VORAXAZE Powder for solution for injection Ref.[28329] Active ingredients: Glucarpidase

Glucarpidase is intended for use under medical supervision.

In order to take into account all MTX doses and infusion durations that could be administered to a patient, it is recommended to utilise local treatment protocols or guidelines if available, to determine when glucarpidase should be administered.

Recommendations for intervention with glucarpidase are considered when plasma MTX levels are greater than 2 standard deviations of the mean expected MTX excretion curve. Also, administration of glucarpidase should optimally occur within 60 hours from the start of the HDMTX infusion, because life‐threatening toxicities may not be preventable beyond this time point. Clinical data however show that glucarpidase continues to be effective beyond this time window.

Recommendations for intervention with glucarpidase are detailed below:

^* start supportive care when ≥120 µM.

As a further guide for patients receiving short infusion MTX regimens, glucarpidase administration may be considered as detailed below:

Posology

The recommended dose is a single dose of 50 Units per kilogram (kg) by bolus intravenous (IV) injection over 5 minutes.

Once the diagnosis of delayed methotrexate (MTX) elimination or risk for MTX toxicity is established, glucarpidase should be administered without delay; for patients with delayed MTX elimination the optimal time window for administration is within 48–60 hours from the start of the high dose MTX infusion. Folinic acid, also known as leucovorin, is a competitive substrate of glucarpidase that may compete for the MTX binding sites (see also Section 4.5). It is therefore recommended that folinic acid should not be administered within the 2 hours before or after glucarpidase administration to minimise any potential interaction.

Intracellular MTX will continue to inhibit reduction of folate to its active form following glucarpidase administration thus folinic acid will continue to be needed no earlier than 2 hours post glucarpidase administration in order to replenish the intracellular source of biologically active folate. (see also Section 4.4)

Specific populations

Patients with renal impairment

A study of the pharmacokinetics of glucarpidase in the absence of MTX in 4 subjects with severe renal impairment (CLcr <30 mL/min) showed that the mean pharmacokinetic parameters were similar to those observed in healthy subjects. On this basis, no dose adjustment of glucarpidase is recommended for patients with renal impairment.

Paediatric population

No dose adjustment is required for the paediatric population. See section 4.4.

Method of administration

Reconstitute each vial of Voraxaze 1,000 units with 1 mL of sterile 0.9% sodium chloride solution before use. Reconstitution should take place immediately prior to use (do not further dilute). It should be administered intravenously by bolus intravenous injection over 5 minutes.

After reconstitution with 1 mL of sterile 0.9% sodium chloride solution each 1 mL will contain 1,000 units of glucarpidase.

A syringe suitable for withdrawing small volumes should be used to remove the solution from the vials. It may not always be possible to withdraw a full 1 mL from the vial but removal of at least 0.90 mL from the vial will provide an adequate amount of glucarpidase for dosing purposes.

Flush intravenous line before and after administration.

The safety profile of the nine patients who have received the highest doses of Voraxaze in clinical studies (single dose range of 90.9–188.7 U/kg and/or cumulative dose range of 150.0–201.8 U/kg) was similar to the safety profile of all patients.

In case of overdose, it is recommended to stop glucarpidase dosing, patients should be observed and appropriate supportive care should be provided.

Unopened vials: 4 years.

Chemical and physical in-use stability following reconstitution has been demonstrated for 24 hours at 2-8ºC. From a microbiological point of view, Voraxaze should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C–8°C).

Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

3 mL type 1 glass vials (Ph Eur) with a bromobutyl stopper and standard blue flip off seal.

Pack size of 1 vial.

Each vial should be reconstituted with 1 mL of sterile 0.9% sodium chloride solution. Reconstitution should take place immediately prior to use (do not further dilute). It should be administered intravenously by bolus intravenous injection over 5 minutes.

After reconstitution with 1 mL of sterile 0.9% sodium chloride solution each 1 mL will contain 1,000 units of glucarpidase. A syringe suitable for withdrawing small volumes should be used to remove the solution from the vials. It may not always be possible to withdraw a full 1 mL from the vial but removal of at least 0.90 mL from the vial will provide an adequate amount of glucarpidase for dosing purposes.

Any unused product or waste material should be disposed of in accordance with local requirements.