Oncaspar
1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Oncaspar 750 U/ml solution for injection/infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One ml of solution contains 750 Units (U)** of pegaspargase*. 
One vial of 5 ml solution contains 3,750 Units. 
 
* The active substance is a covalent conjugate of Escherichia coli-derived L-asparaginase with 
monomethoxypolyethylene glycol 
**One unit is defined as the quantity of enzyme required to liberate 1 µmol ammonia per minute at 
pH 7.3 and 37°C 
 
The potency of this medicinal product should not be compared to the one of another pegylated or 
non-pegylated protein of the same therapeutic class. For more information, see section 5.1. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection/infusion. 
Clear, colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
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). 
 
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. 
 



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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. 
 
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. 
 



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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). 
 
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), and 
hypofibrinogenaemia 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. 
 
Hepatic effects 
Combination therapy with Oncaspar and 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. 
 



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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 
An 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. 
 



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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. 
 
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. 
 



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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 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, 
Oncaspar 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). 
 
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*** 



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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 

Skin and subcutaneous 
tissue disorders 

Very common: Rash 
Not known: Toxic epidermal necrolysis* 

Musculoskeletal and 
connective tissue disorders Common: Pain in extremities 

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 
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, neutrophil 
count decreased, 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 
 
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. 



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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. 
 
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 national reporting system 
listed in Appendix V 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, other antineoplastic 
agents, ATC code: L01XX24 
 
Mechanism of action 
 
The mechanism of action of L-asparaginase is the enzymatic cleavage of the amino acid L-asparagine 
into aspartic acid and ammonia. Depletion of L-asparagine in blood results in inhibition of 
protein-synthesis, DNA-synthesis and RNA-synthesis, especially in leukaemic blasts which are not 
able to synthesise L-asparagine, thus undergoing apoptosis. 
 
Normal cells, in contrast, are capable of synthesising L-asparagine and are less affected by its rapid 
depletion during treatment with the enzyme L-asparaginase. The PEGylation does not change the 
enzymatic properties of L-asparaginase, but it influences the pharmacokinetics and immunogenicity of 
the enzyme. 
 
Pharmacodynamic effects 
 
Anti-leukaemic effect of L-asparaginase is related to a sustained L-asparagine depletion in blood and 
cerebrospinal fluid (CSF). The pharmacodynamic (PD) effect of Oncaspar was assessed after 
intramuscular (Study CCG-1962) and intravenous administration (AALL07P4). 
 
In Study CCG-1962, PD effect of Oncaspar was assessed through serial measurements of asparagine 
in serum (n=57) and CSF (n=50) of newly diagnosed paediatric patients with standard-risk ALL who 
received three intramuscular doses of Oncaspar (2,500 Units/m2 BSA), one each during induction and 
two during delayed intensification treatment phases. A reduction in serum asparagine concentration 
was evident by the 4th day after the first Induction dose and reached an apparent nadir by the 10th day 
after the dose. Serum asparagine concentrations of approximately 1 µM persisted for approximately 
3 weeks. Asparagine concentration fell to <3 µM when asparaginase activity was >0.1 U/mL. CSF 
asparagine of 2.3 µM pre-treatment fell to 1.1 µM on Day 7 and 0.6 µM on Day 28 of Induction 
(see Clinical efficacy and safety). 
 
In Study AALL07P4, the PD effect of Oncaspar was assessed in 47 evaluable subjects with high risk 
B-precursor ALL who received intravenous doses of Oncaspar 2,500 U/m2 BSA during the Induction 
and Consolidation phases. Plasma L-asparagine concentrations were depleted to below the assay limit 
of quantification within 24 hours following the Induction and first Consolidation dose of Oncaspar and 
depletion was sustained for approximately two weeks. CSF asparagine concentrations were reduced by 
the 4th day following the Induction dose, and remained largely undetectable by the 18th day after 
dosing. 
 
Based on results from these two studies, a 2,500 U/m2 BSA dose of Oncaspar administered 
intramuscular (CCG-1962) and intravenous (AALL07P4) provides maintenance of L-asparagine 
depletion for approximately two weeks following dosing. 
 



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Clinical efficacy and safety 
 
Oncaspar efficacy and safety were evaluated on the basis of three clinical studies using Oncaspar 
solution for injection/infusion in the first line treatment of ALL: Study CCG-1962 in standard risk 
ALL patients; Study AALL07P4 in high risk ALL patients; Study DFCI 11-001 enrolled both standard 
and high-risk ALL patients. 
 
Oncaspar efficacy in ALL in patients with relapse/refractory disease and a history of prior clinical 
allergic reaction to native E. coli L-asparaginase was based on a pool of 94 patients from six 
open-label studies [ASP-001, ASP-201A, ASP-302, ASP-304, ASP-400 and ASP-001C/003C]. 
 
First-Line (ALL patients non-hypersensitive to native E. coli L-asparaginase) 
The safety and efficacy of Oncaspar was evaluated in an open-label, multicentre, randomised, 
active-controlled study (Study CCG-1962). In this study, 118 paediatric patients aged 1 to 9 years with 
previously untreated standard-risk ALL were randomised 1:1 to Oncaspar or native E. coli 
L-asparaginase as part of combination therapy. Oncaspar was administered intramuscularly at a dose 
of 2,500 Units/m2 BSA on Day 3 of the 4-week Induction phase and on Day 3 of each of two 8-week 
Delayed Intensification (DI) phases. Native E. coli L-asparaginase was administered intramuscularly 
at a dose of 6,000 Units/m2 BSA three times weekly for a total of 9 doses during induction and for a 
total of 6 doses during each delayed intensification phase. 
 
The primary determination of efficacy was based on demonstration of similar asparagine depletion 
(magnitude and duration) in the Oncaspar and native E. coli L-asparaginase arms. The 
protocol-specified goal was achievement of asparagine depletion to a serum concentration of ≤1 µM. 
The proportion of patients with this level of depletion was similar between the 2 study arms during all 
3 phases of treatment at the protocol-specified time points. 
 
In all phases of treatment, serum asparagine concentrations decreased within 4 days of the first dose of 
asparaginase in the treatment phase and remained low for approximately 3 weeks for both Oncaspar 
and native E. coli L-asparaginase arms. Serum asparagine concentrations during the induction phase 
are shown in Figure 1. The patterns of serum asparagine depletion in the 2 delayed intensification 
phases are similar to the pattern of serum asparagine depletion in the induction phase. 
 
Figure 1: Mean (± standard error) serum asparagine during Study CCG-1962 induction phase 

 
Note: Oncaspar (2,500 Units/m2 BSA intramuscular) was administered on Day 3 of the 4-week 

induction phase. Native E. coli L-asparaginase (6,000 Units/m2 BSA intramuscular) was 
administered 3 times weekly for 9 doses during induction. 

 
CSF asparagine concentrations were determined in 50 patients during the induction phase. CSF 
asparagine decreased from a mean pre-treatment concentration of 3.1 µM to 1.7 µM on Day 4 ± 1 and 
1.5 µM at 25 ± 1 days after administration of Oncaspar. These findings were similar to those observed 
in the native E. coli L-asparaginase treatment arm. 
 

0.1 

1.0 

10.0 

100.0 

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 
Days After First Dose of L-Asparaginase 

As
pa

ra
gi

ne
 (µ

M
) 

Native E. coli L-

Asparaginase Oncaspar® 
 E. coli 



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Event-free survival (EFS) for the Oncaspar and native E. coli L-asparaginase arms is summarised in 
Table 2, Study CCG-1962 was not designed to evaluate differences in EFS rates. 
 
Table 2: Event-free survival rate at 3, 5 and 7 years (Study CCG-1962) 
 
 Oncaspar native E. coli L-asparaginase 
3-Year EFS Rate, % 
(95% CI) 

83 
(73, 93) 

79 
(68, 90) 

5-Year EFS Rate, % 
(95% CI) 

78 
(67, 88) 

73 
(61, 85) 

7-Year EFS Rate, % 
(95% CI) 

75 
(63, 87) 

66 
(52, 80) 

 
In Study CCG-1962, the most common adverse reactions were infections, including two 
life-threatening infections (1 patient in each arm). In general, incidence and type of adverse reactions 
Grade 3 and 4 were similar between the two treatment groups. Two patients in the Oncaspar arm had 
allergic reactions during Delayed Intensification (DI) DI #1 (Grade 1 allergic reaction and Grade 3 
hives). 
 
A pilot study was conducted for newly diagnosed patients from 1 to <31 years of age with high risk 
B-precursor ALL (Study AALL07P4). This was an open label, controlled, randomised study 
comparing an investigational pegylated asparaginase product to Oncaspar as a component of 
multi-agent chemotherapy in the first line treatment of ALL. White blood cell (WBC) criteria were: 
a) Age 1-10 years: WBC ≥50,000/μL; b) Age 10-30 years: Any WBC; c) Prior steroid therapy: Any 
WBC. Patients were not allowed prior cytotoxic chemotherapy with the exception of steroids and 
intrathecal cytarabine. A total of 166 patients were enrolled in this study; 54 patients were randomised 
to treatment with 2,500 U/m2 BSA Oncaspar and 111 patients were randomised to the investigational 
pegylated asparaginase product. Oncaspar was administered intravenously at a dose of 2,500 Units/m2 
BSA during Induction, Consolidation, Delayed Intensification, and Interim Maintenance phases in 
patients with high-risk ALL receiving augmented Berlin-Frankfurt-Münster therapy. The percentage 
of patients in the Oncaspar treatment arm with evaluable minimal residual disease (MRD) negative 
status (<0.1% leukaemia cells in bone marrow) at Day 29 of Induction was 80% (40/50). At 4-years, 
the EFS and overall survival (OS) for the Oncaspar treatment arm were 81.8% [95% CI 62.9-91.7%] 
and 90.4% [95% CI 78.5-95.9%], respectively. Overall, in the group receiving Oncaspar, the rate of all 
grade hypersensitivity was 5.8%, anaphylactic reactions was 19.2%, and pancreatitis 7.7%. Grade 3 or 
higher febrile neutropenia was 15.4%. 
 
Study DFCI 11-001, conducted by the Dana-Farber Cancer Institute (DFCI), is an ongoing, 
active-controlled, randomised multicentre study of an intravenous investigational pegylated 
asparaginase product versus Oncaspar, in children and adolescents aged 1 to <22 years with newly 
diagnosed ALL treated with a DFCI ALL consortium therapeutic backbone. A total of 239 patients 
were randomised, 237 of whom were treated with study drug (146 male and 91 female), of these, 
119 patients (115 with a diagnosis of ALL) were treated with Oncaspar 2500 U/m2. Treatment was 
administered during Induction (Day 7), and then every 2 weeks for a total of 30 weeks post-Induction 
therapy. Randomisation of patients was stratified based on risk group (standard/high/very high risk), 
including both B- and T-cell ALL. The percentage of patients in the Oncaspar arm with evaluable Low 
End-Induction MRD (<0.001 detectable disease) at Day 32 was 87.9% (80/91). The One-year EFS 
was 98.0 [95%CI 92.3, 99.5]; the One-year OS was 100 [95% CI 100, 100] in this study. 
 
