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Voraxaze is a brand name for Glucarpidase. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Voraxaze is indicated to reduce toxic plasma methotrexate concentration in adults and children (aged 28 days and older) with delayed methotrexate elimination or at risk of methotrexate toxicity.
Verbatim from this product's EMA label. Tap a section to expand.
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:
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.
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.
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.
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.
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 6 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.
4. 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. 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. 90 mL from the vial will provide an adequate amount of glucarpidase for dosing purposes. Flush intravenous line before and after administration.
1. 4 Special warnings and precautions for use Traceability 4 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. 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.
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Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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
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 national reporting system listed in Appendix V.
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.
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