VORAXAZE 1000 UNITATI powder for injection medication leaflet

Voraxaze 1,000 units powder for solution for injection.

After reconstitution with 1 mL of sterile 0.9% sodium chloride solution, each vial contains a nominal1,000 units of glucarpidase*.

*Produced in Escherichia coli cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

White to off-white powder for solution for injection.

Voraxaze is indicated to reduce toxic plasma methotrexate concentration in adults and children (aged28 days and older) with delayed methotrexate elimination or at risk of methotrexate toxicity.

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 apatient, it is recommended to utilise local treatment protocols or guidelines if available, to determinewhen glucarpidase should be administered.

Recommendations for intervention with glucarpidase are considered when plasma MTX levels aregreater than 2 standard deviations of the mean expected MTX excretion curve. Also, administration ofglucarpidase should optimally occur within 60 hours from the start of the HDMTX infusion, becauselife‐threatening toxicities may not be preventable beyond this time point. Clinical data however showthat 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 - -* ≥ 5036 hours - ≥ 30 ≥ 3042 hours - ≥ 10 ≥ 1048 hours ≥ 5 ≥ 5 ≥ 5

*start supportive care when ≥ 120 µM.

As a further guide for patients receiving short infusion MTX regimens, glucarpidase administration maybe 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 - ≥ 1048 hours ≥ 5 ≥ 6

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 isestablished, glucarpidase should be administered without delay; for patients with delayed MTXelimination the optimal time window for administration is within 48-60 hours from the start of thehigh dose MTX infusion. Folinic acid, also known as leucovorin, is a competitive substrate ofglucarpidase that may compete for the MTX binding sites (see also Section 4.5). It is thereforerecommended that folinic acid should not be administered within the 2 hours before or afterglucarpidase administration to minimise any potential interaction.

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

Section 4.4)

A study of the pharmacokinetics of glucarpidase in the absence of MTX in 4 subjects with severe renalimpairment (CLcr <30 mL/min) showed that the mean pharmacokinetic parameters were similar tothose observed in healthy subjects.

On this basis, no dose adjustment of glucarpidase is recommended for patients with renal impairment.

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

Reconstitute each vial of Voraxaze 1,000 units with 1 mL of sterile 0.9% sodium chloride solutionbefore use. Reconstitution should take place immediately prior to use (do not further dilute). It shouldbe 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 contain1,000 units of glucarpidase.

A syringe suitable for withdrawing small volumes should be used to remove the solution from thevials. It may not always be possible to withdraw a full 1 mL from the vial but removal of at least0.90 mL from the vial will provide an adequate amount of glucarpidase for dosing purposes.

Flush intravenous line before and after administration.

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

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

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 tomonitor these throughout treatment with high dose MTX therapy, as described below.

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

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 ofadministration of glucarpidase. In clinical studies, DAMPA concentrations above 1 µmol/L have beenobserved 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 a48 hour-period after glucarpidase should be based on the MTX concentration from a sample takenprior to glucarpidase administration. Within 48 hours after glucarpidase administration MTXconcentrations determined by immunoassay may not be reliably used to monitor for rebound andconfirmatory HPLC data should be considered.

Over 48 hours after glucarpidase administration immunoassay results will be reliable in the majority ofpatients 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 1µmol/l beyond 4 days.

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

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

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

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

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

There are no data from the use of glucarpidase in pregnant women. Glucarpidase is administered incombination with MTX, which is contraindicated in pregnancy. As use of MTX, a genotoxic andteratogenic agent, is a prerequisite for the use of glucarpidase, the medicinal product is not thought topresent an additional risk to patients already receiving MTX. Reproductive studies of glucarpidase inanimals were not performed. It is unknown whether glucarpidase causes harmful effects duringpregnancy 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.

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

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

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

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

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 reactionsare 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 inorder 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 andmediastinal disorders Rare Pleural effusion, Throat tightness

Gastrointestinal disorders Rare Abdominal pain upper, Diarrhoea, Nausea,

Skin and subcutaneous Rare Pruritus, Rashtissue disorders Very Rare Drug eruption, Skin reaction

Renal and urinarydisorders Very Rare Crystalluria*

General disorders and Uncommon Feeling hotadministration site Rare Pyrexia, Rebound effectconditions Very Rare Infusion site reaction

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

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

It is recommended that patients are monitored for signs and symptoms of anaphylaxis and an acuteallergic 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 followingadministration, of which 32 received 1 dose and 11 received 2 or 3 doses of glucarpidase. Antibodytiters were determined using a bridging enzyme-linked immunosorbent assay (ELISA) foranti- glucarpidase antibodies. Neutralizing antibodies were detected in 22 of the 43 patients whotested positive for anti-glucarpidase binding antibodies.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The safety profile of the nine patients who have received the highest doses of Voraxaze in clinicalstudies (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 andappropriate supportive care should be provided.

