Consumer medicine information

Fasturtec

Rasburicase

BRAND INFORMATION

Brand name

Fasturtec

Active ingredient

Rasburicase

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fasturtec.

What is in this leaflet

This leaflet answers some common questions about Fasturtec.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you using Fasturtec against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Fasturtec is used for

Fasturtec contains rasburicase rys, which is a recombinant urate-oxidase enzyme. Fasturtec is used to prevent or to decrease the high levels of uric acid in your blood that can occur as a result of chemotherapy for cancers of the blood, such as leukemia or lymphoma. Normal amounts of uric acid in the blood are removed by the kidneys. If there are high levels of uric acid in the blood, your kidneys may not be able to remove the excess, and may be damaged. Fasturtec converts uric acid into a substance called allantoin, which is easier for your kidneys to remove.

Your doctor may have prescribed Fasturtec for another reason.

Ask your doctor or pharmacist if you have any questions about why this medicine has been prescribed for you.

Fasturtec is not addictive.

This medicine is available only with a doctor's prescription.

Before you are given Fasturtec

When you must not be given it

You should not be given Fasturtec if you have any of the following conditions;

  • G6PD (glucose-6-phosphate dehydrogenase) deficiency
  • Any condition that causes haemolytic anaemia

Do not use Fasturtec if you have an allergy to it, other uricases or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to Fasturtec may include skin rash, itchiness, shortness of breath, or difficulty breathing.

Do not use Fasturtec if you are pregnant or intend to become pregnant. Fasturtec is not recommended for use during pregnancy, unless you and your doctor have discussed the risks and benefits involved.

Do not use Fasturtec if you are breast-feeding or plan to breastfeed. It is not known whether Fasturtec passes into breast milk.

Do not use Fasturtec after the expiry date (EXP) printed on the pack. If you use this medicine after the expiry date has passed, it may not work (as well).

Do not use Fasturtec if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start using Fasturtec, talk to your doctor or pharmacist.

Before you are given it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Tell your doctor or pharmacist if you are pregnant or intend to become pregnant. Your doctor or pharmacist will discuss the possible risks and benefits of using Fasturtec during pregnancy.

Tell your doctor or pharmacist if you are breast-feeding or plan to breast-feed. Your doctor or pharmacist will discuss the possible risks and benefits of using Fasturtec during breastfeeding.

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • a previous history of allergy, asthma, or allergic reactions.

If you have not told your doctor or pharmacist about any of the above, tell them before you start using Fasturtec.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Fasturtec may interfere with each other.

Your doctor or pharmacist may have more information on medicines to be careful with or avoid while using Fasturtec.

How Fasturtec is given

How much is given

The dose of Fasturtec is calculated according to your body weight. The usual dose is 0.2 mg for each kilogram you weigh. Your doctor may change the dose in some circumstances. Fasturtec is normally given once a day, and may be given for a number of days.

How it is given

Fasturtec is given to you as an infusion into one of your veins (this is called an intravenous infusion). The infusion will be given over 30 minutes. Fasturtec must only be given under the supervision of a trained doctor.

If you are given too much (overdose)

Your doctor will decide what dose of Fasturtec you need, and this will be given under close supervision. The risk of an overdosage in these circumstances is low. In the event of an overdose occurring, your doctor will decide on the treatment necessary.

Your doctor or pharmacist has information on how to recognise and treat an overdose. Ask your doctor or pharmacist if you have any concerns.

While you are using Fasturtec

Things you must do

Tell any other doctors, dentists, and pharmacists who are treating you that you are using Fasturtec.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are using Fasturtec.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given this medicine.

If you become pregnant while you are being given this medicine, tell your doctor immediately.

Things you must not do

Do not give Fasturtec to anyone else, even if they have the same condition as you.

Do not use Fasturtec to treat any other complaints unless your doctor or pharmacist tells you to.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Fasturtec.

Fasturtec helps most people with high uric acid levels, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

If you get any side effects, do not stop using Fasturtec without first talking to your doctor or pharmacist.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • diarrhoea
  • fever
  • headache
  • nausea
  • vomiting
  • seizures

These are the most common side effects of Fasturtec. These side effects can also occur as a result of the chemotherapy drugs you may be receiving.

