPA interferes with the immunoassays [see Warnings and Precautions (5.2)]. Following administration of Voraxaze 50 Units/kg to patients in Study 1, methotrexate concentration measured by a chromatographic method was reduced by ≥ 97% within 15 minutes in all 22 treatment-evaluable patients, and was maintained at a > 95% reduction up to 8 days in 20 of the 22 patients [see Clinical Studies (14)].

    Pharmacokinetics

The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in eight healthy subjects following an intravenous injection of Voraxaze 50 Units/kg over 5 minutes. Serum glucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidase concentrations were measured by ELISA.

Serum glucarpidase activity levels declined with a mean elimination half-life (t1/2) of 5.6 hours. The mean Cmax was 3.3 μg/mL and the mean area under the curve (AUC0-inf) was 23.3 μg•h/mL. The mean systemic clearance (CL) was 7.5 mL/min. The mean volume of distribution (Vd) was 3.6 L, suggesting that glucarpidase distribution is restricted to plasma volume. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for a longer t1/2 of 9 hours.

Renal Impairment

The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in four subjects with severe renal impairment (creatinine clearance <30 mL/min). Following an intravenous dose of 50 Units/kg of Voraxaze, the mean pharmacokinetic parameters were similar to those observed in healthy subjects except for a longer t1/2 of 8.2 hours as compared to 5.6 hours in healthy subjects by the enzymatic assay.

Drug Interactions

In a study of cancer patients receiving a high-dose methotrexate (≥1 g/m2) and leucovorin rescue regimen, intravenous administration of 50 Units/kg Voraxaze 2 hours before leucovorin reduced (6S)-leucovorin AUC0-3h by 33% and Cmax by 52%, and also reduced its active metabolite, (6S)-5-methyltetrahydrofolate, AUC0-3h by 92% and Cmax by 93% [see Drug Interactions (7.1)].

    Carcinogenesis, Mutagenesis, Impairment of Fertility

Voraxaze has not been evaluated in animals for carcinogenic or mutagenic potential or for impairment of fertility.

Since Voraxaze is used as a single dose, it does not have a daily dosing schedule.

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