ALL patients hypersensitive to native E. coli L-asparaginase  
Six open-label studies evaluated Oncaspar in relapse/refractory haematological diseases. In these 
studies a total of 94 patients with ALL diagnosis with a history of prior clinical allergic reaction to 
native E. coli L-asparaginase were exposed to Oncaspar. One patient received Oncaspar doses of 
250 and 500 Units/m2 BSA intravenously. The remaining patients were treated with 2,000 or 
2,500 U/m2 BSA administered intramuscularly or intravenously. Patients received Oncaspar as a 
single agent or in combination with multi-agent chemotherapy. Overall, from five studies analysed 
based on 65 ALL patients exposed to Oncaspar using the highest therapeutic response during the 



13 

entire study, complete remission was observed in 30 patients (46%), partial remission in 7 patients 
(11%) and haematological improvement in 1 patient (2%). In the other study, with 29 hypersensitive 
ALL patients exposed to Oncaspar, 11 patients were evaluated for response during induction. Of these, 
3 patients (27%) achieved complete remission, 1 patient (9%) had partial remission, 1 patient (9%) 
had haematologic improvement and 2 patients (18%) had therapeutic efficacy. Therapeutic efficacy 
was defined as a clinical improvement which did not meet the criteria for other beneficial outcomes. 
During the maintenance phase, 19 patients were evaluated, with 17 patients (89%) achieving complete 
remission, and 1 patient (5%) with therapeutic efficacy. 
 
5.2 Pharmacokinetic properties 
 
Oncaspar pharmacokinetic properties were based on asparaginase activity measured by an enzymatic 
assay after intramuscular (CCG-1962) and intravenous (AALL07P4, DFCI 11-001) administration. 
 
In Study CCG-1962, mean asparaginase activity reached peak value of 1 U/mL on Day 5 after the 
injection. The mean half-life after absorption from the injection site was 1.7 days and the elimination 
half-life was 5.5 days. The volume of distribution at steady-state and clearance were estimated at 
1.86 L/m2 and 0.169 L/m2 per day, respectively. 
 
In Study AALL07P4, PK parameters after a single 2,500 U/m2 intravenous dose during Induction were 
calculated by noncompartmental PK analysis from sequential plasma samples and are depicted in 
Table 3 (see section 5.1). The Cmax and AUC of Oncaspar trended lower in males, subjects with larger 
BMI, and subjects >10 years. During Induction, following a single intravenous dose of Oncaspar 
2,500 U/m2, asparaginase activity ≥0.1 U/mL was sustained for up to 18 days post-dose in 95.3% of 
subjects. 
 
Table 3: Pharmacokinetic Parameters After a Single intravenous Dose of Oncaspar 
2,500 U/m2 BSA During Induction (N=47; Study AALL07P4) 
PK Parameters Arithmetic Mean (SD) 
Cmax (mU/mL)* 1638 (459.1) 
Tmax (hr)* 1.25 (1.08, 5.33)† 
AUC0-t (mUday/mL)* 14810 (3555) 
AUC0–∞ (mUday/mL)ǂ 16570 (4810) 
t1/2 (day)ǂ 5.33 (2.33) 
CL (L/day)ǂ 0.2152 (0.1214) 
Vss (L)ǂ 1.95 (1.13) 
* N=47 evaluable subjects. 
† Median (10th, 90th percentiles). 
ǂ N= 46 evaluable subjects. 

 
In Study DFCI 11-001, assessments of asparaginase activity were performed following a single 
intravenous dose of Oncaspar 2,500 U/m2 BSA during Induction, and every two weeks during 
post-Induction (see section 5.1). During Induction, plasma asparaginase activity ≥0.1 U/mL was 
sustained in 93.5% of subjects 18 days after administration. During the post-Induction phase, a nadir 
(trough) asparaginase activity above 0.4 U/mL was sustained in 100% of subjects from Week 7 up 
until Week 25. These results indicate that, when Oncaspar 2,500 U/m2 BSA is administered as single 
and repeated doses every two weeks, clinically relevant asparaginase activity is sustained over the 
entire dosing interval (i.e., two weeks). 
 
Patients with newly diagnosed ALL received a single intramuscular injection of Oncaspar (2,500 U/m² 
BSA) or native asparaginase from E. coli (25,000 U/m² BSA) or from Erwinia (25,000 U/m² BSA). 
The plasma elimination half-life of Oncaspar was statistically significantly longer (5.7 days) than the 
plasma elimination half-lives of the native asparaginases from E. coli (1.3 days) and Erwinia 
(0.65 days). The immediate cell death of leukaemic cells in vivo, measured by rhodamine 
fluorescence, was the same for all three L-asparaginase preparations. 
 



14 

ALL patients with several relapses were treated either with Oncaspar or with native asparaginase from 
E. coli as part of an induction therapy. Oncaspar was given intramuscular in a dose of 2,500 U/m² 
BSA on days 1 and 15 of induction. The mean plasma half-life of Oncaspar was 8 days in 
non-hypersensitive patients (AUC 10.35 U/ml/day), and 2.7 days in hypersensitive patients (AUC 
3.52 U/ml/day). 

Specific populations 
The controlled studies were not designed to formally evaluate the pharmacokinetics of Oncaspar in 
specific populations. A population pharmacokinetic evaluation of Oncaspar based on data obtained 
from Studies AALL07P4 (IV), DFCI 11-001 (IV), and CCG-1962 (IM) identified that clearance 
(linear and saturable) increased approximately proportionally to BSA and volume of distribution 
increased slightly more proportionally to BSA. No statistically significant differences in PK 
characteristics between male and female subjects were identified in this analysis. 
 
The impact of renal and hepatic impairment on the PK of Oncaspar has not been evaluated. As 
pegaspargase is a protein with a high molecular weight, it is not excreted renally, and no change of 
pharmacokinetic of Oncaspar in patients with renal impairment is foreseen. 
 
Since the proteolytic enzymes responsible for Oncaspar metabolism are ubiquitously distributed in 
tissues the exact role of the liver is unknown: however any decrease in liver function is not expected to 
present clinical relevant problems in the use of Oncaspar. 
 
There are no data available for elderly patients. 
 
5.3 Preclinical safety data 
 
Acute toxicity 
Only very high doses of pegaspargase given to mice intraperitoneally as a single dose (25,000 –
 100,000 U/kg body weight) caused the death of 14% of all treated mice. Mild hepatotoxicity was 
observed with the same doses. Adverse reactions were loss of body weight, piloerection and reduced 
activity. Reduced splenic weight might be a sign of potential immunosuppressant effect of the 
treatment. 
 
Pegaspargase was well tolerated both in rats and dogs when administered intravenously in single doses 
up to 500 U/kg body weight. 
 
Repeated dose toxicity 
A 4-week study in rats treated with a dose of pegaspargase of 400 U/kg/day intraperitoneally resulted 
in a fall in food intake and body weight compared to the control group. 
 
A 3-month study in mice with pegaspargase at doses up to 500 U/kg intraperitoneally or 
intramuscularly resulted in slight hepatocellular changes only at the highest intraperitoneal dose. 
 
A temporary suppression in body weight gain and a temporary reduction in total leukocyte counts 
were observed in dogs which were treated with pegaspargase 1200 U/kg weekly for 2 weeks. 
Increased serum glutamic pyruvic transaminase activity also occurred in one out of four dogs. 
 
Immunogenicity 
No immunogenic response was detected in a 12-week study in mice in which pegaspargase was 
administered weekly at the dose of 10.5 U/mouse intramuscularly or intraperitoneally. 
 
Reproductive toxicity 
No studies of reproductive toxicity were conducted with pegaspargase. 
 
Embryotoxicity studies with L-asparaginase have showed evidence of teratogenic potential in rats 
treated from day 6 to 15 of gestation with a No Observed Effect Level (NOEL) for teratogenic effects 
at 300 U/kg intravenously. In rabbits, doses of 50 or 100 U/kg intravenous on days 8 and 9 of 



15 

gestation induced viable fetuses with congenital malformations: no NOEL has been determined. 
Multiple malformations and embryolethal effects were observed with doses in the therapeutic range. 
Investigations of the effect on fertility and peri- and postnatal development were not conducted. 
 
Carcinogenicity, mutagenicity, fertility 
Long-term investigations of carcinogenicity or studies of the effect on fertility in animals were not 
conducted with pegaspargase. 
 
Pegaspargase was not mutagenic in the Ames test using Salmonella typhimurium strains. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium dihydrogen phosphate monohydrate 
Disodium phosphate heptahydrate 
Sodium chloride 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial: 
8 months. 
 
Chemical and physical in-use stability of the diluted solution has been demonstrated for 48 hours at 
2°C-8°C. From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlled 
and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C–8°C). 
Do not freeze. 
 
6.5 Nature and contents of container 
 
5 ml solution in a vial (type I glass) with stopper (rubber) and a seal (aluminium) with flip-off cap. 
Pack size of 1. 
 
6.6 Special precautions for disposal and other handling 
 
This medicinal product can cause irritation on contact. The solution must therefore be handled and 
administered with particular caution. Inhalation of the vapour and contact with the skin and mucous 
membranes, especially the eyes, must be avoided. In case of contact, irrigate with plenty of water for 
at least 15 minutes. 
 
The solution can be diluted with 5% glucose solution or sodium chloride 9 mg/ml (0.9%) solution for 
injection before intravenous injection (see section 4.2). 
 
Do not use if the solution is cloudy or a precipitate has formed. 



16 

Do not shake. 
 
Oncaspar is for single use only. Any unused medicinal product or waste material should be disposed 
of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1070/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 14 January 2016 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


17 

 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Oncaspar 750 U/ml powder for solution for injection/infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 3,750 Units (U)** of pegaspargase*. 
After reconstitution, 1 ml of solution contains 750 U pegaspargase (750 U/ml). 
 
* The active substance is a covalent conjugate of Escherichia coli-derived L-asparaginase with 
monomethoxypolyethylene glycol 
**One unit is defined as the quantity of enzyme required to liberate 1 µmol ammonia per minute at 
pH 7.3 and 37°C 
 
The potency of this medicinal product should not be compared to the one of another pegylated or 
non-pegylated protein of the same therapeutic class. For more information, see section 5.1. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for injection/infusion. 
White to off-white powder. 
 
4. CLINICAL PARTICULARS 
 
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). 
 
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. 
 



18 

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. 
 



19 

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). 
 
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), and 
hypofibrinogenaemia 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. 
 
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. 



20 

 
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. 
 
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 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. 
 



21 

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. 
 
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. 
 



22 

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 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, 
Oncaspar 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). 
 
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* 



23 

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 

Skin and subcutaneous 
tissue disorders 

Very common: Rash 
Not known: Toxic epidermal necrolysis* 

Musculoskeletal and 
connective tissue disorders Common: Pain in extremities 

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 
 
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, neutrophil 
count decreased, 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 
 
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 or 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. 



