Fasturtec 1.5 mg/ml powder and solvent for concentrate for solution for infusion.

After reconstitution, 1 ml of Fasturtec concentrate contains 1.5 mg rasburicase.

Fasturtec is a recombinant urate-oxidase enzyme produced by genetically modified Saccharomyces cerevisiae strain. Rasburicase is a tetrameric protein with identical subunits of a molecular mass of about 34 kDa.

1 mg corresponds to 18.2 EAU*.

*One enzyme activity unit (EAU) corresponds to the enzyme activity that converts 1 μmol of uric acid into allantoin per minute under the operating conditions described: +30 °C ± 1 °C TEA pH 8.9 buffer.

For a full list of excipients, see section 6.1.

Powder and solvent for concentrate for solution for infusion.

The powder is an entire or broken white to off white pellet.

The solvent is a colourless and clear liquid.

Treatment and prophylaxis of acute hyperuricaemia, in order to prevent acute renal failure, in patients with haematological malignancy with a high tumour burden and at risk of a rapid tumour lysis or shrinkage at initiation of chemotherapy.

Fasturtec should be administered under the supervision of a physician trained in chemotherapy of haematological malignancies.

Fasturtec is to be used immediately prior to and during the initiation of chemotherapy only, as at the present, there is insufficient data to recommend multiple treatment courses.

The recommended dose for Fasturtec is 0.20 mg/kg/day. Fasturtec is administered as a once daily 30 minute intravenous infusion in 50 ml of a sodium chloride 9 mg/ml (0.9%) solution (see section 6.6).

The duration of treatment with Fasturtec may be up to 7 days, the exact duration should be based upon adequate monitoring of uric acid levels in plasma and clinical judgment.

Administration of rasburicase does not require any change in the timing or schedule of initiation of cytoreductive chemotherapy.

Rasburicase solution should be infused over 30 minutes. 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 infusion of chemotherapeutic agents and rasburicase. For instruction on use, see section 6.6.

Because rasburicase may degrade uric acid in vitro, special precautions must be used during sample handling for plasma uric acid measurements, see section 6.6.

Additional information on special populations

Renally or hepatically impaired patients: No dose adjustment is necessary.

Paediatric patients: As no adjustment is necessary, the recommended dose is 0.20 mg/kg/day.

Hypersensitivity to the active substance or to any of the excipients.

G6PD deficiency and other cellular metabolic disorders known to cause haemolytic anaemia. Hydrogen peroxide is a by-product 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.

Rasburicase like other proteins, has the potential to induce allergic responses in humans. Clinical experience with Fasturtec demonstrates that patients should be closely monitored for the onset of allergic-type undesirable effects, especially severe hypersensitivity reactions including anaphylaxis (see section 4.8). In such cases, treatment should immediately and permanently be discontinued and appropriate therapy initiated.

Caution should be used in patients with a history of atopic allergies.

At present, there is insufficient data available on patients being retreated to recommend multiple treatment courses. Anti-rasburicase antibodies have been detected in treated patients and healthy volunteers administered rasburicase.

Methaemoglobinaemia has been reported in patients receiving Fasturtec. Fasturtec should immediately and permanently be discontinued in patients having developed methaemoglobinaemia, and appropriate measures initiated (see section 4.8).

Haemolysis has been reported in patients receiving Fasturtec. In such case, treatment should immediately and permanently be discontinued and appropriate measures initiated (see section 4.8).

Administration of Fasturtec reduces the uric acid levels 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. Fasturtec is not directly effective in the treatment of these abnormalities. Therefore, patients must be monitored closely.

Fasturtec has not been investigated in the patients with hyperuricemia in the context of myeloproliferative disorders.

There is no data available to recommend the sequential use of Fasturtec and allopurinol.

To ensure accurate measurement of uric acid plasma level during treatment with Fasturtec, a strict sample handling procedure must be followed (see section 6.6).

No metabolism studies have been performed. Rasburicase being an enzyme itself, it would be an unlikely candidate for drug-drug interactions.

For rasburicase no clinical data on exposed pregnancies are available. Animal studies with respect to effects on parturition and postnatal development have not been performed (see section 5.3). The potential risk for humans is unknown. Fasturtec should not be used during pregnancy or in breast-feeding women.

It is unknown whether rasburicase is excreted in human milk.

No studies on the effects on the ability to drive and use machines have been performed.

Fasturtec is concomitantly administered as supportive care to cytoreductive chemotherapy of advanced malignancies, the causality of adverse events is therefore difficult to assess due to the significant burden of adverse events expected from the underlying disease and its treatment.

The most significant drug-related adverse events were common allergic reactions, mainly rashes and urticaria. Cases of hypotension (< 1%), bronchospasm (< 1%), rhinitis (< 0.1%) and severe hypersensitivity reactions (< 1%), including anaphylaxis (< 0.1%) have also been attributed to Fasturtec.

In clinical trials, haematological disorders such as haemolysis, haemolytic anaemia and methaemoglobinaemia are uncommonly caused by Fasturtec. The enzymatic digestion of uric acid to allantoin by rasburicase produces hydrogen peroxide and haemolytic anaemia or methaemoglobinaemia have been observed in certain at risk populations such as those with G6PD deficiency.

