4.1. Therapeutic indications

Oncaspar is indicated as a component of antineoplastic combination therapy in acute lymphoblastic leukaemia (ALL) in paediatric patients from birth to 18 years, and adult patients.

4.2. Posology and method of administration

Oncaspar should be prescribed and administered by physicians and/or health care personnel experienced in the use of antineoplastic products. It should only be given in a hospital setting where appropriate resuscitation equipment is available. Patients should be closely monitored for any adverse reactions throughout the administration period (see section 4.4).

Posology

Oncaspar is usually administered as part of combination chemotherapy protocols with other antineoplastic agents (see also section 4.5).

Recommended premedication

Premedicate patients with paracetamol, an H-1 receptor blocker (e.g. diphenhydramine), and an H-2 receptor blocker (e.g. famotidine) 30-60 minutes prior to administration of Oncaspar to decrease the risk and severity of both infusion and hypersensitivity reactions (see section 4.4).

Paediatric patients and adults ≤21 years

The recommended dose in patients with a body surface area (BSA) ≥0.6 m2 and who are ≤21 years of age is 2,500 U of pegaspargase (equivalent to 3.3 ml Oncaspar)/m2 body surface area every 14 days.

Children with a body surface area <0.6 m2 should receive 82.5 U of pegaspargase (equivalent to 0.1 ml Oncaspar)/kg body weight every 14 days.

Adults >21 years

Unless otherwise prescribed, the recommended posology in adults aged >21 years is 2,000 U of pegaspargase (equivalent to 2.67 ml Oncaspar)/m2 body surface area every 14 days.

Treatment may be monitored based on the trough serum asparaginase activity measured before the next administration of pegaspargase. If asparaginase activity values fail to reach target levels, a switch to a different asparaginase preparation could be considered (see section 4.4).

Special populations

Renal impairment

As pegaspargase is a protein with a high molecular weight, it is not excreted renally, and no dose adjustment is necessary in patients with renal impairment.

Hepatic impairment

No dose adjustment is necessary in patients with hepatic impairment.

Elderly

There are limited data available for patients older than 65 years.

Method of administration

Oncaspar can be given by intramuscular (IM) injection or intravenous (IV) infusion.

For smaller volumes, the preferred route of administration is intramuscular. When Oncaspar is given by intramuscular injection the volume injected at one site should not exceed 2 ml in children and adolescents, and 3 ml in adults. If a higher volume is given, the dose should be divided and given at several injection sites.

Intravenous infusion of Oncaspar is usually given over a period of 1 to 2 hours in 100 ml sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution.

The diluted solution can be given together with an already-running infusion of either sodium chloride 9 mg/ml or 5% glucose. Do not infuse other medicinal products through the same intravenous line during administration of Oncaspar.

For instructions on reconstitution and dilution of this medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe hepatic impairment (bilirubin >3 times upper limit of normal [ULN]; transaminases >10 times ULN).

History of serious thrombosis with prior L-asparaginase therapy.

History of pancreatitis, including pancreatitis related to previous L-asparaginase therapy (see section 4.4).

History of serious haemorrhagic events with prior L-asparaginase therapy (see section 4.4).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number

of the administered product should be clearly recorded.

Asparaginase antibodies

The presence of anti-asparaginase antibodies may be associated with low asparaginase activity levels due to potential neutralising activity of these antibodies. In such cases, a switch to a different asparaginase preparation should be considered.

Measurement of the asparaginase activity level in serum or plasma may be undertaken in order to rule out an accelerated reduction of asparaginase activity.

Hypersensitivity

Hypersensitivity reactions to pegaspargase, including life-threatening anaphylaxis, can occur during therapy, including in patients with known hypersensitivity to E. coli-derived asparaginase formulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye swelling, erythema, decreased blood pressure, bronchospasm, dyspnoea, pruritus and rash (see sections 4.3 and 4.8).

Premedicate patients 30-60 minutes prior to administration of Oncaspar (see section 4.2).

As a routine precautionary measure, the patient should be monitored for an hour after administration; resuscitation equipment and other appropriate means for the treatment of anaphylaxis should be available (epinephrine, oxygen, intravenous steroids, etc.). Oncaspar should be discontinued in patients with serious hypersensitivity reactions (see sections 4.3 and 4.8). Depending on the severity of the symptoms, administration of antihistamines, corticosteroids and vasopressors may be indicated as a counter-measure.

Pancreatic effects

Pancreatitis, including haemorrhagic or necrotising pancreatitis with fatal outcomes, has been reported in patients receiving Oncaspar (see section 4.8).

Patients should be informed of the signs and symptoms of pancreatitis which, if left untreated, could become fatal.

If pancreatitis is suspected, Oncaspar should be discontinued; if pancreatitis is confirmed, Oncaspar should not be restarted.

Serum amylase and/or lipase levels should be monitored frequently to identify early signs of pancreatic inflammation. Blood glucose levels should be monitored, as impaired glucose tolerance may occur with concomitant use of Oncaspar with prednisone.

Coagulopathy

Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving pegaspargase (see section 4.8). Oncaspar should be discontinued in patients with serious thrombotic events.

Increased prothrombin time (PT), increased partial thromboplastin time (PTT), hypofibrinogenaemia and antithrombin III decrease can occur in patients receiving pegaspargase. Coagulation parameters should be monitored at baseline and periodically during and after treatment, particularly when other medicinal products with anticoagulant effects (such as acetylsalicylic acid and non steroidal anti inflammatory medicinal products) are used simultaneously (see section 4.5), or when concomitant chemotherapy regimen including methotrexate, daunorubicin, corticosteroids is administered. When there is a marked decrease in fibrinogen or antithrombin III (ATIII) deficiency, consider appropriate replacement therapy.

Osteonecrosis

In the presence of glucocorticoids, osteonecrosis (avascular necrosis) is a possible complication of hypercoagulability observed in children and adolescents with a higher incidence seen in girls (see sections 4.5 and 4.8). Therefore, a close monitoring in children and adolescent patients is recommended in order to detect any clinical signs/symptoms of osteonecrosis. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment as per standard guidelines of treatment of ALL and supportive care principles.

Hepatic effects

Combination therapy with Oncaspar and other hepatotoxic products can result in severe hepatic toxicity.

Caution is required when Oncaspar is given in combination with hepatotoxic products, especially if there is pre-existing hepatic impairment. Patients should be monitored for changes in liver function parameters.

There may be an increased risk of hepatotoxicity in Philadelphia chromosome positive patients, for whom treatment with tyrosine kinase inhibitors (e.g., imatinib) is combined with L-asparaginase therapy. This should be taken into account when considering the use of Oncaspar in these patient populations.

Hepatic veno-occlusive disease (VOD), including severe, life-threatening and potentially fatal cases have been observed in patients treated with Oncaspar in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy (see section 4.8).

Signs and symptoms of VOD include rapid weight gain, fluid retention with ascites, hepatomegaly, thrombocytopenia and rapid increase of bilirubin. The identification of risk factors like pre-existing liver disease or history of VOD is essential for its prevention. Prompt recognition and appropriate management of VOD remain imperative. Patients who experience this condition should be treated according to standard medical practice.

Due to the risk of hyperbilirubinaemia, it is recommended to monitor bilirubin levels at baseline and prior to each dose.

Central nervous system effects

Combination therapy with Oncaspar can result in central nervous system toxicity. Cases of encephalopathy (including reversible posterior leukoencephalopathy syndrome) have been reported (see section 4.8).

Oncaspar may cause central nervous system signs and symptoms manifesting as somnolence, confusion, convulsions. Patients should be closely monitored for such symptoms, especially if Oncaspar is used in association with neurotoxic products (such as vincristine and methotrexate; see section 4.5).

Myelosuppression

Pegaspargase may cause myelosuppression, either directly or indirectly (by altering the myelosuppressive effects of other agents such as methotrexate or 6-mercaptopurine). Therefore, use of Oncaspar could increase the risk of infections.

The decrease in the number of circulating lymphoblasts is often quite marked, and normal or too low leukocyte counts are often seen in the first days after the start of therapy. This can be associated with a marked rise in the serum uric acid level. Uric acid nephropathy may develop. To monitor the therapeutic effect, the peripheral blood count and the patient's bone marrow should be monitored closely.

Hyperammonaemia

Asparaginase facilitates the rapid conversion of asparagine and glutamine to aspartic acid and glutamic acid, with ammonia as the shared by-product of both reactions (see section 5.1). Intravenous administration of asparaginase may therefore cause serum levels of ammonia to rise sharply following administration.