24 

 
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. 
 
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). 
 



25 

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 national reporting system 
listed in Appendix V 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, other antineoplastic 
agents, ATC code: L01XX24 
 
Mechanism of action 
 
The mechanism of action of L-asparaginase is the enzymatic cleavage of the amino acid L-asparagine 
into aspartic acid and ammonia. Depletion of L-asparagine in blood results in inhibition of 
protein-synthesis, DNA-synthesis and RNA-synthesis, especially in leukaemic blasts which are not 
able to synthesise L-asparagine, thus undergoing apoptosis. 
 
Normal cells, in contrast, are capable of synthesising L-asparagine and are less affected by its rapid 
depletion during treatment with the enzyme L-asparaginase. The PEGylation does not change the 
enzymatic properties of L-asparaginase, but it influences the pharmacokinetics and immunogenicity of 
the enzyme. 
 
Pharmacodynamic effects 
 
Anti-leukaemic effect of L-asparaginase is related to a sustained L-asparagine depletion in blood and 
cerebrospinal fluid (CSF). The pharmacodynamic (PD) effect of Oncaspar was assessed after 
intramuscular (Study CCG-1962) and intravenous administration (AALL07P4). 
 
In Study CCG-1962, PD effect of Oncaspar was assessed through serial measurements of asparagine 
in serum (n=57) and CSF (n=50) of newly diagnosed paediatric patients with standard-risk ALL who 
received three intramuscular doses of Oncaspar (2,500 Units/m2 BSA), one each during induction and 
two during delayed intensification treatment phases. A reduction in serum asparagine concentration 
was evident by the 4th day after the first Induction dose and reached an apparent nadir by the 10th day 
after the dose. Serum asparagine concentrations of approximately 1 µM persisted for approximately 
3 weeks. Asparagine concentration fell to <3 µM when asparaginase activity was >0.1 U/mL. CSF 
asparagine of 2.3 µM pre-treatment fell to 1.1 µM on Day 7 and 0.6 µM on Day 28 of Induction 
(see Clinical efficacy and safety). 
 
In Study AALL07P4, the PD effect of Oncaspar was assessed in 47 evaluable subjects with high risk 
B-precursor ALL who received intravenous doses of Oncaspar 2,500 U/m2 BSA during the Induction 
and Consolidation phases. Plasma L-asparagine concentrations were depleted to below the assay limit 
of quantification within 24 hours following the Induction and first Consolidation dose of Oncaspar and 
depletion was sustained for approximately two weeks. CSF asparagine concentrations were reduced by 
the 4th day following the Induction dose, and remained largely undetectable by the 18th day after 
dosing. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


26 

 
Based on results from these two studies, a 2,500 U/m2 BSA dose of Oncaspar administered 
intramuscular (CCG-1962) and intravenous (AALL07P4) provides maintenance of L-asparagine 
depletion for approximately two weeks following dosing. 
 
Clinical efficacy and safety 
Oncaspar efficacy and safety were evaluated on the basis of three clinical studies using Oncaspar 
solution for injection/infusion in the first line treatment of ALL: Study CCG-1962 in standard risk 
ALL patients; Study AALL07P4 in high risk ALL patients; Study DFCI 11-001 enrolled both standard 
and high-risk ALL patients. 
 
Oncaspar efficacy in ALL in patients with relapse/refractory disease and a history of prior clinical 
allergic reaction to native E. coli L-asparaginase was based on a pool of 94 patients from six 
open-label studies [ASP-001, ASP-201A, ASP-302, ASP-304, ASP-400 and ASP-001C/003C]. 
 
First-Line (ALL patients non-hypersensitive to native E. coli L-asparaginase) 
The safety and efficacy of Oncaspar was evaluated in an open-label, multicentre, randomised, 
active-controlled study (Study CCG-1962). In this study, 118 paediatric patients aged 1 to 9 years with 
previously untreated standard-risk ALL were randomised 1:1 to Oncaspar or native E. coli 
L-asparaginase as part of combination therapy. Oncaspar was administered intramuscularly at a dose 
of 2,500 Units/m2 BSA on Day 3 of the 4-week Induction phase and on Day 3 of each of two 8-week 
Delayed Intensification (DI) phases. Native E. coli L-asparaginase was administered intramuscularly 
at a dose of 6,000 Units/m2 BSA three times weekly for a total of 9 doses during induction and for a 
total of 6 doses during each delayed intensification phase. 
 
The primary determination of efficacy was based on demonstration of similar asparagine depletion 
(magnitude and duration) in the Oncaspar and native E. coli L-asparaginase arms. The 
protocol-specified goal was achievement of asparagine depletion to a serum concentration of ≤1 µM. 
The proportion of patients with this level of depletion was similar between the 2 study arms during all 
3 phases of treatment at the protocol-specified time points. 
 
In all phases of treatment, serum asparagine concentrations decreased within 4 days of the first dose of 
asparaginase in the treatment phase and remained low for approximately 3 weeks for both Oncaspar 
and native E. coli L-asparaginase arms. Serum asparagine concentrations during the induction phase 
are shown in Figure 1. The patterns of serum asparagine depletion in the 2 delayed intensification 
phases are similar to the pattern of serum asparagine depletion in the induction phase. 
 
Figure 1: Mean (± standard error) serum asparagine during Study CCG-1962 induction phase 

 
Note: Oncaspar (2,500 Units/m2 BSA intramuscular) was administered on Day 3 of the 4-week 

induction phase. Native E. coli L-asparaginase (6,000 Units/m2 BSA intramuscular) was 
administered 3 times weekly for 9 doses during induction. 

 

0.1 

1.0 

10.0 

100.0 

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 
Days After First Dose of L-Asparaginase 

As
pa

ra
gi

ne
 (µ

M
) 

Native E. coli L-

Asparaginase Oncaspar® 
 E. coli 



27 

CSF asparagine concentrations were determined in 50 patients during the induction phase. CSF 
asparagine decreased from a mean pre-treatment concentration of 3.1 µM to 1.7 µM on Day 4 ± 1 and 
1.5 µM at 25 ± 1 days after administration of Oncaspar. These findings were similar to those observed 
in the native E. coli L-asparaginase treatment arm. 
 
Event-free survival (EFS) for the Oncaspar and native E. coli L-asparaginase arms is summarised in 
Table 2, Study CCG-1962 was not designed to evaluate differences in EFS rates. 
 
Table 2: Event-free survival rate at 3, 5 and 7 years (Study CCG-1962) 
 
 Oncaspar native E. coli L-asparaginase 
3-Year EFS Rate, % 
(95% CI) 

83 
(73, 93) 

79 
(68, 90) 

5-Year EFS Rate, % 
(95% CI) 

78 
(67, 88) 

73 
(61, 85) 

7-Year EFS Rate, % 
(95% CI) 

75 
(63, 87) 

66 
(52, 80) 

 
In Study CCG-1962, the most common adverse reactions were infections, including two 
life-threatening infections (1 patient in each arm). In general, incidence and type of adverse reactions 
Grade 3 and 4 were similar between the two treatment groups. Two patients in the Oncaspar arm had 
allergic reactions during Delayed Intensification (DI) DI #1 (Grade 1 allergic reaction and Grade 3 
hives). 
 
A pilot study was conducted for newly diagnosed patients from 1 to <31 years of age with high risk 
B-precursor ALL (Study AALL07P4). This was an open label, controlled, randomised study 
comparing an investigational pegylated asparaginase product to Oncaspar as a component of 
multi-agent chemotherapy in the first line treatment of ALL. White blood cell (WBC) criteria were: 
a) Age 1-10 years: WBC ≥50,000/μL; b) Age 10-30 years: Any WBC; c) Prior steroid therapy: Any 
WBC. Patients were not allowed prior cytotoxic chemotherapy with the exception of steroids and 
intrathecal cytarabine. A total of 166 patients were enrolled in this study; 54 patients were randomised 
to treatment with 2,500 U/m2 BSA Oncaspar and 111 patients were randomised to the investigational 
pegylated asparaginase product. Oncaspar was administered intravenously at the dose of 
2,500 Units/m2 BSA during Induction, Consolidation, Delayed Intensification, and Interim 
Maintenance phases in patients with high-risk ALL receiving augmented Berlin-Frankfurt-Münster 
therapy. The percentage of patients in the Oncaspar treatment arm with evaluable minimal residual 
disease (MRD) negative status (<0.1% leukaemia cells in bone marrow) at Day 29 of Induction was 
80% (40/50). At 4-years, the EFS and overall survival (OS) for the Oncaspar treatment arm were 
81.8% [95% CI 62.9-91.7%] and 90.4% [95% CI 78.5-95.9%], respectively. Overall, in the group 
receiving Oncaspar, the rate of all grade hypersensitivity was 5.8%, anaphylactic reactions was 19.2%, 
and pancreatitis 7.7%. Grade 3 or higher febrile neutropenia was 15.4%. 
 
Study DFCI 11-001, conducted by the Dana-Farber Cancer Institute (DFCI), is an ongoing, 
active-controlled, randomised multicentre study of an intravenous investigational pegylated 
asparaginase product versus Oncaspar, in children and adolescents aged 1 to <22 years with newly 
diagnosed ALL treated with a DFCI ALL consortium therapeutic backbone. A total of 239 patients 
were randomised, 237 of whom were treated with study drug (146 male and 91 female), of these, 
119 patients (115 with a diagnosis of ALL) were treated with Oncaspar 2500 U/m2. Treatment was 
administered during Induction (Day 7), and then every 2 weeks for a total of 30 weeks post-Induction 
therapy. Randomisation of patients was stratified based on risk group (standard/high/very high risk), 
including both B- and T-cell ALL. The percentage of patients in the Oncaspar arm with evaluable Low 
End-Induction MRD (<0.001 detectable disease) at Day 32 was 87.9% (80/91). The One-year EFS 
was 98.0 [95%CI 92.3, 99.5]; the One-year OS was 100 [95% CI 100, 100] in this study. 
 
ALL patients hypersensitive to native E. coli L-asparaginase  
Six open-label studies evaluated Oncaspar in relapse/refractory haematological diseases. In these 
studies a total of 94 patients with ALL diagnosis with a history of prior clinical allergic reaction to 



28 

native E. coli L-asparaginase were exposed to Oncaspar. One patient received Oncaspar doses of 
250 and 500 Units/m2 BSA intravenously. The remaining patients were treated with 2,000 or 
2,500 U/m2 BSA administered intramuscularly or intravenously. Patients received Oncaspar as a 
single agent or in combination with multi-agent chemotherapy. Overall, from five studies analysed 
based on 65 ALL patients exposed to Oncaspar using the highest therapeutic response during the 
entire study, complete remission was observed in 30 patients (46%), partial remission in 7 patients 
(11%) and haematological improvement in 1 patient (2%). In the other study, with 29 hypersensitive 
ALL patients exposed to Oncaspar, 11 patients were evaluated for response during induction. Of these, 
3 patients (27%) achieved complete remission, 1 patient (9%) had partial remission, 1 patient (9%) 
had haematologic improvement and 2 patients (18%) had therapeutic efficacy. Therapeutic efficacy 
was defined as a clinical improvement which did not meet the criteria for other beneficial outcomes. 
During the maintenance phase, 19 patients were evaluated, with 17 patients (89%) achieving complete 
remission, and 1 patient (5%) with therapeutic efficacy. 
 
