Pegaspargase

Pegaspargase is the covalent conjugate of Escherichia coli-derived L-asparaginase with monomethoxypolyethylene glycol. PEGylation does not change the enzymatic properties of L-asparaginase, but it changes its pharmacokinetics and immunogenicity. The potency of Oncaspar should not be compared with that of another pegylated or non-pegylated protein of the same therapeutic class.

Mechanism of Action

• Enzymatic action: L-asparaginase splits the amino acid L-asparagine into aspartic acid and ammonia.
• Asparagine depletion: leukaemic blasts cannot synthesise L-asparagine, so depleting it in the blood inhibits their protein, DNA and RNA synthesis and they undergo apoptosis. Normal cells can make their own asparagine and are less affected by its rapid depletion.
• Pharmacodynamic effect: the anti-leukaemic effect is related to a sustained fall in L-asparagine in blood and cerebrospinal fluid. In newly diagnosed children with standard-risk ALL given intramuscular doses of 2,500 U/m², serum asparagine was clearly reduced by day 4 after the first induction dose and reached its lowest level by day 10. Concentrations of about 1 µM persisted for about 3 weeks, and asparagine fell below 3 µM once asparaginase activity exceeded 0.1 U/mL. Cerebrospinal fluid asparagine fell from 2.3 µM before treatment to 1.1 µM on day 7 and 0.6 µM on day 28 of induction.

Pharmacokinetics

• Absorption: after an intramuscular injection, mean asparaginase activity peaked at about 1 U/mL on day 5; the mean half-life of absorption from the injection site was 1.7 days. After a single 2,500 U/m² intravenous dose during induction, the mean peak was 1,638 mU/mL, reached after a median of 1.25 hours.
• Distribution: volume of distribution at steady state is about 1.86 L/m² after intramuscular dosing and about 1.95 L after an intravenous dose.
• Metabolism: as a protein, it is expected to be broken down by proteolytic enzymes throughout the body.
• Elimination: elimination half-life is about 5.5 days after intramuscular dosing and about 5.3 days after an intravenous dose; clearance is 0.169 L/m² per day (intramuscular) and 0.215 L/day (intravenous). Because of its high molecular weight it is not excreted by the kidneys. Asparaginase activity of at least 0.1 U/mL was sustained for up to 18 days after a single intravenous dose in 93.5–95.3% of patients, and with doses every two weeks, trough activity above 0.4 U/mL was sustained in all patients from week 7 to week 25.
• Special populations: peak concentration and AUC tended to be lower in males, in patients with a larger body mass index and in patients over 10 years of age. The SmPC gives no dose adjustment for renal or hepatic impairment, but severe hepatic impairment is a contraindication.

• Acute lymphoblastic leukaemia (ALL): as a component of antineoplastic combination therapy, in paediatric patients from birth to 18 years and in adult patients. It is usually given as part of combination chemotherapy protocols with other antineoplastic agents.

• Hypersensitivity to the active substance or to any of the excipients.
• Severe hepatic impairment (bilirubin above 3 times the upper limit of normal; transaminases above 10 times the upper limit of normal).
• History of serious thrombosis with prior L-asparaginase therapy.
• History of pancreatitis, including pancreatitis related to previous L-asparaginase therapy.
• History of serious haemorrhagic events with prior L-asparaginase therapy.

The reactions below come from clinical studies and post-marketing experience of Oncaspar in ALL, mainly studies DFCI 11-001 and AALL07P4, in which 2,500 U/m² was given intravenously. The most common reactions (above 10% in at least two studies) were increased ALT, AST and blood bilirubin, prolonged activated partial thromboplastin time, hypertriglyceridaemia, hyperglycaemia and febrile neutropenia. The most common severe (grade 3–4) reactions, at above 5%, were increased ALT, AST and bilirubin, febrile neutropenia, hyperglycaemia, increased lipase and pancreatitis.

Very common (≥1/10): febrile neutropenia; hypersensitivity, urticaria, anaphylactic reaction; decreased appetite, hyperglycaemia; embolism (including pulmonary embolism, venous thrombosis, limb venous thrombosis and superficial thrombophlebitis in study DFCI 11-001); pancreatitis, diarrhoea, abdominal pain, nausea; rash; weight decreased, hypoalbuminaemia, increased ALT and AST, hypertriglyceridaemia, decreased blood fibrinogen, increased lipase and amylase, prolonged activated partial thromboplastin time, increased blood bilirubin, decreased antithrombin III and decreased neutrophil count.

Common (≥1/100 to <1/10): infections, sepsis; anaemia, coagulopathy; hyperlipidaemia, hypercholesterolaemia; seizure, peripheral motor neuropathy, syncope; thrombosis (including CNS thrombosis); hypoxia; vomiting, stomatitis, ascites; hepatotoxicity, fatty liver; pain in extremities; prolonged prothrombin time, increased INR, hypokalaemia, increased blood cholesterol, hypofibrinogenaemia, increased gamma-glutamyl transferase.

Rare (≥1/10,000 to <1/1,000): posterior reversible leukoencephalopathy syndrome; necrotising and haemorrhagic pancreatitis; hepatic necrosis, jaundice, cholestasis, hepatic failure.

Not known: bone marrow failure; anaphylactic shock; diabetic ketoacidosis, hypoglycaemia; confusional state; somnolence; tremor (observed with other asparaginases of the class); cerebrovascular accident, haemorrhage, superior sagittal sinus thrombosis; pancreatic pseudocyst; parotitis (other asparaginases); veno-occlusive disease; toxic epidermal necrolysis (other asparaginases); osteonecrosis; acute renal failure (other asparaginases); pyrexia; increased blood urea, anti-pegaspargase antibodies, decreased platelet count, hyperammonaemia.

Important serious reactions: Oncaspar can cause mild to moderate myelosuppression of all three cell lines. About half of all serious haemorrhages and thromboses affect cerebral vessels and can cause stroke, seizure, headache or loss of consciousness. Central nervous system dysfunction can appear as convulsions and, less often, confusion and somnolence. Acute pancreatitis can occur commonly, and pseudocysts have been reported up to four months after the last treatment. Changes in endocrine pancreatic function, mainly abnormal glucose metabolism, are common; diabetic ketoacidosis and hyperosmolar hyperglycaemia have been described and generally respond to insulin. Hepatic changes are common, and rapid weight gain, ascites, enlarged liver, rising bilirubin and persistent thrombocytopenia may signal severe veno-occlusive disease. Specific antibodies to pegaspargase have been found; uncommonly they were linked to hypersensitivity reactions, and neutralising antibodies that reduce efficacy were also recorded.

• Protein-bound medicines: the fall in serum proteins caused by pegaspargase can increase their toxicity.
• Methotrexate and cytarabine: by inhibiting protein synthesis and cell division, pegaspargase can disturb the action of substances that need cell division, for example methotrexate. If methotrexate or cytarabine is given beforehand, the action of pegaspargase can be increased; if they are given afterwards, its effect can be weakened.
• Vincristine: immediately preceding or simultaneous treatment increases the toxicity of pegaspargase, and giving Oncaspar before vincristine may increase vincristine neurotoxicity. Vincristine should be given at least 12 hours before Oncaspar.
• Glucocorticoids (for example prednisone): changes in coagulation parameters (fall in fibrinogen, antithrombin III deficiency) can be more pronounced, and glucose tolerance may be impaired. In children and adolescents, particularly girls, the combination may raise the risk of glucocorticoid-induced osteonecrosis, probably through higher dexamethasone exposure.
• Anticoagulants and antiplatelet medicines (coumarin, heparin, dipyridamole, acetylsalicylic acid, non-steroidal anti-inflammatory medicines): fluctuating coagulation factors can promote bleeding and/or thrombosis, so caution is needed. The same applies to regimens containing methotrexate, daunorubicin or corticosteroids.
• Hepatotoxic medicines: combination with other hepatotoxic products can cause severe hepatic toxicity. DrugBank also advises avoiding excessive or chronic alcohol use, since alcohol and pegaspargase can both be hepatotoxic. Hepatotoxicity may be higher in Philadelphia chromosome-positive patients when a tyrosine kinase inhibitor such as imatinib is combined with L-asparaginase.
• Metabolism of other medicines: pegaspargase can interfere with the metabolism and clearance of other medicines, through its effects on protein synthesis and liver function and its combination with chemotherapy known to interact with CYP enzymes.
• Oral contraceptives: an indirect interaction cannot be ruled out, so their concomitant use is not recommended; another method should be used.
• Live vaccines: simultaneous vaccination may increase the risk of severe infections. Live vaccines should be given no earlier than 3 months after the end of the entire anti-leukaemic treatment.

Oncaspar should be prescribed and administered by physicians and/or health care personnel experienced in the use of antineoplastic products. It should be given only in a hospital where appropriate resuscitation equipment is available, and patients should be closely monitored for adverse reactions throughout administration. It is usually part of combination chemotherapy protocols. Doses are expressed in units (U) of enzyme activity.

Premedication

Patients are premedicated with paracetamol, an H1 receptor blocker (for example diphenhydramine) and an H2 receptor blocker (for example famotidine) 30–60 minutes before each dose, to lower the risk and severity of infusion and hypersensitivity reactions.

Recommended Dose

• Children and adults up to 21 years with a body surface area of at least 0.6 m²: 2,500 U (3.3 mL Oncaspar) per m² of body surface area every 14 days.
• Children with a body surface area below 0.6 m²: 82.5 U (0.1 mL Oncaspar) per kg body weight every 14 days.
• Adults over 21 years: unless otherwise prescribed, 2,000 U (2.67 mL Oncaspar) per m² of body surface area every 14 days.
• Treatment may be monitored by trough serum asparaginase activity before the next dose. If activity does not reach target levels, a switch to a different asparaginase preparation could be considered.

Method of Administration

• Oncaspar is given by intramuscular injection or intravenous infusion. For smaller volumes, intramuscular injection is preferred; the volume at one site should not exceed 2 mL in children and adolescents or 3 mL in adults, and larger doses are divided between several sites.
• Intravenous infusion usually runs over 1 to 2 hours in 100 mL of sodium chloride 9 mg/mL (0.9%) or 5% glucose solution. The diluted solution can run alongside an infusion of either fluid already in progress, but no other medicine is infused through the same line during the Oncaspar infusion.
• Reconstitution and dilution are described in section 6.6 of the SmPC.

Special Populations

• Renal impairment: no dose adjustment, because the high-molecular-weight protein is not excreted by the kidneys.
• Hepatic impairment: no dose adjustment is stated in the SmPC, but severe hepatic impairment is a contraindication (see above).
• Elderly: limited data in patients older than 65 years.

Traceability

To improve the traceability of biological medicines, the name and batch number of the administered product must be clearly recorded.

Hypersensitivity

Hypersensitivity reactions, including life-threatening anaphylaxis, can occur, even in patients with known hypersensitivity to E. coli-derived asparaginases. Other signs include angioedema, lip or eye swelling, erythema, falling blood pressure, bronchospasm, dyspnoea, pruritus and rash. Patients are premedicated and monitored for an hour after administration, with resuscitation equipment and means to treat anaphylaxis (adrenaline, oxygen, intravenous steroids) available. Oncaspar is stopped in serious hypersensitivity; antihistamines, corticosteroids and vasopressors may be needed.

Asparaginase Antibodies

Anti-asparaginase antibodies may neutralise the enzyme and lead to low asparaginase activity. Serum or plasma activity can be measured, and a switch to a different asparaginase preparation should be considered.

Pancreatitis

Pancreatitis, including haemorrhagic or necrotising forms with fatal outcomes, has been reported. Patients are told the signs and symptoms. If pancreatitis is suspected Oncaspar is stopped; if it is confirmed Oncaspar must not be restarted. Serum amylase and/or lipase are monitored frequently, and blood glucose is monitored because glucose tolerance may be impaired with prednisone.

Coagulopathy and Thrombosis

Serious thrombotic events, including sagittal sinus thrombosis, can occur, and Oncaspar is stopped in serious thrombosis. Prothrombin time, partial thromboplastin time, fibrinogen and antithrombin III can change. Coagulation parameters are monitored at baseline and periodically during and after treatment, particularly with anticoagulant-acting medicines or regimens containing methotrexate, daunorubicin or corticosteroids. Replacement therapy is considered when fibrinogen falls markedly or antithrombin III is deficient.

Osteonecrosis

With glucocorticoids, osteonecrosis is a possible complication of hypercoagulability in children and adolescents, with a higher incidence in girls. These patients should be monitored closely for signs and symptoms.

Liver Effects and Veno-Occlusive Disease

Combination with other hepatotoxic products can cause severe liver toxicity, especially with pre-existing liver impairment; liver parameters are monitored. Hepatic veno-occlusive disease, including severe, life-threatening and fatal cases, has occurred with standard chemotherapy, including during induction. Signs are rapid weight gain, fluid retention with ascites, hepatomegaly, thrombocytopenia and rapidly rising bilirubin. Because of the risk of hyperbilirubinaemia, bilirubin is checked at baseline and before each dose.

Nervous System, Bone Marrow and Ammonia

Combination therapy can cause central nervous system toxicity, including encephalopathy (reversible posterior leukoencephalopathy syndrome), with somnolence, confusion and convulsions, especially with neurotoxic products such as vincristine and methotrexate. Myelosuppression, direct or through other agents such as methotrexate or 6-mercaptopurine, can increase the risk of infection; blood counts and bone marrow are monitored closely. Marked falls in lymphoblasts can raise serum uric acid, and uric acid nephropathy may develop. Intravenous asparaginase can raise serum ammonia sharply (nausea, vomiting, headache, dizziness, rash; in severe cases encephalopathy, especially in older adults), and ammonia levels are monitored if symptoms occur.

Contraception, Pregnancy, Breastfeeding and Fertility

• Contraception: men and women must use effective contraception during treatment and for at least 6 months after the last dose. Oral contraception is not considered sufficiently safe, so women of childbearing potential should use another, non-oral method.
• Pregnancy: there are limited data on L-asparaginase and none on Oncaspar in pregnant women. Animal studies with L-asparaginase showed teratogenicity. Oncaspar should not be used in pregnancy unless the woman’s condition requires it.
• Breastfeeding: it is not known whether pegaspargase passes into breast milk, and a risk to the infant cannot be excluded. Breastfeeding should be stopped during treatment and not restarted until after Oncaspar has been discontinued.
• Fertility: no studies of the effect on fertility have been done.

Sodium

Oncaspar contains less than 1 mmol (23 mg) of sodium per dose, that is essentially sodium-free.

Effect on Driving

Oncaspar has a major influence on the ability to drive and use machines. Somnolence, confusion, dizziness, syncope and seizures have been reported with Oncaspar and other chemotherapy. Patients should not drive or operate machines if they experience these or other impairing reactions.

Store the unopened vials in a refrigerator at 2–8 °C. Do not freeze. Because the vials must stay refrigerated, Oncaspar is moved and held in a continuous cold chain (2–8 °C, never frozen) from dispatch until the hospital pharmacy or ward prepares it. For the reconstituted and diluted product, see Shelf Life. Each pack contains one Type I glass vial with a chlorobutyl stopper and aluminium flip-off seal holding 3,750 U.

• Unopened vial: 3 years.
• Reconstituted solution: chemical and physical in-use stability has been shown for 24 hours below 25 °C. From a microbiological point of view it should be used immediately unless the method of reconstitution rules out the risk of microbial contamination; if not used immediately, in-use times and conditions are the responsibility of the user.
• Diluted solution: chemical and physical in-use stability has been shown for 48 hours at 2–8 °C. From a microbiological point of view it should be used immediately.

Prescription only (Rx), subject to restricted medical prescription (Annex II B of the marketing authorisation). It is prescribed and administered by physicians and/or health care personnel experienced in the use of antineoplastic products, in a hospital setting. It is supplied to the hospital that administers it, in a cold chain at 2–8 °C.