In addition, grade 3 or 4 adverse reactions possibly attributable to Fasturtec and reported in the clinical trials, are listed below, by system organ class and by frequency. Frequencies are defined as: common ( 1/100, < 1/10), uncommon ( 1/1,000, < 1/100).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

In view of the mechanism of action of Fasturtec, an overdose will lead to low or undetectable plasma uric acid concentrations and increased production of hydrogen peroxide. Thus patients suspected of receiving an overdose should be monitored for haemolysis, and general supportive measures should be initiated as no specific antidote for Fasturtec has been identified.

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

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 impairment of renal function and renal failure resulting from the precipitation of crystals of uric acid in renal tubules. Rasburicase is a highly potent uricolytic agent that catalyses enzymatic oxidation of uric acid into allantoin, a water soluble product, easily excreted by the kidneys in the urine.

The enzymatic oxidation of uric acid leads to stoichiometric formation of hydrogen peroxide. The increased of hydrogen peroxide over ambient levels can be eliminated by endogenous antioxidants and the only increased risk is for haemolysis in G6PD 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 Fasturtec.

A randomised comparative phase III study, using the recommended dose, showed a significantly more rapid onset of action of Fasturtec in comparison with allopurinol. At 4 hours post first dose, there was a significant difference in the mean percentage change from baseline plasma uric acid concentration (p < 0.0001) in the Fasturtec group (-86.0%) compared to that for the allopurinol group (-12.1%).

Time to first confirmation of normal levels of uric acid in hyperuricaemic patients is four hours for Fasturtec and 24 hours for allopurinol. In addition this rapid control of uric acid in this population is accompanied by improvements in renal function. In turn, this allows efficient excretion of the serum phosphate load preventing further deterioration of renal function from calcium/phosphorus precipitation.

Paediatric patients

In pivotal clinical studies, 246 patients (< 18 years) were treated with rasburicase at doses of 0.15 mg/kg/day or 0.20 mg/kg/day for 1 to 8 days (mainly 5 to 7 days). Efficacy results on 229 eva luable patients showed an overall response rate (normalization of plasma uric acid levels) of 96.1%. Safety results on 246 patients were consistent with the adverse events profile in the overall population.

In long term safety studies, an analysis of data from 867 patients (< 18 years) treated with rasburicase at 0.20 mg/kg/day for 1 to 24 days (mainly 1 to 4 days) showed consistent findings with pivotal clinical studies in terms of efficacy and safety.

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, an impaired liver function is not expected to affect the pharmacokinetics.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. The interpretation of the non-clinical studies is hampered due to the presence of endogenous urate oxidase in standard animal models.

Powder:

alanine

mannitol

disodium phosphate dodecahydrate

disodium phosphate dihydrate

sodium dihydrogen phosphate dihydrate

Solvent:

poloxamer 188

water for injection

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

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 agent infusions and rasburicase.

No filter should be used for infusion.

Do not use any glucose solution for dilution due to potential incompatibility.

3 years.

After reconstitution or dilution an immediate use is recommended. However, the in-use stability has been demonstrated for 24 hours between +2 °C and 8 °C.

Powder in vial: store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions of the reconstituted or the diluted medicinal product, see section 6.3.

Fasturtec is supplied as a pack of:

3 vials of 1.5 mg rasburicase and 3 ampoules of 1 ml solvent. The powder is supplied in 3 ml clear glass (type I) vial with a rubber stopper and the solvent in a 2 ml clear glass (type I) ampoule.

1 vial of 7.5 mg rasburicase and 1 ampoule of 5 ml solvent. The powder is supplied in 10 ml clear glass (type I) vial with a rubber stopper and the solvent in a 5 ml clear glass (type I) ampoule.

Not all pack sizes may be marketed.

Rasburicase must be reconstituted with the entire volume of the supplied solvent ampoule (1.5 mg rasburicase vial to be reconstituted with the 1 ml solvent ampoule; 7.5 mg rasburicase vial to be reconstituted with the 5 ml solvent ampoule). Reconstitution results in a solution with a concentration of 1.5 mg/ml rasburicase to be further diluted with sodium chloride 9 mg/ml (0.9%) intravenous solution.

Reconstitution of the solution:

Add the content of one ampoule of solvent to one vial containing rasburicase and mix by swirling very gently under controlled and validated aseptic conditions.

Do not shake.

Inspect visually prior to use. Only clear and colourless solutions without particles should be used.

For single-use only, any unused solution should be discarded.

The solvent contains no preservative. Therefore the reconstituted solution should be diluted under controlled and validated aseptic conditions.

Dilution before infusion:

The required volume of the reconstituted solution depends on the patient's body weight. The use of several vials may be necessary to obtain the quantity of rasburicase required for one administration. The required volume of the reconstituted solution, taken from one or more vials, is to be further diluted with sodium chloride 9 mg/ml (0.9%) solution to make a total volume of 50 ml. The concentration of rasburicase in the final solution for infusion depends on the patient's body weight.

The reconstituted solution contains no preservative. Therefore the diluted solution should be infused immediately.

Infusion:

The final solution should be infused over 30 minutes.

Sample handling:

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 pre-chilled tubes containing heparin anticoagulant. Samples must be immersed in an ice/water bath. Plasma samples should immediately be prepared by centrifugation in a pre-cooled centrifuge (4 °C). Finally, plasma must be maintained in an ice/water bath and analysed for uric acid within 4 hours.

sanofi-aventis

174, avenue de France

F - 75013 Paris

France

EU/1/00/170/001-002

Date of first authorisation: 23 February 2001

Date of latest renewal: 23 February 2006

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu