Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Sanofi-aventis groupe, 54, rue La Boétie, F-75008 Paris, France
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.
In a randomised comparative phase III study, performed in 52 paediatric patients, 27 patients were treated with rasburicase at the recommended dose of 0.20 mg/kg/day, intravenously, for 4 to 7 days (≤5 years: n=11; 6-12 years: n=11; 13-17 years: n=5), and 25 patients with allopurinol daily oral doses for 4 to 8 days. Results 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.
In a randomized (1:1:1), multi-center, 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 at a dose of 0.2 mg/kg/day, intravenously, from day 1 through day 3 followed by oral allopurinol at a dose of 300 mg once a day from day 3 through day 5 (overlap on day 3: rasburicase and allopurinol administered approximately 12 hours apart) (arm B: n=92), or oral allopurinol at a dose of 300 mg once a day 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 to day 7 after initiation of antihyperuricemic treatment) was 87% in arm A, 78% in arm B, and 66% in arm C. 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 two arms containing rasburicase and 5% of patients in the allopurinol arm at 4 hours 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 paediatric patients (mean age 7 years, range 0 to17) 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 evaluable 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 paediatric patients (mean age 7.3 years, range 0 to17) 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.
The pharmacokinetics of rasburicase were evaluated in both paediatric and adult patients with leukaemia, lymphoma or other haematological malignancies.
After infusion of rasburicase at a dose of 0.20 mg/kg/day, steady state is achieved at day 2-3. Minimal accumulation of rasburicase (<1.3 fold) was observed between days 1 and 5 of dosing.
The mean volume of distribution ranged from 110-127 ml/kg in paediatric patients and from 75.8 to 138 ml/kg in adult patients, respectively, which is comparable to the physiological vascular volume.
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.
Clearance of rasburicase was ca. 3.5 ml/h/kg. The mean terminal half-life was similar between paediatric and adult patients and ranged from 15.7 to 22.5 hours. Clearance is increased (ca. 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.
In adults (≥ the age of 18 years), age, gender, baseline liver enzymes and creatinine clearance did not impact the pharmacokinetics of rasburicase. A cross-study comparison revealed that after administration of rasburicase at 0.15 or 0.20 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.
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.
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