Asparaginase

Asparaginase is an enzyme that hydrolyses the amino acid asparagine to aspartic acid and ammonia. Spectrila contains asparaginase produced in Escherichia coli by recombinant DNA technology, and its strength is expressed in units (U): one unit is the amount of enzyme that liberates one micromole of ammonia per minute at pH 7.3 and 37 °C. The doses, units and pharmacokinetic figures on this page apply to Spectrila only and cannot be transferred to other asparaginase preparations.

Mechanism of Action

• Asparagine depletion: lymphoblastic tumour cells have very little asparagine synthetase and depend on asparagine from outside the cell. When asparaginase removes it from the serum, protein synthesis in these cells is disturbed, while most normal cells are spared. The enzyme may also harm rapidly dividing normal cells that rely to some degree on external asparagine.
• Spread into tissues: because asparagine moves down its concentration gradient, levels also fall in extravascular spaces such as the cerebrospinal fluid.
• Measured effect: in children with newly diagnosed ALL, serum asparagine fell from about 40 μM before the dose to below 0.5 μM (the quantification limit) at the end of the infusion and stayed there until at least three days after the last infusion. Values returned to normal within 1–3 weeks.
• Glutamine: asparaginase also splits glutamine to glutamic acid and ammonia, but far less efficiently. Glutamine levels are only moderately affected and vary widely between patients.

Pharmacokinetics

• Absorption: asparaginase is not absorbed from the gastrointestinal tract, so Spectrila must be given intravenously.
• Distribution: it stays mainly in the vascular space; the volume of distribution at steady state averaged 2.47 L (SD 0.45 L). It does not appear to cross the blood–brain barrier in measurable amounts. In seven adults given 5,000 U/m², median peak serum activity was 2,324 U/L (range 1,625–4,819 U/L), reached about 2 hours after the end of the infusion. With 5,000 U/m² every third day, trough activity ranged from 108 to 510 U/L.
• Metabolism: not known; it is thought to be degraded in the reticulo-histiocytic system and by serum proteases.
• Elimination: the mean terminal half-life of serum activity was 25.8 hours (SD 9.9 hours; range 14.2–44.2 hours).
• Activity and depletion: in trials most patients reached trough activity above 100 U/L, which nearly always matched complete asparagine depletion in serum and cerebrospinal fluid. Even activity of 10–100 U/L usually depleted asparagine completely.
• Children: the pharmacokinetics of 5,000 U/m² were also measured in 14 children and adolescents aged 2–14 years with newly diagnosed ALL; the SmPC gives the values.

• Acute lymphoblastic leukaemia (ALL): as a component of antineoplastic combination therapy for the treatment of ALL in paediatric patients from birth to 18 years and in adults.

• Hypersensitivity to the active substance, to any native (non-pegylated) E. coli asparaginase preparation or to any of the excipients.
• Pancreatitis.
• Severe hepatic impairment (bilirubin more than 3 times the upper limit of normal, or transaminases more than 10 times the upper limit).
• Pre-existing known coagulopathy (for example haemophilia).
• A history of pancreatitis, serious haemorrhage or serious thrombosis with earlier asparaginase therapy.

The primary toxicity of asparaginase comes from immune reactions to the bacterial protein, ranging from transient flushing, rash and urticaria to bronchospasm, angioedema and anaphylaxis. Reduced protein synthesis also causes liver impairment, acute pancreatitis, hyperglycaemia, coagulation disorders (thrombosis or bleeding) and raised blood fats. Because Spectrila is usually given with other cancer medicines, its effects are often hard to separate from theirs. The frequencies below come from trials in 125 children with newly diagnosed ALL and from post-marketing experience with other E. coli-derived asparaginase preparations in children and adults.

Very common (≥1/10): hypersensitivity (flushing, rash, hypotension, oedema or angioedema, urticaria, dyspnoea), hyperglycaemia, hypoalbuminaemia, diarrhoea, nausea, vomiting, abdominal pain, oedema, fatigue; laboratory changes with raised transaminases, bilirubin, alkaline phosphatase, cholesterol, triglycerides, VLDL, lipoprotein lipase activity, urea, ammonia and LDH, and lowered antithrombin III, fibrinogen, cholesterol, LDL and total protein.

Common (≥1/100 to <1/10): disseminated intravascular coagulation, anaemia, leukopenia, thrombocytopenia; hypersensitivity with bronchospasm; hypoglycaemia, decreased appetite, weight loss; depression, hallucination, confusion; neurological signs and symptoms (agitation, dizziness, somnolence); thrombosis (especially cavernous sinus or deep vein thrombosis), haemorrhage; acute pancreatitis; back and joint pain; raised amylase and lipase; abnormal electroencephalogram.

