4.1. Therapeutic indications

Voraxaze is indicated to reduce toxic plasma methotrexate concentration in adults and children (aged 28 days and older) with delayed methotrexate elimination.

4.2. Posology and method of administration

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 national or 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:

MTX Dose:

≤ 1 g/m2

1-8 g/m2

8-12 g/m2

Infusion duration:

Over 36-42 hours

Over 24 hours

Over ≤ 6 hours

Hours following start of MTX infusion

Threshold plasma MTX concentration (µM)

24 hours

-

-*

≥ 50

36 hours

-

≥ 30

≥ 30

42 hours

-

≥ 10

≥ 10

48 hours

≥ 5

≥ 5

≥ 5

*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:

MTX Dose:

3-3.5 g/m2

5 g/m2

Hours following start of MTX infusion

Threshold plasma MTX concentration (µM)

24 hours

≥ 20

-

36 hours

-

≥ 10

48 hours

≥ 5

≥ 6

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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.

Paediatric population

No formal evaluation of the effect of age on the pharmacokinetics of glucarpidase has been performed.

No data are available in children aged less than 28 days.

It is important to measure baseline plasma MTX concentations and renal function and to continue to monitor these throughout treatment with high dose MTX therapy, as described below.

A high performance chromatography (HPLC) method is recommended for measuring MTX concentrations following glucarpidase administration. Current immunoassays are unreliable for samples collected following glucarpidase administration due to 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA), an inactive metabolite of MTX formed following glucarpidase administration, interfering with the measurement of MTX concentration. This interference results in an overestimation of the MTX concentration. The effect of DAMPA interference will decline over time as DAMPA is eliminated.

DAMPA concentrations in patients treated with glucarpidase fell within a mean half-life of 8.6 hours. In the majority of patients DAMPA concentrations had fallen to below 1 µmol/l within 48 hours of administration of glucarpidase. In clinical studies, DAMPA concentrations above 1 µmol/L have been observed beyond 3 days in a small minority (≤3%) of patients.

In the absence of more specific HPLC assay it is recommended that the dose of folinic acid used in a 48 hour-period after glucarpidase should be based on the MTX concentration from a sample taken prior to glucarpidase administration. Within 48 hours after glucarpidase administration MTX concentrations determined by immunoassay may not be reliably used to monitor for rebound and confirmatory HPLC data should be considered.

Over 48 hours after glucarpidase administration immunoassay results will be reliable in the majority of patients and so can be used to adjust the folinic acid dose or monitor for rebound. In clinical studies, ~9% patients with baseline MTX concentration ≥ 50µmol/l had DAMPA levels that persisted above 1 µmol/l beyond 4 days.

Routine monitoring of plasma MTX concentrations should be continued in accordance with local guidelines.

Glucarpidase does not reverse pre-existing renal damage or renal failure that occurs as a consequence of MTX administration, but instead removes MTX to reduce the risk of sustaining further renal toxicity. As such, other supportive care, including hydration and alkalinisation of the urine, should be started at the onset of MTX administration and continued in accordance with local treatment guidelines.

Allergic type hypersensitivity reactions are possible following adminstration of glucarpidase see section 4.8.

4.5. Interaction with other medicinal products and other forms of interaction

Glucarpidase can decrease folinic acid concentration, which may decrease the effect of folinic acid rescue unless it is dosed as recommended (see section 4.2).

Glucarpidase may also reduce the concentrations of other folate analogs or folate analog metabolic inhibitors.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of glucarpidase in pregnant women. Glucarpidase is administered in combination with MTX, which is contraindicated in pregnancy. As use of MTX, a genotoxic and teratogenic agent, is a prerequisite for the use of glucarpidase, the medicinal product is not thought to present an additional risk to patients already receiving MTX. Reproductive studies of glucarpidase in animals were not performed. It is unknown whether glucarpidase causes harmful effects during pregnancy and/or on the foetus/newborn child or whether it can affect reproductive capacity. Glucarpidase should only be given to a pregnant woman if clearly needed.

Breast-feeding

It is unknown whether glucarpidase/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from glucarpidase therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There is no or limited amount of data on the impact of glucarpidase on human fertility. Fertility studies in animals were not performed. It is unknown whether glucarpidase affects fertility.

4.7. Effects on ability to drive and use machines

Glucarpidase has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most frequent related adverse reactions were burning sensation (<1%), headache (<1%), paraesthesia (2%), flushing (2%), feeling hot (<1%).

Tabulated summary of adverse reactions

Table 1 gives the adverse reactions observed from the combination of pooled clinical study data (489 patients) and reported adverse reactions during the Post Marketing period. The adverse reactions are presented by system organ class and frequency categories defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000). Within each frequency grouping undesirable effects are presented in order of decreasing seriousness

Table 1 Adverse reactions reported for glucarpidase

System organ class

Frequency

Adverse reactions

Immune system disorders

Rare

Hypersensitivity

Very Rare

Anaphylactic reaction

Nervous system disorders

Uncommon

Burning sensation, Headache, Paraesthesia

Rare

Hypoaesthesia, Somnolence, Tremor

Cardiac disorders

Very Rare

Tachycardia

Vascular disorders

Uncommon

Flushing

Rare

Hypotension

Respiratory, thoracic and mediastinal disorders

Rare

Pleural effusion, Throat tightness

Gastrointestinal disorders

Rare

Abdominal pain upper, Diarrhoea, Nausea, Vomiting

Skin and subcutaneous tissue disorders

Rare

Pruritus, Rash

Very Rare

Drug eruption, Skin reaction

Renal and urinary disorders

Very Rare

Crystalluria*

General disorders and administration site conditions

Uncommon

Feeling hot

Rare

Pyrexia, Rebound effect

Very Rare

Infusion site reaction

*Crystalluria is the preferred term; the adverse reaction refers to DAMPA crystalluria

Description of selected adverse reactions

As with any intravenous protein product, infusion-related reactions or hypersensitivity reactions are possible.

It is recommended that patients are monitored for signs and symptoms of anaphylaxis and an acute allergic reaction. Medical support must be readily available when glucarpidase is administered.

As with all therapeutic proteins, there is potential for immunogenicity. 205 patients who received one (n=176), 2 (n=27), or 3 (n=2) doses of glucarpidase were evaluated for anti-glucarpidase antibodies. Forty-three of these 205 patients (21%) had detectable anti-glucarpidase antibodies following administration, of which 32 received 1 dose and 11 received 2 or 3 doses of glucarpidase. Antibody titers were determined using a bridging enzyme-linked immunosorbent assay (ELISA) for anti- glucarpidase antibodies. Neutralizing antibodies were detected in 22 of the 43 patients who tested positive for anti-glucarpidase binding antibodies.

Paediatric population

The incidence of adverse events related to glucarpidase did not differ between paediatric and adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.