The symptoms of hyperammonaemia are often transient in nature and can include: nausea, vomiting, headache, dizziness and rash. In severe cases, encephalopathy can develop with or without hepatic impairment, especially in older adults, which can be life-threatening or fatal. If symptoms of hyperammonaemia exist, ammonia levels should be monitored closely.

Contraception

Effective non-oral method of contraception must be used during Oncaspar treatment and for at least 6 months after Oncaspar discontinuation. Since an indirect interaction between the oral contraceptives and pegaspargase cannot be ruled out, the use of oral contraception is not considered an acceptable method of contraception (see sections 4.5 and 4.6).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

The decrease in serum proteins caused by pegaspargase can increase the toxicity of other medicinal products that are protein bound.

In addition, by inhibiting protein synthesis and cell division, pegaspargase can disturb the mechanism of action of other substances which require cell division for their effect, e.g., methotrexate.

Methotrexate and cytarabine can interact differently with Oncaspar: their prior administration can increase the action of pegaspargase synergistically. If these substances are given subsequently, the effect of pegaspargase can be weakened antagonistically.

Pegaspargase can interfere with metabolism and clearance of other medicinal products, based on its effects on protein synthesis and hepatic function, as well as from its combined use with other chemotherapy products known to interact with CYP enzymes.

The use of Oncaspar can lead to fluctuation in coagulation factors. This can promote the tendency to bleeding and/or thrombosis. Caution is therefore needed when anticoagulants such as coumarin, heparin, dipyridamole, acetylsalicylic acid or non-steroidal anti-inflammatory medicinal products are given concomitantly, or when concomitant chemotherapy regimen including methotrexate, daunorubicin, corticosteroids is administered.

When glucocorticoids (e.g., prednisone) and pegaspargase are given at the same time, alterations in coagulation parameters (e.g., fall in fibrinogen and antithrombin III deficiency, ATIII) can be more pronounced.

Pegaspargase may increase the risk of glucocorticoid-induced osteonecrosis in children and adolescents when both treatments are given simultaneously, with a higher incidence seen in girls, through a potential increase in exposure of dexamethasone (see sections 4.4 and 4.8).

Immediately preceding or simultaneous treatment with vincristine can increase the toxicity of pegaspargase. Administration of Oncaspar before vincristine may increase the neurotoxicity of vincristine. Therefore, vincristine should be given at least 12 hours prior to administration of Oncaspar in order to minimise toxicity.

An indirect interaction cannot be ruled out between pegaspargase and oral contraceptives due to pegaspargase hepatotoxicity that may impair the hepatic clearance of oral contraceptives. Therefore, the concomitant use of Oncaspar with oral contraceptives is not recommended. Another method than oral contraception should be used in women of childbearing potential (see sections 4.4 and 4.6).

Simultaneous vaccination with live vaccines may increase the risk of severe infections attributable to the immunosuppressive activity of pegaspargase, the presence of the underlying disease and combination chemotherapy (see section 4.4). Vaccination with live vaccines should therefore be given no earlier than 3 months after termination of the entire antileukaemic treatment.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Men and women should use effective contraception during treatment and for at least 6 months after Oncaspar discontinuation. Since an indirect interaction between oral contraceptives and pegaspargase cannot be ruled out, oral contraceptives are not considered sufficiently safe in such clinical situation. A method other than oral contraception should be used in women of childbearing potential (see sections 4.4 and 4.5).

Pregnancy

There are limited data on the use of L-asparaginase and no data on the use of Oncaspar in pregnant women. No reproduction studies in animals with pegaspargase were performed but studies in animals with L-asparaginase have shown teratogenicity (see section 5.3). Therefore and due to its pharmacological properties, Oncaspar should not be used during pregnancy unless the clinical conditions of the woman require treatment with pegaspargase.

Breast-feeding

It is not known whether pegaspargase is excreted in breast milk. Based on its pharmacological properties, any risk to the breast-fed newborns/infants cannot be excluded. As a precautionary measure, breast-feeding should be discontinued during treatment with Oncaspar and should not be restarted until after discontinuation of Oncaspar.

Fertility

No studies investigating the effect of pegaspargase on fertility have been performed.

4.7. Effects on ability to drive and use machines

Oncaspar has a major influence on the ability to drive and use machines. The following adverse reactions have been reported in patients treated with Oncaspar along with other chemotherapy medicinal products: somnolence, confusion, dizziness, syncope, seizure.

Patients should be advised not to drive or operate machines while receiving Oncaspar if they experience these or other adverse reactions which can impair their ability to drive or operate machines (see section 4.4).

4.8. Undesirable effects

Summary of the safety profile

The adverse reactions described in this section are derived from clinical studies data and post-marketing experience of Oncaspar in ALL patients. The safety profile is based on randomised, controlled, prospective, open-label multicentre studies using Oncaspar at a dose of 2500 U/m2 administered intravenously as a comparative treatment (studies DFCI 11-001 and AALL07P4). In addition, the safety profile included data from other Oncaspar studies such as the study comparing the pharmacokinetics of the liquid and lyophilized formulations of pegaspargase (CL2-95014-002), its roll over study (CL2-95014-003) and studies using the intramuscular route of administration (studies CCG-1962 and CCG-1991) were also considered to determine the safety profile (see section 5.1 for CCG-1962 and CCG-1991).

The most common adverse reactions with Oncaspar (observed in at least 2 studies with a frequency of >10%) included: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, activated partial thromboplastin time prolonged, hypertriglyceridaemia, hyperglycaemia, and febrile neutropenia.

The most common, severe adverse reactions with Oncaspar (graded 3 or 4) observed in studies DFCI 11-001 and AALL07P4 with a frequency of >5% included: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, febrile neutropenia, hyperglycaemia, lipase increased, and pancreatitis.

Tabulated list of adverse reactions

Adverse reactions and their frequencies are reported in Table 1. Frequencies are defined by the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions reported with Oncaspar therapy

MedDRA standard system organ class

Adverse reaction

Infections and infestations

Common: Infections, sepsis

Blood and lymphatic system disorders

Very common: Febrile neutropenia

Common: Anaemia, coagulopathy

Not known: Bone marrow failure

Immune system disorders

Very common: Hypersensitivity, urticaria, anaphylactic reaction

Not known: Anaphylactic shock

Metabolism and nutrition disorders

Very common: Decreased appetite, hyperglycaemia

Common: Hyperlipidaemia, hypercholesterolaemia

Not known: Diabetic ketoacidosis, hypoglycaemia

Psychiatric disorders

Not known: Confusional state

Nervous system disorders

Common: Seizure, peripheral motor neuropathy, syncope

Rare: Posterior reversible leukoencephalopathy syndrome

Not known: Somnolence, tremor*

Vascular disorders

Very common: Embolism**

Common: Thrombosis***

Not known: Cerebrovascular accident, haemorrhage, superior sagittal sinus thrombosis

Respiratory, thoracic and mediastinal disorders

Common: Hypoxia

Gastrointestinal disorders

Very common: Pancreatitis, diarrhoea, abdominal pain, nausea

Common: Vomiting, stomatitis, ascites

Rare: Pancreatitis necrotising, pancreatitis haemorrhagic

Not known: Pancreatic pseudocyst, parotitis*

Hepatobiliary disorders

Common: Hepatotoxicity, fatty liver

Rare: Hepatic necrosis, jaundice, cholestasis, hepatic failure

Not known: Veno-occlusive disease

Skin and subcutaneous tissue disorders

Very common: Rash

Not known: Toxic epidermal necrolysis*

Musculoskeletal and connective tissue disorders

Common: Pain in extremities

Not known: Osteonecrosis (see sections 4.4 and 4.5)

Renal and urinary disorders

Not known: Renal failure acute*

General disorders and administration site conditions

Not known: Pyrexia

Investigations

Very common: Weight decreased, hypoalbuminaemia, alanine aminotransferase increased, aspartate aminotransferase increased, hypertriglyceridaemia, blood fibrinogen decreased, lipase increased, amylase increased, activated partial thromboplastin time prolonged, blood bilirubin increased, antithrombin III decreased****, neutrophil count decreased****

Common: Prothrombin time prolonged. international normalised ratio increased, hypokalaemia, blood cholesterol increased, hypofibrinogenaemia, gamma-glutamyl transferase increased

Not known: Blood urea increased, anti-pegaspargase antibodies, platelet count decreased, hyperammonaemia

*Adverse reactions observed with other asparaginases in the class

**Cases of pulmonary embolism, venous thrombosis, venous thrombosis limb, and thrombophlebitis superficial were observed in DFCI 11-001

***Legend: CNS thrombosis

**** Cases of antithrombin III and neutrophil count decreased were observed in CL2-95014-002 and CL2-95014-003 studies

Description of selected adverse reactions

The following adverse reactions have been observed in association with asparaginase therapy. Although they have not been specifically associated with the use of pegaspargase, they may occur with the use of Oncaspar:

Blood and lymphatic system disorders

Oncaspar can cause mild to moderate myelosuppression, and all three blood cell lines can be affected.

About half of all serious haemorrhages and thromboses affect cerebral vessels and can lead to e.g., stroke, seizure, headache or loss of consciousness.

Nervous system disorders

Oncaspar may cause central nervous system dysfunctions manifesting as convulsions, and less frequently confusional state and somnolence (mildly impaired consciousness).

In rare cases, a reversible posterior leukoencephalopathy syndrome (RPLS) may occur.

In very rare cases, mild tremor in the fingers has been described.

Gastrointestinal disorders

About half of patients develop mild to moderate gastrointestinal reactions such as loss of appetite, nausea, vomiting, abdominal cramps, diarrhoea and weight loss.

Acute pancreatitis can occur commonly. There have been isolated reports of formation of pseudocysts (up to four months after the last treatment).

Haemorrhagic or necrotising pancreatitis occurs rarely. One case of pancreatitis with simultaneous acute parotitis has been described with L-asparaginase treatment. In single cases, haemorrhagic or necrotising pancreatitis with fatal outcome has been reported.

Serum amylase can rise during and also after the conclusion of Oncaspar therapy.

Renal and urinary disorders

Acute renal failure may develop in rare cases during treatment with L-asparaginase-containing regimens.

Skin and subcutaneous tissue disorders

Allergic reactions can manifest on the skin. One case of toxic epidermal necrolysis (Lyell's syndrome) has been described in association with L-asparaginase.

Endocrine disorders

Alterations in endocrine pancreatic function are observed commonly and are expressed mainly in the form of abnormal glucose metabolism. Both diabetic ketoacidosis and hyperosmolar hyperglycaemia have been described, which generally respond to administration of insulin.

Metabolism and nutrition disorders

An alteration in serum lipid levels was observed and changes in serum lipid values, in most cases without clinical symptoms, are very common.

A rise in serum urea occurs regularly, is dose-independent and nearly always a sign of pre-renal metabolic imbalance.

General disorders and administration site conditions

Pyrexia can occur after the injection, which usually subsides spontaneously.

Immune system disorders

Specific antibodies to pegaspargase have been detected; uncommonly they were associated with hypersensitivity reactions. Neutralising antibodies reducing clinical efficacy were also recorded.

Hypersensitivity reactions to Oncaspar, including life-threatening anaphylaxis, angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnoea, pruritus and rash, can occur during therapy (see sections 4.3 and 4.4).

Hepatobiliary disorders

Alteration of liver parameters is common. A dose-independent rise in serum transaminases, and serum bilirubin is commonly observed.

A rapid weight gain, fluid retention with ascites, hepatomegaly, associated with rapid increase of serum bilirubin and persistent thrombocytopenia might indicate a risk of developing a severe VOD, which if left untreated, can be fatal (see section 4.4).

Fatty liver can be observed very frequently. There have been rare reports of cholestasis, icterus, hepatic cell necrosis and hepatic failure with fatal outcome.

Impaired protein synthesis can lead to a decline in the serum proteins. There is a dose-independent decrease in serum albumin in the majority of patients during the treatment.

The types of adverse reactions with Oncaspar are similar to those observed with native non-pegylated L-asparaginase (e.g., native E. coli asparaginase).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Cases of accidental overdose have been reported with Oncaspar. Following overdose, increased liver enzymes, rash and hyperbilirubinaemia have been observed. There is no specific pharmacological treatment for the overdose. In case of overdose, patients must be carefully monitored for signs and symptoms of adverse reactions, and appropriately managed with symptomatic and supportive treatment.