Rasburicase

In humans, uric acid is the final product of purine breakdown. When many malignant cells are destroyed, and during chemotherapy that shrinks the tumour, plasma uric acid can rise sharply, and uric acid crystals can precipitate in the renal tubules, impairing kidney function and causing renal failure. Rasburicase is a highly potent uricolytic agent that removes uric acid enzymatically.

Mechanism of Action

• The enzyme: rasburicase is a tetrameric protein of identical subunits (about 34 kDa each), made by a genetically modified Saccharomyces cerevisiae strain. One milligram corresponds to 18.2 enzyme activity units.
• Uric acid breakdown: it catalyses the oxidation of uric acid to allantoin, a water-soluble product that is easily excreted by the kidneys in urine.
• Hydrogen peroxide: the oxidation produces hydrogen peroxide. Endogenous antioxidants normally deal with the extra peroxide; the only increased risk is haemolysis in patients with G6PD deficiency or inherited anaemias.
• Dose-related effect: in healthy volunteers, plasma uric acid fell in proportion to dose across the range 0.05 to 0.20 mg/kg.
• Clinical study: in a randomised phase III study in 52 children and adolescents, 27 patients received rasburicase 0.20 mg/kg/day intravenously for 4 to 7 days and 25 received daily oral allopurinol for 4 to 8 days. Four hours after the first dose, plasma uric acid had fallen by 86.0% with rasburicase and by 12.1% with allopurinol. In hyperuricaemic patients, normal uric acid levels were first confirmed after 4 hours with rasburicase and 24 hours with allopurinol.

Pharmacokinetics

• Exposure: after infusion of 0.20 mg/kg/day, steady state is reached on day 2 to 3, with minimal accumulation (below 1.3-fold) between days 1 and 5.
• Distribution: the mean volume of distribution is 110–127 mL/kg in children and adolescents and 75.8–138 mL/kg in adults, comparable to the physiological vascular volume. As a protein, rasburicase is not expected to bind to plasma proteins.
• Metabolism: it is expected to be broken down like other proteins, by peptide hydrolysis, and is unlikely to be involved in drug–drug interactions.
• Elimination: clearance is about 3.5 mL/h/kg and the mean terminal half-life is 15.7 to 22.5 hours, similar in children and adults. Renal elimination is a minor pathway.
• Special populations: clearance is about 35% higher in children and adolescents than in adults, giving lower exposure. In adults, age, sex, baseline liver enzymes and creatinine clearance did not affect the pharmacokinetics. In a cross-study comparison, body-weight-normalised clearance was about 40% lower in Japanese (n = 20) than in Caucasian (n = 26) subjects. Impaired liver function is not expected to affect the pharmacokinetics.

• Acute hyperuricaemia in haematological malignancy: treatment and prophylaxis of acute hyperuricaemia, in order to prevent acute renal failure, in adults, children and adolescents (aged 0 to 17 years) with haematological malignancy with a high tumour burden and at risk of a rapid tumour lysis or shrinkage at initiation of chemotherapy.

• Hypersensitivity to rasburicase 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; to prevent possible haemolytic anaemia induced by hydrogen peroxide, rasburicase is contraindicated in patients with these disorders.

Rasburicase is given as supportive care alongside chemotherapy for advanced malignancies, so it is difficult to tell which adverse events it causes: the underlying disease and its treatment are expected to cause many themselves. The most commonly reported reactions were nausea, vomiting, headache, fever and diarrhoea. Haemolysis, haemolytic anaemia and methaemoglobinaemia were uncommon in clinical trials; they occur in at-risk groups such as patients with G6PD deficiency.

Very common (≥1/10): headache, diarrhoea, vomiting, nausea, fever.

Common (≥1/100 to <1/10): allergy and allergic reactions (rashes and urticaria).

Uncommon (≥1/1,000 to <1/100): haemolysis, haemolytic anaemia, methaemoglobinaemia, severe hypersensitivity reactions, hypotension, bronchospasm, convulsion (from post-marketing experience).

Rare (≥1/10,000 to <1/1,000): anaphylaxis, rhinitis.

Not known: anaphylactic shock (with a potentially fatal outcome), involuntary muscle contraction (from post-marketing experience).

Grade 3 or 4 vomiting, nausea and fever were common, and grade 3 or 4 headache and diarrhoea were uncommon. Anaphylaxis, haemolysis and methaemoglobinaemia are the most important serious reactions (see Special Instructions).

• No interaction studies have been performed. Rasburicase is an enzyme and is an unlikely candidate for drug–drug interactions; being a protein, it is expected to be broken down by peptide hydrolysis and not to bind to plasma proteins.
• Chemotherapy: infuse rasburicase through a different line from the one used for chemotherapeutic agents, to prevent possible incompatibility. If a separate line is not possible, flush the line with saline between the two infusions.
• Laboratory tests: rasburicase can degrade uric acid in a blood sample in vitro, so special precautions are needed when handling samples for plasma uric acid measurement (SmPC section 6.6).

Rasburicase is given under the supervision of a physician trained in chemotherapy of haematological malignancies. It is used immediately before and during the start of chemotherapy only, because there are not enough data to recommend multiple treatment courses. It does not require any change in the timing or schedule of starting cytoreductive chemotherapy.

Recommended Dose

• Dose: 0.20 mg/kg/day, given once daily as a 30-minute intravenous infusion in 50 mL of sodium chloride 9 mg/mL (0.9%) solution.
• Duration: up to 7 days. The exact duration is based on adequate monitoring of plasma uric acid and on clinical judgement.
• Infusion line: use a different line from chemotherapy, or flush with saline between infusions.
• Preparation: the powder is reconstituted with the solvent supplied and diluted before use (see SmPC section 6.6 for the instructions).

Special Populations

• Children and adolescents (0 to 17 years): no adjustment is necessary; the dose is also 0.20 mg/kg/day.
• Renal or hepatic impairment: no dose adjustment is necessary.

Allergic Reactions and Anaphylaxis

Like other proteins, rasburicase can cause allergic responses, including anaphylaxis and anaphylactic shock with a potentially fatal outcome. Patients must be closely monitored for allergic-type reactions, especially severe hypersensitivity. In a severe allergic reaction, treatment must be stopped immediately and permanently and appropriate therapy started. Caution is needed in patients with a history of atopic allergies.

G6PD Deficiency, Haemolysis and Methaemoglobinaemia

Rasburicase is contraindicated in G6PD deficiency and other cellular metabolic disorders known to cause haemolytic anaemia (see Contraindications). Methaemoglobinaemia and haemolysis have been reported in patients receiving rasburicase. In either case, treatment must be stopped immediately and permanently and appropriate measures started.

Other Tumour Lysis Abnormalities

By lowering uric acid, rasburicase reduces the chance of renal failure from uric acid crystals in the renal tubules. Tumour lysis can also cause hyperphosphataemia, hyperkalaemia and hypocalcaemia, which rasburicase does not treat directly, so patients must be monitored closely.

Repeated Courses and Antibodies

There are not enough data on retreatment to recommend multiple courses. Anti-rasburicase antibodies have been detected in treated patients and in healthy volunteers. Rasburicase has not been investigated in hyperuricaemia associated with myeloproliferative disorders.

Uric Acid Measurement

Because rasburicase can degrade uric acid in the sample in vitro, a strict sample-handling procedure must be followed to measure plasma uric acid accurately during treatment (SmPC section 6.6).

Sodium and Traceability

Each vial contains up to 10.5 mg of sodium (the 1.5 mg vial 2.1 mg), equivalent to 0.53% of the WHO recommended maximum daily intake of 2 g sodium for an adult. Rasburicase is a biological medicinal product, so the name and batch number of the product given should be clearly recorded.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women. Animal results could not be interpreted, because standard animal models have their own urate oxidase. Teratogenic effects cannot be ruled out, so rasburicase should be used in pregnancy only if strictly necessary, and it is not recommended in women of childbearing potential not using contraception.
• Breastfeeding: it is unknown whether rasburicase passes into human milk. As a protein, the dose reaching the infant is expected to be very low; the advantage of breastfeeding should be weighed against the potential risk for the infant.
• Fertility: there are no data on the effect of rasburicase on fertility.

Effect on Driving

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

Store the powder in vials in a refrigerator at 2–8 °C, in the original package to protect it from light. Do not freeze. Handle as a cold-chain product during transport and storage. After reconstitution or dilution, immediate use is recommended; in-use stability has been shown for 24 hours at 2–8 °C.

3 years when stored as above. After reconstitution or dilution, use immediately; in-use stability has been demonstrated for 24 hours between 2 °C and 8 °C.

Prescription only (Rx), under restricted medical prescription (Annex II B). Rasburicase is given by intravenous infusion under the supervision of a physician trained in chemotherapy of haematological malignancies, so it is supplied to the hospital that administers it, in a cold chain at 2–8 °C.