Pharmacotherapeutic group: Detoxifying agent for antineoplastic treatment, ATC code: V03AF09.

Mechanism of action and pharmacodynamic effects

Glucarpidase is a recombinant bacterial enzyme that hydrolyses the carboxyl-terminal glutamateresidue from folic acid and structurally related molecules such asMTX. Glucarpidase converts MTX toits inactive metabolites DAMPA and glutamate. Because both DAMPA and glutamate are metabolisedby the liver, glucarpidase provides an alternative route for MTX elimination in patients with renaldysfunction during high-dose MTX treatment.

Due to its large molecular size, glucarpidase does not cross the cellular membrane and therefore doesnot counteract the intracellular antineoplastic effects of high-dose MTX.

The efficacy of glucarpidase has been evaluated in four open-label multi-center, compassionate use,single arm, open label studies in patients with delayed MTX elimination due to renal dysfunction. Theprimary endpoint in the clinical studies was referred to as a clinically important reduction (CIR) in

MTX concentration and was based on central MTX HPLC data. A patient was considered to haveachieved a CIR if all central MTX HPLC plasma concentrations after the first dose of glucarpidasewere ≤1 µmol/L.

In Study 001, 44 male and female patients were in the Safety population (median age 53.0; range 10 -78 years) and received a median dose of 50 U/kg (range 9.80 to 58.14 U/kg). Of the 28 patients withcentral HPLC data, 85.7% (95% CI: 68.5% to 94.3%) achieved a CIR.

In Study 002, 214 male and female patients were in the Safety population (median age 17.0; range 0 -82 years) and received a median dose of 49.23 U/kg (range 10.87 to 63.73 U/kg). Of the 84 patientswith central HPLC data, 54.8% (95% CI: 44.2% to 65.0%) achieved a CIR.

In Study 003, 69 male and female patients were in the Safety population (median age 15.0; range 0 -71 years) and received a median dose of 50 U/kg (range 16.64 to 100 U/kg). Of the 30 patients withcentral HPLC data, 66.7% (95% CI: 48.8% to 80.8%) achieved a CIR.

In Study 006, 149 male and female patients were in the Safety population (median age 18.0; range 10- 78 years) and received a median dose of 48.73 U/kg (range 17.86 to 98.04 U/kg). Of the 27 patientswith central HPLC data, 51.9% (95% CI: 34.0% to 69.3%) achieved a CIR.

A total of 169 patients were included in the pooled central MTX HPLC population and received amedian initial dose of 50 Units/kg (range 11 to 60 Units/kg). A CIR was achieved by 61.5% (95% CI:54.0% to 68.5%) of patients in the central MTX HPLC population that was sustained for up to 8 days.

Amedian reduction of > 98% in MTX concentration occurred within 15 minutes followingglucarpidase administration.

Rebound (defined as MTX concentration increase of at least 1 μmol/L and at least two times the post-glucarpidase nadir) occurred in 19.4% of patients in the central MTX HPLC population. Overall halfof the patients with rebound had a maximum absolute increase in MTX concentration of between 1and 2 µmol/L, and only 1 patient had an increase of >10 µmol/L (this patient had a pre-glucarpidase

MTX concentration of 165.86 µmol/L and received a glucarpidase dose of 10.53 U/kg). Of the 4patients who had rebound after their first glucarpidase dose and received a second glucarpidase dose,there was a median reduction of MTX concentration of 84% and 2 achieved a CIR.

Of the 410 patients in the pooled renal evaluable population (patients who had at least one post-glucarpidase renal function assessment) who developed serum creatinine (sCr) common toxicitycriteria grade ≥2 at pre-glucarpidase baseline, 262 (63.9%) recovered to grade 0 or 1. In the renalevaluable population there was a 3.5-fold increase in mean sCr concentration from pre-MTX to pre-glucarpidase baseline (0.79mg/dL to 2.79 mg/dL). After administration of glucarpidase, sCr continuedto rise (mean increase of 0.24 mg/dL over three days), then began to decrease. The mean sCr value atday 22 was 1.27 mg/dL. For the 258 patients for whom days to recovery could be calculated, themedian time to recovery was 12.5 days (range 1-213 days).

The pooled clinical safety database for glucarpidase includes data for 232 patients up to 17 years ofage. Within the central MTX HPLC population 0% (0/1) patient aged ≥28 days to <2 years (Infant

Subgroup), 31.3% (5/16) patients aged ≥2 to <12 years (Child Subgroup) and 49.1% 27/55 patientsaged ≥12 to <18 years of age achieved a CIR. A median reduction of ≥ 95% in MTX concentrationoccurred within 15 minutes following glucarpidase administration in all paediatric subgroups.

This medicinal product has been authorised under “Exceptional Circumstances”. This means that dueto the rarity of the disease and for ethical reasons it has not been possible to obtain completeinformation on this medicinal product. The European Medicines Agency will review any newinformation which may become available every year and this SmPC will be updated as necessary.

The pharmacokinetics of glucarpidase in the absence of MTX were studied in 8 healthy subjectsfollowing glucarpidase 50 Units/kg administered as an intravenous injection over 5 minutes. Serumglucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidaseconcentrations were measured by enzyme linked immunosorbent assay (ELISA). The mean maximumserum concentration (Cmax) was 3.3 μg/mL and the mean area under the curve (AUC0-INF) was23.3 μg·h/mL. The pharmacokinetic parameters derived from the serum total glucarpidaseconcentrations were similar to those generated by serum glucarpidase activity levels except forelimination half-life as described below.

A clinically relevant accumulation of glucarpidase after a repeat injection within a MTX cycle has notbeen observed.

The mean volume of distribution (Vd) was 3.55 L.

The product is an enzyme, and therefore a protein. The metabolism of such products entails thedegradation to small peptides and individual amino acids and therefore, the metabolic pathways aregenerally understood. Classical biotransformation studies are therefore not required and have not beenconducted.

The ability of the main metabolite produced by the action of glucarpidase on MTX (DAMPA) toinduce or inhibit CYP450 metabolising isoenzymes has been investigated in vitro, which revealedpossible enzyme induction with CYP1A2 and CYP2C9. Modest induction would only be expected in aminority of patients who have the highest DAMPA exposure.

Serum glucarpidase activity levels declined with a mean elimination half-life (t1/2) of 5.6 hours andserum total glucarpidase concentration declined with a mean t1/2 of 9 hours. The mean systemicclearance (CL) was 7.5 mL/min.

A study of the pharmacokinetics of glucarpidase in the absence of MTX in 4 subjects with severe renalimpairment (CLcr <30 mL/min) showed that the mean pharmacokinetic parameters were similar tothose observed in healthy subjects.

On this basis, no dose adjustment of glucarpidase is recommended for patients with renal impairment.

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

Generally, effects in non-clinical studies were observed at exposures considered sufficiently in excessof the maximum human exposure indicating little relevance to clinical use.

The carcinogenic, genotoxic and reproductive toxicity potential of glucarpidase have not been studied.

Decreased platelets were reported in a 14 day dog study and intravenous human equivalent doses of278 and 1389 Units/kg were associated with increasing severe dose related toxicity which resulted indeaths or premature euthanasia.

Trometamol

Zinc acetate dihydrate

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts (see section 6.6).

Unopened vials: 5 years

Chemical and physical in-use stability following reconstitution has been demonstrated for 24 hours at2-8ºC. From a microbiological point of view, Voraxaze should be used immediately afterreconstitution. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unlessreconstitution 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. Reconstitutionshould take place immediately prior to use (do not further dilute). It should be administeredintravenously by bolus intravenous injection over 5 minutes.

After reconstitution with 1 mL of sterile 0.9% sodium chloride solution each 1 mL will contain1,000 units of glucarpidase. A syringe suitable for withdrawing small volumes should be used toremove the solution from the vials. It may not always be possible to withdraw a full 1 mL from thevial but removal of at least 0.90 mL from the vial will provide an adequate amount of glucarpidase fordosing purposes.

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

SERB SAS40 Avenue George V75008 Paris

France

EU/1/21/1586/001

Date of first authorisation: 11 January 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu