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Asparaginase

(US Adopted Name)

Drug Nomenclature

AsparaginaseSynonyms: l-Asparaginase; l-Asparagine Amidohydrolase; Asparaginasa; L-Asparaginaasi; L-Asparaginas; L-Asparaginasum; MK-965; NSC-109229; Re-82-TAD-15
USAN: Asparaginase
CAS: 9015-68-3
ATC code: L01XX02
Read code: y07wE

Note. Asparaginase (USAN) is an enzyme isolated from Escherichia coli, or obtained from other sources. See also Colaspase and Crisantaspase, below.

Incompatibility. Asparaginase is incompatible with rubber. Licensed product information recommends that it should not be mixed with other drugs.

Storage. Asparaginase should be stored at 2° to 8° (see also Stability, below).

Colaspase

(British Approved Name)

Drug Nomenclature

BAN: Colaspase
CAS: 9015-68-3
ATC code: L01XX02

Note. Colaspase (BAN) is asparaginase obtained from selected strains of Escherichia coli, such as ATCC 9637.

Pharmacopoeias. China, includes Asparaginase obtained from Escherichia coli ASI 357.

Crisantaspase

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

Synonyms: Crisantaspasum; Erwinia l-asparaginase; Krisantaspaasi; Krisantaspas
BAN: Crisantaspase
CAS: 9015-68-3
ATC code: L01XX02

Note. Crisantaspase (BAN) is asparaginase obtained from cultures of Erwinia chrysanthemi (E carotovora).

Pegaspargase

(US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: PEG-l-asparaginase; Pegaspargasa
USAN: Pegaspargase
INN: Pegaspargase [rINN (en)]
INN: Pegaspargasa [rINN (es)]
INN: Pégaspargase [rINN (fr)]
INN: Pegaspargasum [rINN (la)]
INN: Пэгаспаргаза [rINN (ru)]
Chemical name: A conjugate of colaspase with a polyethylene glycol of molecular weight 5000; Monomethoxypolyethylene glycol succinimidyl l-asparaginase
CAS: 130167-69-0
ATC code: L01XX24

Stability. Although asparaginase was routinely kept under refrigeration, information from a manufacturer (Merck Sharp & Dohme) indicated that it would remain stable for 48 hours at 15° to 30°. Licensed product information for pegaspargase states it should not be used if stored at room temperature for more than 48 hours.

Storage. Pegaspargase should be stored at 2° to 8°.

Units

One international unit of asparaginase splits 1 micromole of ammonia from L-asparagine in 1 minute under standard conditions.

Adverse Effects

Asparaginase is a protein and may produce anaphylax-is and other hypersensitivity reactions including fever, rashes, and bronchospasm; there does not appear to be cross-sensitivity between asparaginase derived from Escherichia coli and that from Erwinia chrysanthemi. Hypersensitivity to pegaspargase is less common, but about 30% of patients hypersensitive to the native enzyme experience hypersensitivity to pegaspargase treatment.

Liver function abnormalities occur in many patients, and there may be decreased blood concentrations of fibrinogen and clotting factors, alterations in blood lipids and cholesterol, and hypoalbuminaemia. Hyperammonaemia, due to the production of ammonia from asparagine, may occur. Uraemia, and occasionally renal failure, have been reported. Pancreatitis may occur and may be fatal: there may also be hyperglycaemia due to decreased insulin production, and death from ketoaci-dosis has occurred.

Gastrointestinal disturbances, including nausea and vomiting, and CNS disturbances, including drowsiness, depression, coma, hallucinations, and a Parkinson-like syndrome, have also been reported. Transient bone-marrow depression has occurred rarely, as has marked leucopenia.

Effects on the blood. Central thrombosis or intracranial haemorrhage as well as peripheral thrombosis and haemorrhage have been reported after asparaginase therapy. Although the precise mechanism for this effect remains unclear, asparaginase appears to deplete certain clotting factors as well as antithrombin III, plasminogen, and fibrinogen. These decreases may be dependent on the formulation and resultant asparaginase activity of preparations, and there is some suggestion that crisantaspase may affect coagulation factors less severely than colaspase. A multicentre, retrospective survey of paediatric patients with acute lymphoblastic leukaemia found that use of corticosteroids with colaspase may be an additional risk factor for thromboembolic events.

Precautions

Asparaginase is contra-indicated in patients with pancreatitis, and should be avoided in pregnancy. It should be given cautiously to patients with hepatic impairment. Facilities for the management of anaphylaxis should be available during treatment. Some manufacturers recommend an intradermal test dose at the start of asparaginase treatment to check for hypersensitivity, as described under Uses, below, although such tests may not always be predictive. Re-treatment with asparaginase may be associated with an increased risk of allergic reactions. Serum amylase concentrations should be monitored regularly as should blood glucose concentrations. Asparaginase has been reported to interfere with tests of thyroid function by transient reduction of concentrations of thyroxine-binding globulin.

Interactions

If asparaginase is given before, rather than after, methotrexate the activity of the latter may be reduced. Vincristine neurotoxicity may possibly be increased by use with intravenous asparaginase.

Methotrexate. Asparaginase inhibits protein synthesis and cell replication, and therefore may interfere with the action of drugs such as methotrexate that require cell replication for their antineoplastic effect. It has been suggested that a 24-hour interval between methotrexate and a subsequent dose of asparaginase permits at least an additive therapeutic effect.

Pharmacokinetics

After intravenous injection the plasma half-life of the native enzyme has varied from about 8 to 30 hours; half-lives of up to 49 hours may be seen after intramuscular dosage. The mean half-life of pegaspargase is reported to be between 6 and 14 days. Asparaginase is found in the lymph at about 20% of the concentration in plasma. There is virtually no diffusion into the CSF. Little is excreted in the urine.

Uses and Administration

Asparaginase is an enzyme that acts by breaking down the amino acid L-asparagine to aspartic acid and ammonia. It interferes with the growth of those malignant cells which, unlike most healthy cells, are unable to synthesise L-asparagine for their metabolism, but resistance to its action develops fairly rapidly. Its action is reportedly specific for the G1 phase of the cell cycle. Asparaginase is used mainly for the induction of remissions in acute lymphoblastic leukaemia. Regimens vary, and dosage should follow local protocols, but it may be given intravenously in a dose of 1000 units/kg daily for 10 days after treatment with vincristine and prednisone or prednisolone, or intramuscularly in a dose of 6000 units/m given every third day for 9 doses during treatment with vincristine and prednisone or prednisolone. Alternatively it may be given as pegaspargase, in doses of 2500 units/m every 14 days, preferably by intramuscular injection although the intravenous route may also be used.

Asparaginase is not generally used alone as an induction agent but doses of 200 units/kg daily have been given intravenously for 28 days to adults and children. If pegaspargase is used alone doses are the same as for combination regimens. Children appear to tolerate asparaginase better than adults.

Although not entirely reliable, an intradermal test dose of about 2 units has been recommended in the USA, to test for hypersensitivity before treatment with colaspase or where more than a week has elapsed between doses. Desensitisation has been advocated if no alternative antineoplastic treatment is available. Anaphylaxis with crisantaspase is stated to be rare; however, in the UK if there has been an interruption in treatment, therapy should be resumed with a low dose of 10 units/kg daily and increased to the full dose over 5 days if tolerated. A test dose is not advocated, although reference to local leukaemia protocols is recommended. The incidence of hypersensitivity is also lower in patients given pegaspargase, and again a test dose is not advocated. Pegaspargase has been successfully used in patients hypersensitive to the native enzyme.

For intravenous use a solution of asparaginase in Water for Injections or sodium chloride 0.9% should be given over not less than 30 minutes through a running infusion of sodium chloride 0.9% or glucose 5%. When given intramuscularly no more than 2 niL of a solution in sodium chloride 0.9% should be injected at a single site.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Kidrolase; L-Asp¤; Oncaspar; Australia: Leunase; Belgium: Paronal; Brazil: Elspar; Canada: Kidrolase; Oncaspar¤; Czech Republic: Erwinase; Kidrolase; Denmark: Erwinase¤; Finland: Erwinase; France: Kidrolase; Germany: Crasnitin¤; Erwinase¤; Oncaspar; Greece: Erwinase; Hong Kong: Elspar¤; Leunase; India: Leunase; Ireland: Erwinase; Israel: Kidrolase; Italy: Crasnitin¤; Japan: Leunase; Malaysia: Erwinase¤; Leunase; Mexico: Leunase; Serasa¤; Netherlands: Crasnitin¤; New Zealand: Erwinase; Leunase; Russia: Oncaspar (Онкаспар); South Africa: Laspar; Singapore: Erwinase¤; Leunase; Spain: Leucogen¤; Sweden: Erwinase; Switzerland: Crasnitine¤; Thailand: Erwinase¤; Leunase; United Kingdom: Erwinase; United States: Elspar; Oncaspar

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