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Safety

Rebound effect is defined as a MTX concentration increase of  at least 1 μmol/L and at least two times the post-Voraxaze® nadir.


Overall, half had a maximum absolute increase in MTX concentration of between 1 and 2 μmol/L

  • Only 1 had an increase of >10 μmol/L
  • Of the 4 who had rebound after their first Voraxaze® dose and received a second Voraxaze® dose, there was a median reduction of MTX concentration of 84% and 2 achieved a CIR



Abbreviations: CIR, clinically important reduction; HPLC, high-performance liquid chromatography; MTX, methotrexate.

UNDESIRABLE Effects1


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

Adverse reactions observed for Voraxaze® from the combination of pooled clinical study data (489 patients) and reported adverse reactions during the post marketing period. 


  • The incidence of adverse events related to Voraxaze® did not differ between paediatric
  • The safety profile of the nine patients who had 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


This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.


Abbreviations: DAMPA, 4-deoxy-4-amino-N10-methylpteroic.


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.

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.

Infusion-related reactions (IRR), hypersensitivity reactions

As with any intravenous protein product, IRR or hypersensitivity reactions are possible.

Anaphylaxis

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 Voraxaze® is administered.

Anti-drug antibodies

As with all therapeutic proteins, there is potential for immunogenicity. 205 patients who received 1 (n=176), 2 (n=27), or 3 (n=2) doses of Voraxaze® were evaluated for anti- Voraxaze® antibodies:

  • 43 (21%) had detectable anti-Voraxaze® antibodies following administration, of which 32 received 1 dose and 11 received 2 or 3 doses of Voraxaze®
  • Antibody titres were determined using a bridging enzyme-linked immunosorbent assay (ELISA) for anti-Voraxaze® antibodies
  • Neutralising antibodies were detected in 22 of the 43 patients who tested positive for anti-Voraxaze® binding antibodies