Fasturtec also contains the following excipients: Powder: Alanine, mannitol, disodium phosphate dodecahydrate, disodium diphosphate dihydrate and sodium dihydrogen phosphate dihydrate. Solvent: Poloxamer 188 and Water for Injections.
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.
*One enzymatic activity (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.
Pharmacotherapeutic Group: Detoxifying agents for antineoplastic treatment. ATC Code: V03AF07.
Pharmacology: Pharmacodynamics: 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 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 increase of hydrogen peroxide over ambient levels can be eliminated by endogenous antioxidants and the only increased risk is for haemolysis in glucose-6-phosphate dehydrogenase (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 0.05-0.2 mg/kg of Fasturtec.
Clinical Efficacy and Safety: 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 hrs post-1st 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%) compared to that for the allopurinol group (-12.1%).
Time to 1st confirmation of normal levels of uric acid in hyperuricaemic patients in 4 hrs for Fasturtec and 24 hrs 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.
In a randomized (1:1:1), multicenter, open-label study, 275 adult patients with leukemia and lymphoma at risk for hyperuricemia and tumour lysis syndrome (TLS) were treated with either rasburicase at a dose of 0.2 mg/kg/day. Intravenously, for 5 days (arm A: n=92), rasburicase 0.2 mg/kg/day, IV, from day 1 through day 3 followed by oral allopurinol at a dose of 300 mg once daily from day 3 through day 5 (overlap on day 3: Raburicase and allopurinol administered approximately 12 hrs apart) (arm B: n=92), or oral allopurinol at a dose of 300 mg once daily for 5 days (arm C: n=91). The uric acid response rate (proportion of patients with plasma uric acid levels ≤7.5 mg/dL from day 3-7 after initiation of antihyperuricemic treatment) was 87%, 78%, 66% in arms A, B, C, respectively. The response rate in arm A was significantly greater than in arm C (p=0.0009); the response rate was higher for arm B compared to arm C although this difference was not statistically significant. Uric acid levels were ≤2 mg/dL in 96% of patients in the 2 arms containing rasburicase and 5% of patients in the allopurinol arm at 4 hrs of the day 1 dose. The safety results of patients treated with Fasturtec in study EFC4978 were consistent with the adverse events profile observed in previous clinical studies with predominantly paediatric patients.
In pivotal clinical studies, 246 patients (<18 years) were treated with rasburicase at doses of 0.15 mg/kg/day or 0.2 mg/kg/day for 1-8 days (mainly 5-7 days). Efficacy results on 229 evaluable patients showed an overall response rate (normalization of plasma uric acid levels) of 96.1%. Safety result 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 0.2 mg/kg/day for 1-24 days (mainly 1-4 days) showed consistent findings with pivotal clinical studies in terms of efficacy and safety.
Pharmacokinetics: The pharmacokinetics of rasburicase were evaluated in both paediatric and adult patients with leukemia, lymphoma or other haematological malignancies.
Absorption: After infusion of rasburicase at a dose of 0.2 mg/kg/day, steady state is achieved at days 2-3. Minimal accumulation of rasburicase (<1.3 fold) was observed between day 1 and day 5 of dosing.
Distribution: The mean volume of distribution ranged from 110-127 mL/kg in paediatric patients and from 75.8-138 mL/kg in adult patients, respectively, which is comparable to the physiological vascular volume.
Metabolism: Rasburicase is a protein, and therefore, not expected to bind to proteins, expected that metabolic degradation will follow the pathways of other proteins ie, peptide hydrolysis, and unlikely to be a candidate for drug-drug interactions.
Elimination: Clearance of rasburicase was approximately 3.5 mL/hr/kg. The mean terminal half-life was similar between paediatric and adult patients and ranged from 15.7-22.5 hrs. Clearance is increased (approximately 35%) in children and adolescents compared to adults, resulting in a lower systemic exposure. Renal elimination of rasburicase is considered to be a minor pathway for rasburicase clearance.
Special Patient Population: In adults (≥18 years), age, gender, baseline liver enzymes and creatinine clearance (CrCl) did not impact the pharmacokinetics of rasburicase. A cross-study comparison revealed that after administration of rasburicase at 0.15 or 0.2 mg/kg, the geometric mean values of body-weight normalized clearance were approximately 40% lower in Japanese (n=20) than that in Caucasians (n=26).
As metabolism is expected to occur by peptide hydrolysis, an impaired liver function is not expected to affect the pharmacokinetics.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and genotoxicity. The interpretation of the nonclinical studies is hampered due to the presence of endogenous urate oxidase in standard animal models.
Treatment and prophylaxis of acute hyperuricaemia, in order to prevent acute renal failure, in patients with haematologic 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.
Use Fasturtec immediately prior to and during the initiation of chemotherapy only, as at present, there is insufficient data to recommend multiple treatment courses.
Recommended Dose: 0.2 mg/kg/day, as a once daily 30-min IV infusion in 50 mL of a 9-mg/mL sodium chloride solution (0.9% w/v). (See Instructions for Use/Handling and Disposal under Cautions for Usage)
Duration of Treatment: May be up to 7 days. The exact duration should be based upon adequate monitoring of uric acid levels in plasma and clinical judgement.
Children: No dose adjustment is necessary.
No dose adjustment is necessary for special populations (renally- or hepatically- impaired patient).
Administration: 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 min and should be infused through a different line than that used for infusion of chemotherapeutic agents to prevent any possible drug incompatibility. If use of separate line is not possible, the line should be flushed out with saline solution between infusion of chemotherapeutic agents and rasburicase.
Because rasburicase may degrade uric acid in vitro, special precautions must be used during sample handling for plasma uric acid measurements (see Instructions for Use/Handling and Disposal under Cautions for Usage).
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.
Hypersensitivity to rasburicase or to any of the excipients of Fasturtec.
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 Adverse Reactions). If 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 re-treated 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 Adverse Reactions).
Haemodialysis has been reported in patients receiving Fasturtec. In such cases, treatment should immediately and permanently be discontinued and appropriate measure initiated (see Adverse Reactions).
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 patients with hyperuricaemia in the context of myeloproliferative disorders.
To ensure accurate measurement of uric acid plasma level during treatment with Fasturtec, a strict sample handling procedure must be followed (see Intructions on Use/Handling and Disposal under Cautions for Usage).
Effects on the Ability to Drive or Operate Machinery: No studies on the effect on the ability to drive and use machines have been performed.
Impairment of Fertility: There are no data regarding the effect of rasburicase on fertility.
Use in pregnancy: There are no data from the use of rasburicase in pregnant women. Results from animal studies could not be interpreted due to the presence of endogenous urate oxidase in standard animal models. Because teratogenic effects of rasburicase cannot be ruled out, Fasturtec should only be used during pregnancy if strictly necessary. Fasturtec is not recommended in women of childbearing potential not using contraception.
Use in lactation: It is unknown whether rasburicase is excreted in human milk. As a protein, the dose for the infant is expected to be very low. During treatment with Fasturtec, the advantage of breastfeeding should be weighed against the potential risk for the infant.
Fasturtec is concomitantly administered as supportive care to cytoreductive chemotherapy of advanced malignancies, the casuality 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 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 eg, 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 eg, those with G6PD deficiency.
In addition, grade 3 or 4 adverse reactions possibly attributable to Fasturtec and reported in the clinical trials, are listed as follows by system organ class and by frequency. Frequencies are defined using the following MedDRA convention as: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000).
Nervous System Disorders:
Uncommon: Diarrhea, vomiting, nausea.
General Disorders and Administration Site Conditions:
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
No interaction studies have been carried out. Rasburicase, being an enzyme itself, would be an unlikely candidate for drug-drug interactions.
Incompatibilities: Fasturtec must not be mixed with other medicinal products.
Rasburicase infusion 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.
Instructions for Use/Handling and Disposal: Rasburicase must be reconstituted with the solvent supplied and further diluted only in 9 mg/mL sodium chloride IV solution (0.9% w/v).
Reconstitution: Add the contents of 1 amp of solvent to 1 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 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 quantity of solution (according to the patient's body weight) is to be further diluted with 9 mg/mL sodium chloride solution (0.9% w/v) to make up a total volume of 50 mL. The reconstituted solution contains no preservative. Therefore, the diluted solution should be infused immediately.
Infusion: The final solution should be infused over 30 min.
Sample Handling: If it is necessary to monitor a patient's uric acid level, a strict sample handling procedure must be followed to minimize 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 be immediately 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 hrs.
Powder: Store at 2-8°C (in a refrigerator). Do not freeze. Protect from light.
Reconstituted and Diluted Solutions: Store at 2-8°C.
Shelf-Life: Powder in Vial: 3 years.
Reconstituted/Diluted Solution: 24 hrs.
V03AF07 - rasburicase ; Belongs to the class of detoxifying agents used in antineoplastic treatment.
Infusion (vial) 1.5 mg (powd) x 3 mL + amp (solvent) 2 mL x 3's.