Tell your doctor or pharmacist immediately if you notice any of the following:

  • skin rash
  • hot flushes
  • tightness in the chest
  • difficulty in breathing

These may be signs of serious side effects. You may need urgent medical attention. Serious side effects are rare.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using Fasturtec

Storage

Fasturtec will normally be stored in the pharmacy or on the ward. The injection is kept refrigerated (2-8°C). Do not freeze it.

Disposal

If your doctor or pharmacist tells you to stop using Fasturtec or the injections have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Fasturtec comes as a clear glass vial containing a white powder, along with an ampoule containing liquid to dissolve the powder.

Ingredients

Active ingredients:

  • Each vial contains 1.5 mg rasburicase

Other ingredients:

  • Alanine
  • Mannitol
  • Dibasic sodium phosphate dihydrate
  • Monobasic disodium phosphate
  • Dibasic sodium phosphate dodecahydrate
  • Poloxamer
  • Water for injections

There are three ampoules and three vials in a carton.

Manufacturer

Fasturtec is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park
NSW 2113
Australia

AUST R 80836

Fasturtec is supplied in New Zealand by:

sanofi-aventis new zealand limited
56 Cawley Street
Ellerslie
Auckland

This leaflet was prepared in
December 2021

fasturtec-ccdsv06-cmiv3-07dec21

Published by MIMS March 2022

BRAND INFORMATION

Brand name

Fasturtec

Active ingredient

Rasburicase

Schedule

S4

 

1 Name of Medicine

Rasburicase.

2 Qualitative and Quantitative Composition

Each vial contains 1.5 mg rasburicase.
1 mg of rasburicase corresponds to 18.2 EAU. One enzyme activity unit (EAU) corresponds to the enzyme activity that converts 1 micromol of uric acid into allantoin per minute under the operating conditions described: +30°C ± 1°C TEA pH 8.9 buffer.
Rasburicase is a recombinant urate-oxidase enzyme produced by a genetically modified Saccharomyces cerevisiae strain. Rasburicase is a tetrameric protein with identical sub units of a molecular mass of about 34 kDa.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.
Crimped, colourless glass vial containing white to off-white pellet.

4 Clinical Particulars

4.1 Therapeutic Indications

Rasburicase is indicated for the treatment and prophylaxis of acute hyperuricaemia, in patients with haematological malignancy at risk of a rapid tumour lysis.

4.2 Dose and Method of Administration

Rasburicase is to be used immediately prior to and during the initiation of chemotherapy only, as at present, there is insufficient data to recommend multiple treatment courses.
In patients who are not hyperuricemic at baseline, chemotherapy regimens should be started within 24 hours of first administration of rasburicase. In patients who are hyperuricemic at baseline, chemotherapy regimens should be started within 48 hours of first administration of rasburicase.

Children and adults.

The recommended dose for rasburicase is 0.20 mg/kg/day. Rasburicase is administered as a once daily 30 minute intravenous infusion in 50 mL of a 0.9% sodium chloride solution. The duration of treatment with rasburicase may vary between 5 and 7 days. No dose adjustment is necessary for special populations (renally or hepatically impaired patients). Administration of rasburicase does not require any change in the timing or schedule of initiation of cytoreductive chemotherapy.

Administration.

Do not use an in-line filter. Rasburicase solution should be infused through a different line than that used for infusion of chemotherapeutic agents to prevent any possible drug incompatibility. If use of a separate line is not possible, the line should be flushed out with saline solution between chemotherapeutic agents infusion and rasburicase. Rasburicase should be administered under the supervision of a trained physician. It contains no antimicrobial agent. Rasburicase is for single use in one patient only. Discard any residue.

Uric acid analysis.

If it is necessary to monitor a patient's uric acid level, a strict sample handling procedure must be followed to minimise ex vivo degradation of the analyte. Blood must be collected into prechilled tubes containing heparin anticoagulant. Samples must be immersed in an ice/water bath. Plasma samples should immediately be prepared by centrifugation in a precooled centrifuge (4°C). Finally, plasma must be maintained in an ice/water bath and analysed for uric acid within 4 hours.

