Asparaginase

Registered South African indications:

• Lymphoblastic leukaemia

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to any native (non-pegylated) E.coli-asparaginase preparation
• Severe hepatic impairment (bilirubin >3 times upper limit of normal; transaminases >10 times upper limit of normal)
• Pancreatitis
• Pre-existing known coagulopathy (e.g. haemophilia)
• History of pancreatitis, serious haemorrhage or serious thrombosis with prior asparaginase therapy

Cautions

• Pregnancy
• Breastfeeding
• Elderly
• Acquired or genetically decreased physiologic coagulation inhibitors (protein C, protein S, antithrombin)
• Children with a genetic prothrombotic risk factor
  - Factor V G1691A-mutations
  - Prothrombin G20210A-variation
  - Methylenetetrahydrofolate reductase [MTHFR] T677T-genotype
  - Increased lipoprotein A
  - Hyperhomocysteinaemia
• Philadelphia chromosome-positive patients
• Central venous catheters
• Patients on other antineoplastic agents
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Acute lymphoblastic leukaemia
  - Used as a component of antineoplastic combination therapy for acute lymphoblastic leukaemia

Consult specialist for dosages and regimens

Paed. forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Acute lymphoblastic leukaemia
  - Used as a component of antineoplastic combination therapy for acute lymphoblastic leukaemia

Consult specialist for dosages and regimens

Pregnancy

• Caution; not recommended
• There are no data on the use of asparaginase in pregnant women. No reproduction studies in animals with asparaginase were performed but studies with asparaginase preparations in mice, rats, chicken and rabbits have shown embryotoxic and teratogenic effects. Based on results from animal studies and its mechanism of action, asparaginase should not be used during pregnancy unless the clinical condition of the woman requires treatment with asparaginase
• Women of childbearing potential have to use effective contraception and avoid becoming pregnant while being treated with asparaginase-containing chemotherapy. Since an indirect interaction between components of the oral contraception and asparaginase cannot be ruled out, oral contraceptives are not considered sufficiently safe in such a clinical situation. A method other than oral contraceptives should be used in women of childbearing potential
• Men should use effective contraceptive measures and be advised to not father a child while receiving asparaginase. The time period following treatment with asparaginase when it is safe to become pregnant or father a child is unknown. As a precautionary measure, it is recommended to wait for three months after completion of treatment. However, treatment with other chemotherapeutic agents should also be taken into consideration

Breastfeeding

• Caution; not recommended
• It is unknown whether asparaginase is excreted into human breast milk. Because potential serious adverse reactions may occur in breastfeeding infants, asparaginase should be discontinued during breastfeeding

Fertility

• No human data on the effect of asparaginase on fertility are available

Renal Impairment

• No dose adjustment recommended

Hepatic Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Contraindicated

Elderly

• Caution; no information available
  Limited data available for the treatment of patients ≥65 years

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Hallucination
• Confusion
• Neurological signs and symptoms
  - Agitation
  - Dizziness
  - Somnolence
• Headaches
• Ischaemic stroke
• Reversible posterior leukoencephalopathy syndrome
• Convulsion
• Disturbances in consciousness
• Coma
• Tremor
• Fatigue
• Abnormal electroencephalogram
  - Decreased alpha wave activity
  - Increased theta wave activity
  - Increased delta wave activity

Cardiovascular Disorders

• Thrombosis
• Cavernous sinus thrombosis
• Deep vein thrombosis
• Haemorrhage

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Acute pancreatitis
• Haemorrhagic pancreatitis
• Necrotising pancreatitis
• Parotitis
• Pancreatitis with fatal outcome
• Pancreatic pseudocyst

Hepatobiliary Disorders

• Hepatic failure with potentially fatal outcome
• Hepatic necrosis
• Cholestasis
• Jaundice
• Hepatic steatosis
• Increased transaminases
• Increased blood bilirubin

Genitourinary Disorders

• Increased blood urea
• Increased ammonia

Endocrine and Metabolic Disorders

• Secondary hypothyroidism
• Hypoparathyroidism
• Hyperglycaemia
• Hypoalbuminaemia
• Hypoglycaemia
• Decreased appetite
• Weight loss
• Hyperuricaemia
• Hyperammonaemia
• Diabetic ketoacidosis
• Increased blood alkaline phosphatase
• Increased cholesterol
• Increased triglycerides
• Increased very low density lipoprotein
• Increased lipoprotein lipase activity
• Increased lactate dehydrogenase
• Decreased cholesterol
• Decreased low density lipoprotein
• Decreased total protein
• Increased amylase
• Increased lipase

Musculoskeletal Disorders

• Pain
  - Back pain
  - Joint pain

Immune, Blood and Lymphatic System Disorders

• Infections
• Disseminated intravascular coagulation
• Anaemia
• Leukopenia
• Thrombocytopenia
• Hypersensitivity
  - Flushing
  - Rash
  - Hypotension
  - Oedema/angioedema
  - Urticaria
  - Dyspnoea
  - Bronchospasm
  - Anaphylactic shock
• Oedema
• Decreased antithrombin III
• Decreased fibrinogen

• Other agents metabolized by the liver
• Hepatotoxic agents
• Agents bound to plasma proteins
• Myelosuppressive agents
• Agents known to cause infections
• Vincristine
• Glucocorticoids
• Anticoagulants
• Coumarin
• Heparin
• Dipyridamole
• Acetylsalicylic acid
• Nonsteroidal anti-inflammatory agents
• Methotrexate
• Cytarabine
• Live vaccines

• Full blood count with differential
• Amylase
• Lipase
• Lipid profile
• Hepatic function
• Coagulation parameters
• Blood glucose
• Uric acid levels
• Renal function

Asparaginase hydrolyses asparagine to aspartic acid and ammonia. In contrast to normal cells, lymphoblastic tumour cells have a very limited capacity for synthesizing asparagine because of a significantly reduced expression of asparagine synthetase. Therefore, they require asparagine which diffuses from the extracellular environment. As a result of asparaginase-induced asparagine depletion in serum, protein synthesis in lymphoblastic tumour cells is disturbed while sparing most normal cells. Asparaginase may also be toxic to normal cells that divide rapidly and are dependent to some degree on exogenous asparagine supply.

Injection (per vial) 10 000iu

• Laspar (Bodene) originator