5.2 Pharmacokinetic properties 
 
Oncaspar pharmacokinetic properties were based on asparaginase activity measured by an enzymatic 
assay after intramuscular (CCG-1962) and intravenous (AALL07P4, DFCI 11-001) administration. 
 
In Study CCG-1962, mean asparaginase activity reached peak value of 1 U/mL on Day 5 after the 
injection. The mean half-life after absorption from the injection site was 1.7 days and the elimination 
half-life was 5.5 days. The volume of distribution at steady-state and clearance were estimated at 
1.86 L/m2 and 0.169 L/m2 per day, respectively. 
 
In Study AALL07P4, PK parameters after a single 2,500 U/m2 intravenous dose during Induction were 
calculated by noncompartmental PK analysis from sequential plasma samples and are depicted in 
Table 3 (see section 5.1). The Cmax and AUC of Oncaspar trended lower in males, subjects with larger 
BMI, and subjects >10 years. During Induction, following a single intravenous dose of Oncaspar 
2,500 U/m2, asparaginase activity ≥0.1 U/mL was sustained for up to 18 days post-dose in 95.3% of 
subjects. 
 
Table 3: Pharmacokinetic Parameters After a Single intravenous Dose of Oncaspar 
2,500 U/m2 BSA During Induction (N=47; Study AALL07P4) 
PK Parameters Arithmetic Mean (SD) 
Cmax (mU/mL)* 1638 (459.1) 
Tmax (hr)* 1.25 (1.08, 5.33)† 
AUC0-t (mUday/mL)* 14810 (3555) 
AUC0–∞ (mUday/mL)ǂ 16570 (4810) 
t1/2 (day)ǂ 5.33 (2.33) 
CL (L/day)ǂ 0.2152 (0.1214) 
Vss (L)ǂ 1.95 (1.13) 
* N=47 evaluable subjects. 
† Median (10th, 90th percentiles). 
ǂ N= 46 evaluable subjects. 

 
In Study DFCI 11-001, assessments of asparaginase activity were performed following a single 
intravenous dose of Oncaspar 2,500 U/m2 BSA during Induction, and every two weeks during 
post-Induction (see section 5.1). During Induction, plasma asparaginase activity ≥0.1 U/mL was 
sustained in 93.5% of subjects 18 days after administration. During the post-Induction phase, a nadir 
(trough) asparaginase activity above 0.4 U/mL was sustained in 100% of subjects from Week 7 up 
until Week 25. These results indicate that, when Oncaspar 2,500 U/m2 BSA is administered as single 
and repeated doses every two weeks, clinically relevant asparaginase activity is sustained over the 
entire dosing interval (i.e., two weeks). 
 
Patients with newly diagnosed ALL received a single intramuscular injection of Oncaspar (2,500 U/m² 
BSA) or native asparaginase from E. coli (25,000 U/m² BSA) or from Erwinia (25,000 U/m² BSA). 



29 

The plasma elimination half-life of Oncaspar was statistically significantly longer (5.7 days) than the 
plasma elimination half-lives of the native asparaginases from E. coli (1.3 days) and Erwinia 
(0.65 days). The immediate cell death of leukaemic cells in vivo, measured by rhodamine 
fluorescence, was the same for all three L-asparaginase preparations. 
 
ALL patients with several relapses were treated either with Oncaspar or with native asparaginase from 
E. coli as part of an induction therapy. Oncaspar was given intramuscular in a dose of 2,500 U/m² 
BSA on days 1 and 15 of induction. The mean plasma half-life of Oncaspar was 8 days in 
non-hypersensitive patients (AUC 10.35 U/ml/day), and 2.7 days in hypersensitive patients (AUC 
3.52 U/ml/day). 

Specific populations 
The controlled studies were not designed to formally evaluate the pharmacokinetics of Oncaspar in 
specific populations. A population pharmacokinetic evaluation of Oncaspar based on data obtained 
from Studies AALL07P4 (IV), DFCI 11-001 (IV), and CCG-1962 (IM) identified that clearance 
(linear and saturable) increased approximately proportionally to BSA and volume of distribution 
increased slightly more proportionally to BSA. No statistically significant differences in PK 
characteristics between male and female subjects were identified in this analysis. 
 
The impact of renal and hepatic impairment on the PK of Oncaspar has not been evaluated. As 
pegaspargase is a protein with a high molecular weight, it is not excreted renally, and no change of 
pharmacokinetic of Oncaspar in patients with renal impairment is foreseen. 
 
Since the proteolytic enzymes responsible for Oncaspar metabolism are ubiquitously distributed in 
tissues the exact role of the liver is unknown: however any decrease in liver function is not expected to 
present clinical relevant problems in the use of Oncaspar. 
 
There are no data available for elderly patients. 
 
5.3 Preclinical safety data 
 
Pharmacokinetic/pharmacodynamic nonclinical comparability between the two pharmaceutical forms 
of Oncaspar, solution for injection/infusion, and powder for solution, was demonstrated in dogs after 
single and repeated doses (500 U/kg), by the intravenous route. The below mentioned studies were 
performed on the solution for injection/infusion formulation. 
 
Acute toxicity 
Only very high doses of pegaspargase given to mice intraperitoneally as a single dose (25,000 –
 100,000 U/kg body weight) caused the death of 14% of all treated mice. Mild hepatotoxicity was 
observed with the same doses. Adverse reactions were loss of body weight, piloerection and reduced 
activity. Reduced splenic weight might be a sign of potential immunosuppressant effect of the 
treatment. 
 
Pegaspargase was well tolerated both in rats and dogs when administered intravenously in single doses 
up to 500 U/kg body weight. 
 
Repeated dose toxicity 
A 4-week study in rats treated with a dose of pegaspargase of 400 U/kg/day intraperitoneal resulted in 
a fall in food intake and body weight compared to the control group. 
 
A 3-month study in mice with pegaspargase at doses up to 500 U/kg intraperitoneally or 
intramuscularly resulted in slight hepatocellular changes only at the highest intraperitoneal dose. 
 
A temporary suppression in body weight gain and a temporary reduction in total leukocyte counts 
were observed in dogs which were treated with pegaspargase 1200 U/kg weekly for 2 weeks. 
Increased serum glutamic pyruvic transaminase activity also occurred in one out of four dogs. 



30 

 
Immunogenicity 
No immunogenic response was detected in a 12-week study in mice in which pegaspargase was 
administered weekly at the dose of 10.5 U/mouse intramuscularly or intraperitoneally. 
 
Reproductive toxicity 
No studies of reproductive toxicity were conducted with pegaspargase. 
 
Embryotoxicity studies with L-asparaginase have showed evidence of teratogenic potential in rats 
treated from day 6 to 15 of gestation with a No Observed Effect Level (NOEL) for teratogenic effects 
at 300 U/kg intravenously. In rabbits, doses of 50 or 100 U/kg intravenous on days 8 and 9 of 
gestation induced viable fetuses with congenital malformations: no NOEL has been determined. 
Multiple malformations and embryolethal effects were observed with doses in the therapeutic range. 
Investigations of the effect on fertility and peri- and postnatal development were not conducted. 
 
Carcinogenicity, mutagenicity, fertility 
Long-term investigations of carcinogenicity or studies of the effect on fertility in animals were not 
conducted with pegaspargase.  
 
Pegaspargase was not mutagenic in the Ames test using Salmonella typhimurium strains. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Disodium phosphate heptahydrate 
Sodium dihydrogen phosphate monohydrate 
Sodium chloride 
Sucrose 
Sodium hydroxide (for pH adjustment) 
Hydrochloric acid (for pH adjustment) 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial: 
3 years. 
 
Reconstituted solution 
Chemical and physical in-use stability has been demonstrated for 24 hours below 25°C. From a 
microbiological point of view, unless the method of reconstitution precludes the risk of microbial 
contamination, the product should be used immediately. If not used immediately, in-use storage times 
and conditions are the responsibility of the user. 
 
Diluted solution 
Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C-8°C. From a 
microbiological point of view, the product should be used immediately. If not used immediately, 
in-use storage times and conditions prior to use are the responsibility of the user and would normally 
not be longer than 24 hours at 2°C-8°C, unless reconstitution/dilution has taken place in controlled and 
validated aseptic conditions. 
 



31 

6.4 Special precautions for storage 
 
Store in a refrigerator (2°C–8°C). 
Do not freeze. 
 
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Type I flint glass vial with chlorobutyl elastomer stopper, capped with a 20 mm aluminium flip-off 
seal, containing 3,750 U pegaspargase. 
 
Pack size of 1. 
 
6.6 Special precautions for disposal and other handling 
 
This medicinal product can cause irritation on contact. The powder must therefore be handled and 
administered with particular caution. Inhalation of the vapour and contact with the skin and mucous 
membranes, especially the eyes, must be avoided; if the medicinal product comes in contact with eyes, 
skin or mucous membranes, rinse immediately with plenty of water for at least 15 minutes. 
 
Oncaspar is to be administered intravenously or intramuscularly after reconstitution of the product. 
The powder must be reconstituted with 5.2 ml water for injections prior to administration (see 
section 4.2). 
 
Instructions for handling 
1. Staff should be trained in how to handle and transfer the medicinal product (pregnant staff 

should be excluded from working with this medicinal product). 
2. Aseptic technique must be used. 
3. Procedures for proper handling of antineoplastic agents should be observed. 
4. The use of disposable gloves and protective garments is recommended when handling 

Oncaspar. 
5. All items for administration or cleaning, including gloves, should be placed in high-risk waste 

disposal bags for high-temperature incineration. 
 
Reconstitution 
1. 5.2 ml water for injections are injected into the vial using a syringe and 21 gauge needle. 
2. The vial should be gently swirled until the powder is reconstituted. 
3. After reconstitution, the solution should be clear, colourless and free from visible foreign 

particles. Do not use if the reconstituted solution is cloudy or if a precipitate has formed. Do not 
shake. 

4. The solution should be used within 24 hours after reconstitution, when stored below 25°C. 
 
Administration 
1. Parenteral medicinal products should be inspected for particulate matter prior to administration, 

only a clear, colourless solution free from visible foreign particles should be used. 
2. The medicinal product should be administered intravenously or intramuscularly. The solution 

should be administered slowly. 
For intramuscular injection, the volume should not exceed 2 ml in children and adolescents and 
3 ml in adults. 
For intravenous administration, the reconstituted solution should be diluted in 100 ml sodium 
chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution. 
The diluted solution can be given over 1 to 2 hours 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 (see section 4.2). 
After dilution, the solution should be used immediately. If immediate use is not possible, the 
diluted solution can be stored at 2°C-8°C for up to 48 hours (see section 6.3). 



32 

 
Disposal 
Oncaspar is for single use only. Any unused medicinal product or waste material should be disposed 
of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1070/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 14 January 2016 
Date of latest renewal: 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 

http://www.ema.europa.eu/


33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



34 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
Exelead, Inc. 
6925 Guion Road 
Indianapolis 
Indiana 46268 
USA 
 
Name and address of the manufacturer responsible for batch release 
Les Laboratoires Servier Industrie 
905 Route de Saran 
45520 Gidy  
France 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
Post-authorisation efficacy study (PAES): In order to further define the efficacy and 
safety of Oncaspar in patients with newly diagnosed acute lymphoblastic leukaemia, the 

 
 



35 

Description Due date 
MAH should submit the results of Study CAALL-F01, a prospective multicentre cohort 
study evaluating Oncaspar used in the first-line treatment of children and adolescents 
with ALL along with multi-agent chemotherapy. 
 
The clinical study report should be submitted by: 

 
 
 
 
December 2025 

Post-authorisation efficacy study (PAES): In order to further define the efficacy and 
safety of Oncaspar in adult patients with acute lymphoblastic leukaemia, the MAH 
should submit the results of a multicentre, open label single arm phase II trial evaluating 
the efficacy and toxicity of treatment regimens including Oncaspar in adults (aged 18-60) 
with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic 
leukaemia. 
 
The clinical study report should be submitted by: 

 
 
 
 
 
 
June 2020 

 
 



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



37 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 



38 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Oncaspar 750 U/ml solution for injection/infusion 
pegaspargase 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 ml contains 750 U of pegaspargase. 
One vial of 5 ml solution contains 3750 U. 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium dihydrogen phosphate monohydrate, disodium phosphate heptahydrate, sodium chloride, 
water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection/infusion 
1 vial of 5 ml. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous or intramuscular use. 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not use if a precipitate has formed, or if the solution is cloudy. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 



39 

 
Store in a refrigerator. 
Do not freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1070/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



40 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Oncaspar 750 U/ml powder for solution for injection/infusion 
pegaspargase 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 3,750 U of pegaspargase 
After reconstitution, 1 ml of solution contains 750 U of pegaspargase (750 U/ml). 
 
 
3. LIST OF EXCIPIENTS 
 
Disodium phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, sodium chloride, 
sucrose, and sodium hydroxide and hydrochloric acid (for pH adjustment). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for injection/infusion 
1 vial with 3,750 U pegaspargase. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous or intramuscular use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
After reconstitution, the solution should be used immediately. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
 



41 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Warning: special handling instructions (see package leaflet) 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1070/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



42 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Oncaspar 750 U/ml solution for injection/infusion. 
pegaspargase 
For intravenous or intramuscular use. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 
 



43 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Oncaspar 750 U/ml powder for solution for injection/infusion. 
pegaspargase 
For intravenous or intramuscular use. 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
3,750 U 
 
 
6. OTHER 
 
 



44 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



45 

Package leaflet: Information for the user 
 

Oncaspar 750 U/ml solution for injection/infusion 
pegaspargase 

 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Oncaspar is and what it is used for 
2. What you need to know before you are given Oncaspar 
3. How Oncaspar is given 
4. Possible side effects 
5. How to store Oncaspar 
6. Contents of the pack and other information 
 
 
1. What Oncaspar is and what it is used for 
 
Oncaspar contains pegaspargase, which is an enzyme (asparaginase) that breaks down asparagine, an 
important building block of proteins without which cells cannot survive. Normal cells can make 
asparagine for themselves, while some cancer cells cannot. Oncaspar lowers asparagine level in blood 
cancer cells and stops the cancer cells growing. 
 
Oncaspar is used to treat acute lymphoblastic leukaemia (ALL) in children from birth to 18 years and 
in adults. ALL is a white blood cell cancer type in which certain immature white cells (named 
lymphoblasts) start growing out of control thus preventing the production of functional blood cells. 
Oncaspar is used together with other medicines. 
 
 
2. What you need to know before you are given Oncaspar 
 
Do not use Oncaspar 
- if you are allergic to pegaspargase or to any of the other ingredients of this medicine (listed in 

section 6). 
- if you have severe hepatic disease. 
- if you have ever had pancreatitis. 
- if you have ever had severe bleeding following asparaginase therapy. 
- if you have ever had blood clots following asparaginase therapy. 
 
Tell your doctor if any of these conditions apply to you. If you are the parent of a child who is being 
treated with Oncaspar, please tell the doctor if any of them apply to your child. 
 
Warnings and precautions 
Talk to your doctor before you are given Oncaspar. This medicine may not be suitable for you: 
- if you have had serious allergic reactions to other forms of asparaginase, for example itching, 

flushing or swelling of the airways, because major allergic reactions to Oncaspar can occur. 
- if you suffer from a bleeding disorder or have had serious blood clots. 
- if you get a fever. This medicine may make you more susceptible to infections. 



46 

- if you have had poor liver function or are using other medicines which may harm the liver. 
When Oncaspar is used in combination with other cancer treatments, liver and central nervous 
system damage can occur. 

- if you suffer abdominal pain. Inflammation of the pancreas, that in some cases caused death, can 
occur with Oncaspar treatment. 

 
This medicine can lead to fluctuations in clotting factors and may increase the risk of bleeding and/or 
clotting. 
 
If you are the parent of a child being treated with Oncaspar, tell the doctor if any of the above 
conditions apply to your child. 
 
During treatment with Oncaspar 
During Oncaspar administration you will be closely watched for an hour after the start of treatment for 
any signs of serious allergic reactions. Medical equipment to treat allergic reactions will be available 
nearby. 
 
Additional monitoring tests 
Blood and urine sugar levels, liver and pancreas function and other tests will be carried out regularly 
to monitor your health during and after treatment because this medicine can affect your blood and 
other organs. 
 
Other medicines and Oncaspar 
Tell your doctor if you are using, have recently used or might use any other medicines This is 
important as Oncaspar may increase the side effects of other medicines through its effect on the liver 
which plays an important role in removing medicines from the body. In addition, it is especially 
important to tell your doctor if you are also using any of the following medicines: 
- immunisation with live vaccines within three months of completing your leukaemia treatment. 

This will increase the risk of severe infections. 
- vincristine, another cancer medicine. If used at the same time as Oncaspar there is an increased 

risk of side effects or allergic reactions. 
- medicines which reduce the blood´s ability to clot such as anticoagulants (e.g., 

coumarin/warfarin and heparin), dipyridamol, acetylsalicylic acid or non-steroidal 
anti-inflammatory medicines (such as ibuprofen or naproxen). If used at the same time as 
Oncaspar, there is a higher risk of bleeding disorders. 

- medicines which require cell division for their effect, for example, methotrexate (a medicine 
used for cancer as well as arthritis treatment) may have a decrease in its effect. 

- prednisone, a steroid medicine. If used at the same time as Oncaspar, the effects on the clotting 
ability of your blood are increased. 

- cytarabine, a medicine which can be used in cancer treatment, and could interfere with the 
effects of Oncaspar. 

 
Oncaspar can also cause changes in liver function which can affect the way other medicines work. 
 
Pregnancy and breast-feeding  
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine. 
 
You should not use Oncaspar if you are pregnant because its effects during pregnancy have not been 
studied. Your physician will decide whether your disease requires treatment. Women who are able to 
get pregnant must use reliable contraception during treatment, and for at least 6 months after Oncaspar 
treatment has been discontinued. Oral contraception is not an effective method of contraception while 
on treatment with Oncaspar. Ask your doctor for advice on the best contraceptive method that you can 
use. Men must also use effective contraception while they or their partners are being treated with 
Oncaspar. 
 



47 

It is not known whether pegaspargase is excreted in breast milk. As a precautionary measure, 
breast-feeding should be discontinued during treatment with Oncaspar and should not be re-started 
until after treatment with Oncaspar has been discontinued. 
 
Driving and using machines 
Do not drive or use machines when using this medicine because it may make you feel drowsy, tired or 
confused. 
 
Oncaspar contains sodium 
This medicine contains less than 1 mmol sodium per dose, that is to say essentially ´sodium-free´. 
 
 
3. How Oncaspar is given 
 
Your treatment with Oncaspar has been prescribed by a doctor experienced in medicines used to treat 
cancer. Your doctor will decide what dose of the medicine is needed and how often, based on your age 
and body surface area which is calculated from your height and weight. 
 
The medicine is given as a solution by injection into a muscle or, if more suitable, into a vein. 
 
If you are given too much Oncaspar 
As your doctor will administer the medicine, it is very unlikely you will be given more than you need. 
 
In the unlikely event of accidental overdose, you will be monitored carefully by medical staff and 
treated appropriately. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
Tell your doctor immediately if you get any of the following side effects: 
 
Very common (may affect more than 1 in 10 people) 
- Inflammation or other disorders of the pancreas (pancreatitis) causing severe stomach pain 

which may spread to your back, vomiting, increase in blood sugar levels; 
- Serious allergic reactions with symptoms such as rash, itching, swelling, hives, shortness of 

breath, fast heart beat and drop in blood pressure; 
- Blood clots; 
- Fever with low counts of white blood cells. 
 
Common (may affect up to 1 in 10 people) 
- Severe bleeding or bruising; 
- Violent shaking (seizures) and loss of consciousness; 
- Severe infection with very high fever; 
- Problems with your liver (e.g., change in colour of your skin or urine or stool and laboratory 

results of elevated liver enzymes or bilirubin). 
 
Rare (may affect up to 1 in 1,000 people) 
- Liver failure; 
- Jaundice; 
- Blocked bile flow from the liver (cholestasis); 
- Destruction of liver cells (liver cell necrosis). 
 



48 

Not known (frequency cannot be estimated from the available data) 
- Severe skin reaction called toxic epidermal necrolysis; 
- Loss of kidney function (e.g., change in urine output, swelling of feet and ankles); 
- Stroke; 
- Severe allergic reaction that may cause loss of consciousness and could be life-threatening 

(anaphylactic shock). 
 
Other side effects 
Talk to your doctor if you get any of the following: 
 
Very common (may affect more than 1 in 10 people) 
- Changes in the function of the pancreas; 
- Weight loss; 
- Leg pain (which could be a symptom of thrombosis), chest pain or shortness of breath (which 

may be a symptom of blood clots in the lungs, called pulmonary embolism); 
- Loss of appetite, general weakness, vomiting, diarrhoea, nausea; 
- Increased blood sugar levels. 
 
Common (may affect up to 1 in 10 people) 
- Decreased number of red blood cells; 
- Build-up of fluid in the stomach (ascites); 
- Fever and flu-like symptoms; 
- Mouth sores; 
- Back, joint or abdominal pain; 
- High levels of fat and cholesterol in your blood; low potassium in your blood. 
 
Rare (may affect up to 1 in 1,000 people) 
- Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome characterised by 

headache, confusion, seizures and visual loss which resolves after some time. 
 
Not known (frequency cannot be estimated from the available data) 
- Decreased number of white blood cells and platelets; 
- Palpitations; 
- Fever; 
- Cysts in your pancreas, swelling of the salivary glands; 
- High levels of urea in your blood; antibodies against Oncaspar; high levels of ammonia in your 

blood; decreased blood sugar levels; 
- Sleepiness, confusion, mild twitching of the fingers. 
 
Reporting of side effects 
If you get any side effects you think might be related to your chemotherapy , talk to your doctor. This 
includes any possible side effects not listed in this leaflet. You can also report side effects directly via 
the national reporting system listed in Appendix V. By reporting side effects you can help provide 
more information on the safety of this medicine. 
 
 
5. How to store Oncaspar 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The 
expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C–8°C). 
Do not freeze. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


49 

After the medicine has been diluted, the solution should be used immediately. If immediate use is not 
possible, the diluted solution can be stored at 2°C-8°C for up to 48 hours. 
 
Do not use this medicine if you notice the solution is cloudy or has visible particles. 
 
Do not throw away any medicines via wastewater. Ask the pharmacist how to dispose of unused 
medicines. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Oncaspar contains 
The active substance is pegaspargase. One ml of solution contains 750 units pegaspargase . One vial of 
5 ml solution contains 3750 units of pegaspargase. 
 
The other ingredients are: sodium dihydrogen phosphate monohydrate, disodium phosphate 
heptahydrate, sodium chloride, and water for injections (see section 2 “Oncaspar contains sodium”). 
 
What Oncaspar looks like and contents of the pack 
Oncaspar is a clear, colourless solution for injection contained in a glass vial. Each pack contains 
1 vial. 
 
Marketing Authorisation Holder 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
Manufacturer 
Les Laboratoires Servier Industrie 
905 Route de Saran 
45520 Gidy  
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
S.A. Servier Benelux N.V. 
Tél/Tel: +32 (0)2 529 43 11 
 

Lietuva 
UAB “SERVIER PHARMA” 
Tel: +370 (5) 2 63 86 28 
 

България 
Сервие Медикал ЕООД 
Тел.: +359 2 921 57 00 
 

Luxembourg/Luxemburg 
S.A. Servier Benelux N.V. 
Tel: +32 (0)2 529 43 11 
 

Česká republika 
Servier s.r.o. 
Tel: +420 222 118 111 
 

Magyarország 
Servier Hungaria Kft. 
Tel: +36 1 238 7799 
 

Danmark 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Malta 
V.J. Salomone Pharma Ltd  
Tel: + 356 21 22 01 74 

Deutschland 
Servier Deutschland GmbH 
Tel: +49 (0)89 57095 01 
 

Nederland 
Servier Nederland Farma B.V. 
Tel: + 31 (0)71 5246700 
 



50 

Eesti 
Servier Laboratories OÜ  
Tel:+ 372 664 5040 
 

Norge 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Eλλάδα 
ΣΕΡΒΙΕ ΕΛΛΑΣ ΦΑΡΜΑΚΕΥΤΙΚΗ ΕΠΕ 
Τηλ: + 30 210 939 1000 
 

Österreich 
Servier Austria GmbH 
Tel: +43 (1) 524 39 99 
 

España 
Laboratorios Servier S.L. 
Tel: + 34 91 748 96 30 
 

Polska 
Servier Polska Sp. z o.o. 
Tel: + 48 (0) 22 594 90 00 
 

France 
Les Laboratoires Servier 
Tél: + 33 (0)1 55 72 60 00 
 

Portugal 
Servier Portugal, Lda 
Tel: + 351 21 312 20 00 
 

Hrvatska 
Servier Pharma, d. o. o. 
Tel: + 385 (0)1 3016 222 
 

România 
Servier Pharma SRL 
Tel: + 4 021 528 52 80 
 

Ireland 
Servier Laboratories (Ireland) Ltd. 
Tel: + 353 (0)1 663 8110 
 

Slovenija 
Servier Pharma d. o. o.  
Tel: + 386 (0)1 563 48 11 
 

Ísland 
Servier Laboratories 
c/o Icepharma hf 
Sími: + 354 540 8000 
 

Slovenská republika 
Servier Slovensko spol. s r.o. 
Tel: + 421 2 5920 41 11 
 

Italia 
Servier Italia S.p.A. 
Tel: + 39 (06) 669081 
 

Suomi/Finland 
Servier Finland Oy 
P. /Tel: +358 (0)9 279 80 80 
 

Κύπρος 
CA Papaellinas Ltd. 
Τηλ: + 357 22 741 741 
 

Sverige 
Servier Sverige AB 
Tel : +46 (0)8 522 508 00 
 

Latvija 
SIA Servier Latvia 
Tel: + 371 67502039 
 

United Kingdom 
Servier Laboratories Ltd 
Tel: +44 (0)1753 666409 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
It is strongly recommended that every time Oncaspar is administered to a patient, the name and lot 
number of the product are recorded in order to link the patient and the lot of the product. 
 
In view of the unpredictability of adverse reactions, Oncaspar should be administered only by health 
care personnel experienced in the use of cancer chemotherapeutic medicinal products. 
 

http://www.ema.europa.eu/


51 

Particularly in patients with known hypersensitivity to the other forms of L-asparaginase, 
hypersensitivity reactions to Oncaspar can occur during the therapy, e.g., anaphylaxis. A routine 
precaution is to observe the patients for an hour with resuscitation equipment and other items required 
for the treatment of anaphylaxis in readiness (epinephrine, oxygen, intravenous steroids etc.). 
 
Patients should be informed about possible hypersensitivity reactions to Oncaspar, including 
immediate anaphylaxis. Patients who receive Oncaspar are at increased risk of bleeding and 
thrombotic disorders. It should be explained to patients that Oncaspar should not be used at the same 
time as other medicines associated with an increased risk of bleeding (see section 2 “Other medicines 
and Oncaspar”). 
 
This medicinal product can cause irritation on contact. The solution must therefore be handled and 
administered with particular care. Inhalation of the vapour and contact with the skin and mucosa, 
particularly that of the eyes, must be avoided; if the product comes in contact with eyes, skin, or 
mucous membranes, rinse immediately with plenty of water for at least 15 minutes. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Further detailed information can be found in the SmPC. 
 
 



52 

 
Package leaflet: Information for the user 

 
Oncaspar 750 U/ml powder for solution for injection/infusion 

pegaspargase 
 

 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Oncaspar is and what it is used for 
2. What you need to know before you are given Oncaspar 
3. How Oncaspar is given 
4. Possible side effects 
5. How to store Oncaspar 
6. Contents of the pack and other information 
 
 
1. What Oncaspar is and what it is used for 
 
Oncaspar contains pegaspargase, which is an enzyme (asparaginase) that breaks down asparagine, an 
important building block of proteins without which cells cannot survive. Normal cells can make 
asparagine for themselves, while some cancer cells cannot. Oncaspar lowers asparagine level in blood 
cancer cells and stops the cancer cells growing. 
 
Oncaspar is used to treat acute lymphoblastic leukaemia (ALL) in children from birth to 18 years and 
in adults. ALL is a white blood cell cancer type in which certain immature white cells (named 
lymphoblasts) start growing out of control thus preventing the production of functional blood cells. 
Oncaspar is used together with other medicines. 
 
 
2. What you need to know before you are given Oncaspar 
 
Do not use Oncaspar: 
- if you are allergic to pegaspargase or to any of the other ingredients of this medicine (listed in 

section 6). 
- if you have severe hepatic disease. 
- if you have ever had pancreatitis. 
- if you have ever had severe bleeding following asparaginase therapy. 
- if you have ever had blood clots following asparaginase therapy. 
 
Tell your doctor if any of these conditions apply to you. If you are the parent of a child who is being 
treated with Oncaspar, please tell the doctor if any of them apply to your child. 
 
Warnings and precautions 
Talk to your doctor before you are given Oncaspar. This medicine may not be suitable for you: 
- if you have had serious allergic reactions to other forms of asparaginase, for example itching, 

flushing or swelling of the airways, because major allergic reactions to Oncaspar can occur. 
- if you suffer from a bleeding disorder or have had serious blood clots. 
- if you get a fever. This medicine may make you more susceptible to infections. 



53 

- if you have had poor liver function or are using other medicines which may harm the liver. 
When Oncaspar is used in combination with other cancer treatments, liver and central nervous 
system damage can occur. 

- if you suffer abdominal pain. Inflammation of the pancreas, that in some cases caused death, can 
occur with Oncaspar treatment. 

 
This medicine can lead to fluctuations in clotting factors and may increase the risk of bleeding and/or 
clotting. 
 
If you are the parent of a child being treated with Oncaspar, tell the doctor if any of the above 
conditions apply to your child. 
 
During treatment with Oncaspar 
During Oncaspar administration you will be closely watched for an hour after the start of treatment for 
any signs of serious allergic reactions. Medical equipment to treat allergic reactions will be available 
nearby. 
 
Additional monitoring tests 
Blood and urine sugar levels, liver and pancreas function and other tests will be carried out regularly 
to monitor your health during and after treatment because this medicine can affect your blood and 
other organs. 
 
Other medicines and Oncaspar 
Tell your doctor if you are using, have recently used or might use any other medicines. This is 
important as Oncaspar may increase the side effects of other medicines through its effect on the liver 
which plays an important role in removing medicines from the body. In addition, it is especially 
important to tell your doctor if you are also using any of the following medicines: 
- immunisation with live vaccines within three months of completing your leukaemia treatment. 

This will increase the risk of severe infections. 
- vincristine, another cancer medicine. If used at the same time as Oncaspar there is an increased 

risk of side effects or allergic reactions. 
- medicines which reduce the blood´s ability to clot such as anticoagulants (e.g., 

coumarin/warfarin and heparin), dipyridamol, acetylsalicylic acid or non-steroidal 
anti-inflammatory medicines (such as ibuprofen or naproxen). If used at the same time as 
Oncaspar, there is a higher risk of bleeding disorders. 

- medicines which require cell division for their effect, for example, methotrexate (a medicine 
used for cancer as well as arthritis treatment) may have a decrease in its effect. 

- prednisone, a steroid medicine. If used at the same time as Oncaspar, the effects on the clotting 
ability of your blood are increased. 

- cytarabine, a medicine which can be used in cancer treatment, and could interfere with the 
effects of Oncaspar. 

 
Oncaspar can also cause changes in liver function which can affect the way other medicines work. 
 
Pregnancy and breast-feeding  
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine. 
 
You should not use Oncaspar if you are pregnant because its effects during pregnancy have not been 
studied. Your physician will decide whether your disease requires treatment. Women who are able to 
get pregnant must use reliable contraception during treatment, and for at least 6 months after Oncaspar 
treatment has been discontinued. Oral contraception is not an effective method of contraception while 
on treatment with Oncaspar. Ask your doctor for advice on the best contraceptive method that you can 
use. Men must also use effective contraception while they or their partners are being treated with 
Oncaspar. 
 



54 

It is not known whether pegaspargase is excreted inbreast milk. As a precautionary measure, 
breast-feeding should be discontinued during treatment with Oncaspar and should not be re-started 
until after treatment with Oncaspar has been discontinued. 
 
Driving and using machines 
Do not drive or use machines when using this medicine because it may make you feel drowsy, tired or 
confused. 
 
Oncaspar contains sodium 
This medicine contains less than 1 mmol sodium per dose, that is to say essentially ´sodium-free´. 
 
 
3. How Oncaspar is given 
 
Your treatment with Oncaspar has been prescribed by a doctor experienced in medicines used to treat 
cancer. Your doctor will decide what dose of the medicine is needed and how often, based on your age 
and body surface area which is calculated from your height and weight. 
 
The medicine is given as a solution by injection into a muscle or, if more suitable, into a vein. 
 
If you are given too much Oncaspar 
As your doctor will administer the medicine, it is very unlikely you will be given more than you need. 
 
In the unlikely event of accidental overdose, you will be monitored carefully by medical staff and 
treated appropriately. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
Tell your doctor immediately if you get any of the following side effects: 
 
Very common (may affect more than 1 in 10 people) 
- Inflammation or other disorders of the pancreas (pancreatitis) causing severe stomach pain 

which may spread to your back, vomiting, increase in blood sugar levels; 
- Serious allergic reactions with symptoms such as rash, itching, swelling, hives, shortness of 

breath, fast heart beat and drop in blood pressure; 
- Blood clots; 
- Fever with low counts of white blood cells. 
 
Common (may affect up to 1 in 10 people) 
- Severe bleeding or bruising; 
- Violent shaking (seizures) and loss of consciousness; 
- Severe infection with very high fever; 
- Problems with your liver (e.g., change in colour of your skin or urine or stool and laboratory 

results of elevated liver enzymes or bilirubin). 
 
Rare (may affect up to 1 in 1,000 people) 
- Liver failure; 
- Jaundice; 
- Blocked bile flow from the liver (cholestasis); 
- Destruction of liver cells (liver cell necrosis). 
 



55 

Not known (frequency cannot be estimated from the available data) 
- Severe skin reaction called toxic epidermal necrolysis; 
- Loss of kidney function (e.g., change in urine output, swelling of feet and ankles); 
- Stroke; 
- Severe allergic reaction that may cause loss of consciousness and could be life-threatening 

(anaphylactic shock). 
 
Other side effects 
Talk to your doctor if you get any of the following: 
 
Very common (may affect more than 1 in 10 people) 
- Changes in the function of the pancreas; 
- Weight loss; 
- Leg pain (which could be a symptom of thrombosis), chest pain or shortness of breath (which 

may be a symptom of blood clots in the lungs, called pulmonary embolism); 
- Loss of appetite, general weakness, vomiting, diarrhoea, nausea; 
- Increased blood sugar levels. 
 
Common (may affect up to 1 in 10 people) 
- Decreased number of red blood cells; 
- Build-up of fluid in the stomach (ascites); 
- Fever and flu-like symptoms; 
- Mouth sores; 
- Back, joint or abdominal pain; 
- High levels of fat and cholesterol in your blood; low potassium in your blood. 
 
Rare (may affect up to 1 in 1,000 people) 
- Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome characterised by 

headache, confusion, seizures and visual loss which resolves after some time. 
 
Not known (frequency cannot be estimated from the available data) 
- Decreased number of white blood cells and platelets; 
- Palpitations; 
- Fever; 
- Cysts in your pancreas, swelling of the salivary glands; 
- High levels of urea in your blood; antibodies against Oncaspar; high levels of ammonia in your 

blood; decreased blood sugar levels; 
- Sleepiness, confusion, mild twitching of the fingers. 
 
Reporting of side effects 
If you get any side effects you think might be related to your chemotherapy , talk to your doctor. This 
includes any possible side effects not listed in this leaflet. You can also report side effects directly via 
the national reporting system listed in Appendix V. By reporting side effects you can help provide 
more information on the safety of this medicine. 
 
 
5. How to store Oncaspar 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The 
expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C–8°C). 
Do not freeze. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


56 

After the medicine has been reconstituted and diluted, the solution should be used immediately. If 
immediate use is not possible, the diluted solution can be stored at 2°C-8°C for up to 48 hours. 
 
Do not use this medicine if you notice the reconstituted solution is cloudy or has visible particles. 
 
Do not throw away any medicines via wastewater. Ask the pharmacist how to dispose of unused 
medicines. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Oncaspar contains 
The active substance is pegaspargase. Each vial contains 3,750 U of pegaspargase. 
 
After reconstitution, 1 ml of solution contains 750 U pegaspargase (750 U/ml). 
 
The other ingredients are: disodium phosphate heptahydrate, sodium dihydrogen phosphate 
monohydrate, sodium chloride, sucrose, sodium hydroxide (for pH adjustment), hydrochloric acid (for 
pH adjustment) (see section 2 “Oncaspar contains sodium”). 
 
What Oncaspar looks like and contents of the pack 
Oncaspar is a white to off-white powder. After reconstitution, the solution is clear, colourless and free 
from visible foreign particles. 
Each pack contains 1 glass vial with 3,750 U pegaspargase. 
 
Marketing Authorisation Holder 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
Manufacturer 
Les Laboratoires Servier Industrie 
905 Route de Saran 
45520 Gidy  
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
S.A. Servier Benelux N.V. 
Tél/Tel: +32 (0)2 529 43 11 
 

Lietuva 
UAB “SERVIER PHARMA” 
Tel: +370 (5) 2 63 86 28 
 

България 
Сервие Медикал ЕООД 
Тел.: +359 2 921 57 00 
 

Luxembourg/Luxemburg 
S.A. Servier Benelux N.V. 
Tel: +32 (0)2 529 43 11 
 

Česká republika 
Servier s.r.o. 
Tel: +420 222 118 111 
 

Magyarország 
Servier Hungaria Kft. 
Tel: +36 1 238 7799 
 

Danmark 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Malta 
V.J. Salomone Pharma Ltd  
Tel: + 356 21 22 01 74 

Deutschland Nederland 



57 

Servier Deutschland GmbH 
Tel: +49 (0)89 57095 01 
 

Servier Nederland Farma B.V. 
Tel: + 31 (0)71 5246700 
 

Eesti 
Servier Laboratories OÜ  
Tel:+ 372 664 5040 
 

Norge 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Eλλάδα 
ΣΕΡΒΙΕ ΕΛΛΑΣ ΦΑΡΜΑΚΕΥΤΙΚΗ ΕΠΕ 
Τηλ: + 30 210 939 1000 
 

Österreich 
Servier Austria GmbH 
Tel: +43 (1) 524 39 99 
 

España 
Laboratorios Servier S.L. 
Tel: + 34 91 748 96 30 
 

Polska 
Servier Polska Sp. z o.o. 
Tel: + 48 (0) 22 594 90 00 
 

France 
Les Laboratoires Servier 
Tél: + 33 (0)1 55 72 60 00 
 

Portugal 
Servier Portugal, Lda 
Tel: + 351 21 312 20 00 
 

Hrvatska 
Servier Pharma, d. o. o. 
Tel: + 385 (0)1 3016 222 
 

România 
Servier Pharma SRL 
Tel: + 4 021 528 52 80 
 

Ireland 
Servier Laboratories (Ireland) Ltd. 
Tel: + 353 (0)1 663 8110 
 

Slovenija 
Servier Pharma d. o. o.  
Tel: + 386 (0)1 563 48 11 
 

Ísland 
Servier Laboratories 
c/o Icepharma hf 
Sími: + 354 540 8000 
 

Slovenská republika 
Servier Slovensko spol. s r.o. 
Tel: + 421 2 5920 41 11 
 

Italia 
Servier Italia S.p.A. 
Tel: + 39 (06) 669081 
 

Suomi/Finland 
Servier Finland Oy 
P. /Tel: +358 (0)9 279 80 80 
 

Κύπρος 
CA Papaellinas Ltd. 
Τηλ: + 357 22 741 741 
 

Sverige 
Servier Sverige AB 
Tel : +46 (0)8 522 508 00 
 

Latvija 
SIA Servier Latvia 
Tel: + 371 67502039 
 

United Kingdom 
Servier Laboratories Ltd 
Tel: +44 (0)1753 666409 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
It is strongly recommended that every time Oncaspar is administered to a patient, the name and lot 
number of the product are recorded in order to link the patient and the lot of the product. 
 

http://www.ema.europa.eu/


58 

In view of the unpredictability of adverse reactions, Oncaspar should be administered only by health 
care personnel experienced in the use of cancer chemotherapeutic medicinal products. 
 
Particularly in patients with known hypersensitivity to the other forms of L-asparaginase, 
hypersensitivity reactions to Oncaspar can occur during the therapy, e.g., anaphylaxis. A routine 
precaution is to observe the patients for an hour with resuscitation equipment and other items required 
for the treatment of anaphylaxis in readiness (epinephrine, oxygen, intravenous steroids etc.). 
 
Patients should be informed about possible hypersensitivity reactions to Oncaspar, including 
immediate anaphylaxis. Patients who receive Oncaspar are at increased risk of bleeding and 
thrombotic disorders. It should be explained to patients that Oncaspar should not be used at the same 
time as other medicines associated with an increased risk of bleeding (see section 2 “Other medicines 
and Oncaspar”). 
 
This medicinal product can cause irritation on contact. The powder must therefore be handled and 
administered with particular care. Inhalation of the vapour and contact with the skin and mucosa, 
particularly that of the eyes, must be avoided; if the product comes in contact with eyes, skin, or 
mucous membranes, rinse immediately with plenty of water for at least 15 minutes. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Instructions on how to prepare, store and dispose of Oncaspar 
Instructions for handling 
1. Staff should be trained in how to handle and transfer the medicinal product (pregnant staff 

should be excluded from working with this medicinal product). 
2. Aseptic technique must be used. 
3. Procedures for proper handling of antineoplastic agents should be observed. 
4. The use of disposable gloves and protective garments is recommended when handling 

Oncaspar. 
5. All items for administration or cleaning, including gloves, should be placed in high-risk waste 

disposal bags for high-temperature incineration. 
 
Reconstitution 
1. 5.2 ml water for injections are injected into the vial using a syringe and 21 gauge needle. 
2. The vial should be gently swirled until the powder is reconstituted. 
3. After reconstitution, the solution should be clear, colourless and free from visible foreign 

particles. Do not use if the reconstituted solution is cloudy or if a precipitate has formed. Do not 
shake. 