Preparation.

Rasburicase must be reconstituted with the solvent supplied and further diluted only in 0.9% sodium chloride injection. Do not use any glucose intravenous infusion for dilution due to potential incompatibility. This product should not be mixed with other drugs for its infusion.

Reconstitution of the solution.

Under controlled and validated aseptic conditions, add 1 mL of solvent to each vial containing 1.5 mg of rasburicase and mix by swirling very gently. Do not shake. Inspect visually prior to use. Only clear solutions without particles should be used. The solvent contains no preservative, therefore the solution should be reconstituted immediately prior to further dilution, and in no case be stored for longer than 24 hours at 2-8°C.

Dilution before infusion.

The required quantity of solution (according to the patient's bodyweight) is to be further diluted with 0.9% sodium chloride injection to make up a total volume of 50 mL. As the reconstituted solution contains no preservative the diluted solution should be infused immediately, and in no case be stored for longer than 24 hours at 2-8°C.

Infusion.

The final solution should be infused over 30 minutes. Rasburicase solution should be infused through a different line from that used for infusion of chemotherapeutic agents, to prevent any possible drug incompatibility. If use of a separate line is not possible, the line should be flushed out with saline solution between chemotherapeutic agents infusions and rasburicase.

4.3 Contraindications

Hypersensitivity to rasburicase, other uricases or any of the excipients.
G-6-PD deficiency and other cellular metabolic disorders known to cause haemolytic anaemia. (Hydrogen peroxide is a byproduct of the conversion of uric acid to allantoin. In order to prevent possible haemolytic anaemia induced by hydrogen peroxide, rasburicase is contraindicated in patients with these disorders).

4.4 Special Warnings and Precautions for Use

Administration of rasburicase reduces the uric acid level to below normal levels and by this mechanism reduces the chance of development of renal failure due to precipitation of uric acid crystals in renal tubules as a consequence of hyperuricaemia. Tumour lysis can also result in hyperphosphataemia, hyperkalaemia and hypocalcaemia. Rasburicase is not directly effective in the treatment of these abnormalities. Therefore, patients must be monitored closely.

Hypersensitivity.

Rasburicase, like other proteins, has the potential to induce allergic responses in humans, including anaphylaxis and/or anaphylactic shock with potential fatal outcome. Clinical experience with rasburicase demonstrates that patients should be closely monitored for the onset of allergic type undesirable effects, especially skin allergic reactions, bronchospasm or severe hypersensitivity reactions including anaphylaxis (see Section 4.8 Adverse Effects (Undesirable Effects)). In case of severe allergic reaction, treatment should be immediately and permanently discontinued and appropriate therapy initiated.
Caution should be used in patients with a history of atopic allergies.
At the present, there is insufficient data available on patients being retreated to recommend multiple treatment courses. Antirasburicase antibodies have been detected in treated patients and healthy volunteers administered rasburicase. In healthy volunteers, 53% subjects receiving rasburicase had antirasburicase antibodies one month post-last dose. Most of the positive subjects were no longer positive at 1 year.
Methaemoglobinaemia has been reported in patients receiving rasburicase. It is not known whether patients with deficiency of methaemoglobin reductase or of other enzymes with antioxidant activity are at increased risk of methaemoglobinaemia. Rasburicase should be immediately and permanently discontinued in patients having developed methaemoglobinaemia, and appropriate measures initiated.
Haemolysis has been reported in patients receiving rasburicase. In such cases, treatment should be immediately and permanently discontinued and appropriate measures initiated.
Rasburicase has not been investigated in patients with hyperuricaemia in the context of myeloproliferative disorders.
There is no data available to recommend the sequential use of rasburicase and allopurinol.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vivo drug-drug interaction studies have not been conducted. In rats and baboons, rasburicase did not appear to induce or inhibit hepatic cytochrome P450 isoforms. In vitro, rasburicase did not metabolise 6-mercaptopurine monohydrate, cytarabine or methotrexate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility were observed in male and female rats at intravenous doses up to 10 mg/kg/day at which systemic exposure (plasma AUC) was about 12 times greater than that in humans at the maximum recommended dose. The interpretation of the preclinical studies is hampered due to the presence of endogenous urate oxidase in standard animal models.
(Category B2)
No clinical data on exposed pregnancies are available. Rasburicase has been shown to be teratogenic in rabbits given doses of 10, 50 and 100 times the human dose and in rats given doses 250 times the human dose. Animal studies with respect to effects on parturition and postnatal development have not been performed. The potential risk for humans is unknown. Rasburicase should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.
 It is unknown whether rasburicase is excreted in human milk, therefore it should not be used in breastfeeding women.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Because rasburicase is concomitantly administered as supportive care to cytoreductive chemotherapy of advanced malignancies, a significant burden of adverse events is expected from the underlying disease state and its treatment.
Undesirable effects possibly attributable to rasburicase reported in clinical trials involving 347 subjects are shown in Table 1.
The most significant drug related adverse events were allergic reactions, mainly rashes (1.4%) and urticaria. Cases of rhinitis, hypotension, bronchospasm (< 1%) and severe hypersensitivity reactions including anaphylaxis (< 1%) have also been attributed to rasburicase.
Because the enzymatic conversion of uric acid to allantoin by rasburicase produces hydrogen peroxide, haemolytic anaemia and methaemoglobinaemia have been observed in certain at risk populations such as those with G-6-PD deficiency. In trials, 0.9% subjects developed haemolytic anaemia, one of these subjects was documented to have G-6-PD deficiency.