Uncommon (≥1/1,000 to <1/100): hyperuricaemia, hyperammonaemia, headache.

Rare (≥1/10,000 to <1/1,000): anaphylactic shock; diabetic ketoacidosis; ischaemic stroke, reversible posterior leukoencephalopathy syndrome, convulsion, disturbed consciousness including coma; haemorrhagic or necrotising pancreatitis, parotitis; liver failure with potentially fatal outcome, hepatic necrosis, cholestasis, jaundice.

Very rare (<1/10,000): secondary hypothyroidism, hypoparathyroidism, tremor, pancreatitis with fatal outcome, pancreatic pseudocyst.

Not known: infections, hepatic steatosis.

The most serious reactions are severe hypersensitivity including anaphylactic shock, thromboembolic events, acute pancreatitis and severe liver toxicity. Allergic reactions become more likely with each further dose, and most occur in later treatment phases such as re-induction. Thromboembolic events occur more often in adults than in children, and patients over 55 years usually tolerate treatment less well than paediatric patients.

Asparaginase is usually given within combination protocols, and its effects on protein synthesis and liver function can change the toxicity of other medicines.

• Liver-metabolised, protein-bound or hepatotoxic medicines: asparaginase may increase their toxicity and alter the pharmacokinetics of medicines bound to plasma proteins. Use caution and monitor liver parameters.
• Myelosuppressive and infection-promoting medicines: they add to the myelosuppression and infections that can occur with asparaginase-containing regimens; watch for signs of both.
• Vincristine: toxicity may be additive. Vincristine should be given 3 to 24 hours before asparaginase to minimise it.
• Glucocorticoids and anticoagulants: either can change coagulation parameters. Anticoagulants (for example coumarin, heparin, dipyridamole, acetylsalicylic acid, non-steroidal anti-inflammatory medicines) promote bleeding, glucocorticoids promote thrombosis. Take care when they are given together.
• Methotrexate: asparaginase given before or together with methotrexate weakens its cytotoxic effect, which depends on cell replication. Given 24 hours after methotrexate, it enhances the antitumour effect and reduces the gastrointestinal and haematological effects of methotrexate.
• Cytarabine: prior asparaginase reduces the efficacy of high-dose cytarabine; given after cytarabine, a synergistic effect was seen, most marked at an interval of about 120 hours.
• Live vaccines: they increase the risk of serious infection. Immunisation with live vaccines should take place at the earliest 3 months after the antileukaemic treatment is completed.
• Oral contraceptives: an indirect interaction cannot be ruled out, so oral contraceptives are not considered safe enough and another method should be used.

Spectrila must be prescribed and administered by physicians and healthcare personnel experienced in the use of antineoplastic medicines, and only in a hospital setting where appropriate resuscitation equipment is available. It is usually part of a combination chemotherapy protocol. It is given by intravenous infusion only: the daily amount is diluted in 50–250 mL of sodium chloride 9 mg/mL (0.9%) solution for infusion and infused over 0.5 to 2 hours. It must never be given as a bolus. As a biological medicine, the name and batch number of the product given should be recorded. Reconstitution and dilution instructions are in section 6.6 of the SmPC.

Recommended Dose

• Adults and children older than 1 year: 5,000 units per square metre of body surface area (U/m²) intravenously every third day.
• Infants aged 0–12 months (limited data): under 6 months, 6,700 U/m²; 6–12 months, 7,500 U/m².
• Efficacy and safety data in adults are limited, and data from the post-induction treatment phases are very limited.

Monitoring and Treatment Changes

• Treatment can be monitored by the trough serum asparaginase activity measured three days after a dose. If activity does not reach the target levels, a switch to a different asparaginase preparation may be considered, after seeking expert advice.
• Treatment is stopped in acute pancreatitis. It is interrupted in severe hepatic impairment (bilirubin more than 3 times the upper limit of normal, or transaminases more than 10 times the upper limit), severe hypertriglyceridaemia, hyperglycaemia or a coagulation disorder such as sinus vein thrombosis or severe bleeding.
• If allergic symptoms occur, the infusion is stopped immediately and appropriate treatment given.

Special Populations

• Renal impairment: no dose adjustment.
• Hepatic impairment: no adjustment in mild to moderate impairment; not to be used in severe impairment.
• Elderly: limited data in patients older than 65 years.

Hypersensitivity and Anaphylaxis

Because of the risk of severe anaphylaxis, asparaginase must not be given as an intravenous bolus. An intracutaneous test or a small intravenous test dose can be used, but neither predicts accurately who will react. If allergic symptoms occur, stop the infusion at once; antihistamines and corticosteroids may be needed. Antibodies of several classes (IgG, IgM, IgE) can form. They may cause allergic reactions or inactivate the enzyme, and low asparaginase activity is often accompanied by anti-asparaginase antibodies.

Pancreatitis, Liver, Blood Sugar and Blood Fats

Before treatment, bilirubin, transaminases and coagulation parameters (PTT, PT, antithrombin III, fibrinogen) are measured. Afterwards, bilirubin, transaminases, blood and urine glucose, coagulation parameters including D-dimer, amylase, lipase, triglycerides and cholesterol are monitored closely.

• Acute pancreatitis developed in under 10% of patients; haemorrhagic or necrotising forms are rare and fatal outcomes isolated. Symptoms are abdominal pain, nausea, vomiting and anorexia; amylase and lipase are usually raised but can be normal. Severe hypertriglyceridaemia raises the risk. After pancreatitis, no asparaginase preparation should be given again.
• Hepatotoxicity: severe liver impairment, including cholestasis, jaundice, hepatic necrosis and fatal hepatic failure, is rare.
• Hyperglycaemia results from decreased insulin production, is generally self-limiting, rarely progresses to diabetic ketoacidosis and is aggravated by corticosteroids.
• Hypoalbuminaemia: serum protein, especially albumin, falls very commonly. It should be checked regularly because some medicines depend on serum protein for binding and transport.
• Hyperammonaemia: plasma ammonia should be measured in patients with unexplained neurological symptoms or severe, prolonged vomiting.

Coagulation Disorders and Thrombosis

Reduced synthesis of clotting factors II, V, VII, VIII and IX, of proteins C and S and of antithrombin III can cause thrombosis, disseminated intravascular coagulation or bleeding; thrombosis seems more likely than bleeding. About half of thrombotic events are cerebral, sinus vein thrombosis can occur, and symptomatic thromboses linked to central venous catheters are described. Children with an inherited prothrombotic risk factor had a higher risk of thrombosis during induction with asparaginase and prednisone. Coagulation parameters should be checked often before and during treatment, and expert advice sought if antithrombin III is low.

Neurological Effects

Reversible posterior leukoencephalopathy syndrome may occur rarely, with raised blood pressure, seizures, headache, changes in mental state and acute visual impairment. It is treated symptomatically, and reducing or stopping concomitant immunosuppressive medicines may be necessary. Other nervous system reactions include EEG changes, seizures, dizziness, somnolence, coma and headache; hyperammonaemia and sinus vein thrombosis may need to be excluded.

Hyperuricaemia

Destruction of tumour cells can release large amounts of uric acid, particularly together with other cancer medicines. Alkalinising the urine and giving allopurinol can prevent urate nephropathy.

Philadelphia Chromosome-Positive Patients

Efficacy and safety of Spectrila have not been established in Philadelphia chromosome-positive patients.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception and avoid pregnancy during asparaginase-containing chemotherapy and for 7 months after treatment ends. Oral contraceptives are not considered sufficiently safe; another method should be used. Men should use effective contraception and not father a child during treatment and for 4 months after it.
• Pregnancy: there are no data in pregnant women. Studies of asparaginase preparations in mice, rats, chickens and rabbits showed embryotoxic and teratogenic effects. Spectrila should not be used in pregnancy unless the woman’s clinical condition requires it.
• Breastfeeding: it is unknown whether asparaginase passes into breast milk. Because serious reactions are possible in breastfed infants, the SmPC states that Spectrila should be discontinued during breastfeeding.
• Fertility: no human data are available.

Effect on Driving

Spectrila has a moderate influence on the ability to drive and use machines, mainly through possible effects on the nervous system and the gastrointestinal tract.

Store Spectrila in a refrigerator at 2–8 °C, with the vial kept in its outer carton to protect it from light. Because it is refrigerated, the cold chain should stay unbroken from dispatch to the hospital pharmacy until the powder is reconstituted. For storage after reconstitution and dilution, see Shelf Life. The vial is a colourless 20 mL type I glass vial holding 10,000 units; packs contain 1 or 5 vials, and not all pack sizes may be marketed.

• Unopened vial: 4 years.
• Reconstituted and diluted solution: chemical and physical in-use stability has been shown for 2 days at 2–8 °C. From a microbiological point of view the product should be used immediately; otherwise in-use storage times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless reconstitution and dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx). Spectrila is subject to restricted medical prescription (Annex II B of the marketing authorisation): it is prescribed and administered by physicians and healthcare personnel experienced in antineoplastic therapy, in a hospital setting. It is an intravenous infusion given in hospital, so it is supplied to the hospital or clinic that administers it, delivered in a cold chain at 2–8 °C.