4. The solution should be used within 24 hours after reconstitution, when stored below 25°C. 
 
Administration 
1. Parenteral medicinal products should be inspected for particulate matter prior to administration, 

only a clear, colourless solution free from visible foreign particles should be used. 
2. The medicinal product should be administered intravenously or intramuscularly. The solution 

should be administered slowly. 
For intramuscular injection, the volume should not exceed 2 ml in children and adolescents and 
3 ml in adults. 
For intravenous administration, the reconstituted solution should be diluted in 100 ml sodium 
chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution. 
The diluted solution can be given over 1 to 2 hours together with an already-running infusion of 
either sodium chloride 9 mg/ml (0.9%) solution or 5% glucose. Do not infuse other medicinal 
products through the same intravenous line during administration of Oncaspar. 
After dilution, the solution should be used immediately. If immediate use is not possible, the 
diluted solution can be stored at 2°C-8°C for up to 48 hours. 

 



59 

Disposal 
Oncaspar is for single use only. Any unused medicinal product or waste material should be disposed 
of in accordance with local requirements. 
Further detailed information can be found in the SmPC. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
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{'Title': '2. what you need to know before you are given oncaspar', 'Section_Content': 'do not use oncaspar - if you are allergic to pegaspargase or to any of the other ingredients of this medicine (listed in section 6). - if you have severe hepatic disease. - if you have ever had pancreatitis. - if you have ever had severe bleeding following asparaginase therapy. - if you have ever had blood clots following asparaginase therapy. tell your doctor if any of these conditions apply to you. if you are the parent of a child who is being treated with oncaspar, please tell the doctor if any of them apply to your child. warnings and precautions talk to your doctor before you are given oncaspar. this medicine may not be suitable for you: - if you have had serious allergic reactions to other forms of asparaginase, for example itching, flushing or swelling of the airways, because major allergic reactions to oncaspar can occur. - if you suffer from a bleeding disorder or have had serious blood clots. - if you get a fever. this medicine may make you more susceptible to infections. - if you have had poor liver function or are using other medicines which may harm the liver. when oncaspar is used in combination with other cancer treatments, liver and central nervous system damage can occur. - if you suffer abdominal pain. inflammation of the pancreas, that in some cases caused death, can occur with oncaspar treatment. this medicine can lead to fluctuations in clotting factors and may increase the risk of bleeding and/or clotting. if you are the parent of a child being treated with oncaspar, tell the doctor if any of the above conditions apply to your child. during treatment with oncaspar during oncaspar administration you will be closely watched for an hour after the start of treatment for any signs of serious allergic reactions. medical equipment to treat allergic reactions will be available nearby. additional monitoring tests blood and urine sugar levels, liver and pancreas function and other tests will be carried out regularly to monitor your health during and after treatment because this medicine can affect your blood and other organs. other medicines and oncaspar tell your doctor if you are using, have recently used or might use any other medicines this is important as oncaspar may increase the side effects of other medicines through its effect on the liver which plays an important role in removing medicines from the body. in addition, it is especially important to tell your doctor if you are also using any of the following medicines: - immunisation with live vaccines within three months of completing your leukaemia treatment. this will increase the risk of severe infections. - vincristine, another cancer medicine. if used at the same time as oncaspar there is an increased risk of side effects or allergic reactions. - medicines which reduce the blood´s ability to clot such as anticoagulants (e.g., coumarin/warfarin and heparin), dipyridamol, acetylsalicylic acid or non-steroidal anti-inflammatory medicines (such as ibuprofen or naproxen). if used at the same time as oncaspar, there is a higher risk of bleeding disorders. - medicines which require cell division for their effect, for example, methotrexate (a medicine used for cancer as well as arthritis treatment) may have a decrease in its effect. - prednisone, a steroid medicine. if used at the same time as oncaspar, the effects on the clotting ability of your blood are increased. - cytarabine, a medicine which can be used in cancer treatment, and could interfere with the effects of oncaspar. oncaspar can also cause changes in liver function which can affect the way other medicines work. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine. you should not use oncaspar if you are pregnant because its effects during pregnancy have not been studied. your physician will decide whether your disease requires treatment. women who are able to get pregnant must use reliable contraception during treatment, and for at least 6 months after oncaspar treatment has been discontinued. oral contraception is not an effective method of contraception while on treatment with oncaspar. ask your doctor for advice on the best contraceptive method that you can use. men must also use effective contraception while they or their partners are being treated with oncaspar. it is not known whether pegaspargase is excreted in breast milk. as a precautionary measure, breast-feeding should be discontinued during treatment with oncaspar and should not be re-started until after treatment with oncaspar has been discontinued. driving and using machines do not drive or use machines when using this medicine because it may make you feel drowsy, tired or confused. oncaspar contains sodium this medicine contains less than 1 mmol sodium per dose, that is to say 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{'Title': '3. how oncaspar is given', 'Section_Content': 'your treatment with oncaspar has been prescribed by a doctor experienced in medicines used to treat cancer. your doctor will decide what dose of the medicine is needed and how often, based on your age and body surface area which is calculated from your height and weight. the medicine is given as a solution by injection into a muscle or, if more suitable, into a vein. if you are given too much oncaspar as your doctor will administer the medicine, it is very unlikely you will be given more than you need. in the unlikely event of accidental overdose, you will be monitored carefully by medical staff and treated appropriately. if you have any further questions on the use of this medicine, ask your doctor.', 'Entity_Recognition': [{'Text': 'oncaspar', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'your treatment', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 14}, {'Text': 'oncaspar', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 28}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 76, 'EndOffset': 85}, {'Id': 2, 'BeginOffset': 100, 'EndOffset': 106, 'Score': 0.9705073237419128, 'Text': 'cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.971524178981781}]}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 145, 'EndOffset': 157}, {'Id': 4, 'BeginOffset': 253, 'EndOffset': 259, 'Score': 0.6850162744522095, 'Text': 'height', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 264, 'EndOffset': 270, 'Score': 0.691001296043396, 'Text': 'weight', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 272, 'EndOffset': 284}, {'Text': 'a solution', 'Type': 'TREATMENT', 'BeginOffset': 297, 'EndOffset': 307}, {'Id': 0, 'BeginOffset': 328, 'EndOffset': 334, 'Score': 0.8487392663955688, 'Text': 'muscle', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 1, 'BeginOffset': 364, 'EndOffset': 368, 'Score': 0.9500312805175781, 'Text': 'vein', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 436, 'EndOffset': 448}, {'Id': 3, 'BeginOffset': 533, 'EndOffset': 552, 'Score': 0.8454351425170898, 'Text': 'accidental overdose', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9197511672973633}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 678, 'EndOffset': 691}]}
{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects tell your doctor immediately if you get any of the following side effects: very common (may affect more than 1 in 10 people) - inflammation or other disorders of the pancreas (pancreatitis) causing severe stomach pain which may spread to your back, vomiting, increase in blood sugar levels; - serious allergic reactions with symptoms such as rash, itching, swelling, hives, shortness of breath, fast heart beat and drop in blood pressure; - blood clots; - fever with low counts of white blood cells. common (may affect up to 1 in 10 people) - severe bleeding or bruising; - violent shaking (seizures) and loss of consciousness; - severe infection with very high fever; - problems with your liver (e.g., change in colour of your skin or urine or stool and laboratory results of elevated liver enzymes or bilirubin). rare (may affect up to 1 in 1,000 people) - liver failure; - jaundice; - blocked bile flow from the liver (cholestasis); - destruction of liver cells (liver cell necrosis). not known (frequency cannot be estimated from the available data) - severe skin reaction called toxic epidermal necrolysis; - loss of kidney function (e.g., change in urine output, swelling of feet and ankles); - stroke; - severe allergic reaction that may cause loss of consciousness and could be life-threatening (anaphylactic shock). other side effects talk to your doctor if you get any of the following: very common (may affect more than 1 in 10 people) - changes in the function of the pancreas; - weight loss; - leg pain (which could be a symptom of thrombosis), chest pain or shortness of breath (which may be a symptom of blood clots in the lungs, called pulmonary embolism); - loss of appetite, general weakness, vomiting, diarrhoea, nausea; - increased blood sugar levels. common (may affect up to 1 in 10 people) - decreased number of red blood cells; - build-up of fluid in the stomach (ascites); - fever and flu-like symptoms; - mouth sores; - back, joint or abdominal pain; - high levels of fat and cholesterol in your blood; low potassium in your blood. rare (may affect up to 1 in 1,000 people) - reversible posterior leukoencephalopathy syndrome (rpls), a syndrome characterised by headache, confusion, seizures and visual loss which resolves after some time. not known (frequency cannot be estimated from the available data) - decreased number of white blood cells and platelets; - palpitations; - fever; - cysts in your pancreas, swelling of the salivary glands; - high levels of urea in your blood; antibodies against oncaspar; high levels of ammonia in your blood; decreased blood sugar levels; - sleepiness, confusion, mild twitching of the fingers. reporting of side effects if you get any side effects you think might be related to your chemotherapy , talk to your doctor. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'oncaspar', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 19, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9666446447372437, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6891677975654602}]}, {'Text': 'serious side effects', 'Type': 'PROBLEM', 'BeginOffset': 92, 'EndOffset': 112}, {'Id': 76, 'BeginOffset': 130, 'EndOffset': 141, 'Score': 0.9999991655349731, 'Text': 'immediately', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 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{'Title': '5. how to store oncaspar', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (28). do not freeze. after the medicine has been diluted, the solution should be used immediately. if immediate use is not possible, the diluted solution can be stored at 2-8 for up to 48 hours. do not use this medicine if you notice the solution is cloudy or has visible particles. do not throw away any medicines via wastewater. ask the pharmacist how to dispose of unused medicines. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'oncaspar', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 262, 'EndOffset': 274}, {'Text': 'the solution', 'Type': 'TREATMENT', 'BeginOffset': 293, 'EndOffset': 305}, {'Text': 'the diluted solution', 'Type': 'TREATMENT', 'BeginOffset': 368, 'EndOffset': 388}, {'Text': '48', 'Type': 'NUMBER', 'BeginOffset': 420, 'EndOffset': 422}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 441, 'EndOffset': 454}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 485, 'EndOffset': 491}, {'Text': 'unused medicines', 'Type': 'TREATMENT', 'BeginOffset': 603, 'EndOffset': 619}]}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what oncaspar contains the active substance is pegaspargase. one ml of solution contains 750 units pegaspargase . one vial of 5 ml solution contains 3750 units of pegaspargase. the other ingredients are: sodium dihydrogen phosphate monohydrate, disodium phosphate heptahydrate, sodium chloride, and water for injections (see section 2 "oncaspar contains sodium"). what oncaspar looks like and contents of the pack oncaspar is a clear, colourless solution for injection contained in a glass vial. each pack contains 1 vial.', 'Entity_Recognition': [{'Text': 'oncaspar', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 47, 'EndOffset': 59, 'Score': 0.9596736431121826, 'Text': 'pegaspargase', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9725466966629028, 'RelationshipScore': 0.9987221360206604, 'RelationshipType': 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