Postmarketing data.

Adverse reactions reported during the postmarketing period are detailed below. These reactions are classified within body system categories using the following definitions:
Very common: ≥ 1/10 (≥ 10%), common: ≥ 1/100 and < 1/10 (≥ 1% and < 10%), uncommon: ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1.0%), rare: ≥ 1/10,000 and < 1/1000 (≥ 0.01% and < 0.1%), very rare: < 1/10,000 (< 0.01%), not known: frequency cannot be estimated from available data.

Nervous system disorders.

Uncommon: convulsion. Frequency not known: muscle contractions involuntary.

Blood and lymphatic system disorders.

Uncommon: haemolysis which could be related to G-6-PD deficiency, methemoglobinemia.

Immune system disorders.

Common: allergic reactions. These mainly include rash and urticaria.
Cases of rhinitis, bronchospasm, hypotension, anaphylaxis and/or anaphylactic shock with potential fatal outcome have been reported.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

In view of the mechanism of action of rasburicase, an overdose will lead to low or undetectable plasma uric acid concentrations and increased production of hydrogen peroxide.

Management.

Thus patients suspected of receiving an overdose should be monitored for haemolysis, and general supportive measures should be initiated as no specific antidote for rasburicase has been identified.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment, ATC code: V03AF07.

Mechanism of action.

In humans, uric acid is the final step in the catabolic pathway of purines. The acute increase in plasma levels of uric acid subsequent to the lysis of large numbers of malignant cells and during cytoreductive chemotherapy may lead to degradation of renal function and renal failure which results from the precipitation of crystals of uric acid in renal tubules. Rasburicase is a potent uricolytic agent that catalyses enzymatic oxidation of uric acid into allantoin, a water soluble product, more easily excreted by the kidney in the urine. The enzymatic oxidation of uric acid leads to stoichiometric formation of hydrogen peroxide. The increase of hydrogen peroxide over ambient levels can be eliminated by endogenous antioxidants and the only increased risk for haemolysis is in G-6-PD deficient and inherited anaemia patients.
In healthy volunteers, a marked dose related decrease in plasma uric acid levels was observed across the dose range 0.05 mg/kg to 0.20 mg/kg of rasburicase. This dose related decrease in plasma uric acid levels was seen within four hours post-first dose and remained for up to 24 hours post-last dose of rasburicase.

Clinical trials.

ACT2511 (n = 107) and ACT2694 (n = 131) were phase II, open label, multicentre studies of rasburicase used as uricolytic therapy for the prophylaxis and treatment of hyperuricaemia in patients with leukemia or lymphoma. Patients in ACT2511 received 0.15 mg/kg, while those in ACT2694 received either 0.15 mg/kg (n = 12) or 0.20 mg/kg (n = 119). Primary endpoint was plasma uric acid concentrations over time. Overall, plasma uric acid fell rapidly after the first dose, and remained several-fold below the mean baseline value during rasburicase treatment. The mean percentage reduction (± SD) in uric acid four hours after the first dose was 88% ± 12% in ACT2511 and 84.9% ± 12.6% in ACT2694. (See Table 2.)
EFC2975 was a randomised, multicentre open label phase III study, comparing rasburicase (n = 27) 0.20 mg/kg versus allopurinol (n = 25) for the treatment and prophylaxis of hyperuricaemic patients with leukemia and lymphoma. At 4 hours after the first dose, there was a significant difference (p < 0.0001) in the mean percent reduction from baseline plasma uric acid concentration in the rasburicase group (86.0 ± 7.0%) compared to that for the allopurinol group (12.1 ± 13.3%). Time to first confirmation of normal levels of uric acid in hyperuricaemic patients is four hours for rasburicase and 24 hours for allopurinol. Rasburicase induced excretion of the serum phosphate load prevented further deterioration of renal function from calcium/phosphorus precipitation. (See Table 3.)

5.2 Pharmacokinetic Properties

After infusion of rasburicase at a dose of 0.20 mg/kg/day, steady state is achieved at day 2-3. No unexpected accumulation of rasburicase was observed. In patients the volume of distribution ranged from 110-127 mL/kg, which is comparable to the physiological vascular volume. Clearance of rasburicase was ca. 3.5 mL/h/kg and the elimination half-life ca. 19 hours. The patients included in the pharmacokinetic studies were mainly children and adolescents. Based upon these limited data, it seems that clearance is increased (ca. 35%) in children and adolescents compared to adults, resulting in a lower systemic exposure.
Rasburicase is a protein, and therefore: 1) not expected to bind to proteins; 2) expected that metabolic degradation will follow the pathways of other proteins, i.e. peptide hydrolysis, 3) unlikely to be candidate for drug-drug interactions.
Renal elimination of rasburicase is considered to be a minor pathway for rasburicase clearance. As metabolism is expected to occur by peptide hydrolysis, impaired liver function is not expected to affect the pharmacokinetics.

5.3 Preclinical Safety Data

Genotoxicity.

Assays for gene mutations (histidine reversion in S. typhimurium and mouse lymphoma gene mutation assay), chromosomal damage (cytogenetics in human peripheral blood lymphocytes in vitro and micronucleus test in rats in vivo) and DNA damage (in vitro rat hepatocyte assay) did not provide any evidence of a genotoxic potential.

Carcinogenicity.

Long-term animal studies on carcinogenicity are not available.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients contained in the Fasturtec 1.5 mg vials are: alanine, mannitol, dibasic sodium phosphate dihydrate, monobasic sodium phosphate, dibasic sodium phosphate dodecahydrate. The solvent contains poloxamer and water for injections.

6.2 Incompatibilities

Rasburicase solution should be infused through a different line from that used for infusion of chemotherapeutic agents, to prevent any possible drug incompatibility. If use of a separate line is not possible, the line should be flushed out with saline solution between chemotherapeutic agents infusions and rasburicase.
Do not use any glucose intravenous infusion for dilution due to potential incompatibility. This product should not be mixed with other drugs for its infusion.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. (Refrigerate. Do not freeze).

Reconstituted solution.

The solvent contains no preservative, therefore the solution should be reconstituted immediately prior to further dilution, and in no case be stored for longer than 24 hours at 2-8°C.

Diluted solution.

As the reconstituted solution contains no preservative the diluted solution should be infused immediately, and in no case be stored for longer than 24 hours at 2-8°C.

6.5 Nature and Contents of Container

Fasturtec is a sterile powder supplied in a stoppered clear glass vial, accompanied by a solvent in a clear glass ampoule.
Package size: 3 vials of rasburicase and 3 ampoules of solvent per box.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

No data available.

CAS number.

134774-45-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes