Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Les Laboratoires Servier, 50, rue Carnot, 92284, Suresnes cedex, France
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.
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 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, blood pressure decreased, 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 counter-measure.
Pancreatitis, including haemorrhagic or necrotising pancreatitis with fatal outcomes, have 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. As impaired glucose tolerance may occur with concomitant use of Oncaspar with prednisone, blood glucose levels should be monitored.
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 are used simultaneously, such as acetylsalicylic acid and non-steroidal anti-inflammatory medicinal products (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.
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.
Due to the risk of hyperbilirubinaemia, it is recommended to monitor bilirubin levels at baseline and prior to each dose.
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),
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.
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.
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).
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially ‘sodium-free’.
The decrease in serum proteins caused by pegaspargase can increase the toxicity of other medicinal products that are protein bound.
In addition, by inhibiting protein synthesis and cell division, pegaspargase can disturb the mechanism of action of other substances which require cell division for their effect, e.g., methotrexate. Methotrexate and cytarabine can interact differently with Oncaspar: their prior administration can increase the action of pegaspargase synergistically. If these substances are given subsequently, the effect of pegaspargase can be weakened antagonistically.
Pegaspargase can interfere with metabolism and clearance of other medicinal products, based on its effects on protein synthesis and hepatic function, as well as from its combined use with other chemotherapy products known to interact with CYP enzymes.
The use of Oncaspar can lead to fluctuation in coagulation factors. This can promote the tendency to bleeding and/or thrombosis. Caution is therefore needed when anticoagulants such as coumarin, heparin, dipyridamole, acetylsalicylic acid or non-steroidal anti-inflammatory medicinal products are given concomitantly, or when concomitant chemotherapy regimen including methotrexate, daunorubicin, corticosteroids is administered.
When glucocorticoids (e.g., prednisone) and pegaspargase are given at the same time, alterations in coagulation parameters (e.g., fall in fibrinogen and antithrombin III deficiency, ATIII) can be more pronounced.
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.
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).
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.
It is not known whether pegaspargase is excreted into 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.
No studies investigating the effect of pegaspargase on fertility have been performed.
Oncaspar has 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).
The adverse reactions described in this section are derived from clinical trial 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/m 2 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.
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:
Very common: Febrile neutropenia
Common: Anaemia, coagulopathy
Not known: Bone marrow failure
Very common: Pancreatitis, diarrhoea, abdominal pain, nausea
Common: Vomiting, stomatitis, ascites
Rare: Pancreatitis necrotising, pancreatitis haemorrhagic
Not known: Pancreatic pseudocyst, parotitis*
Not known: Pyrexia
Common: Hepatotoxicity, fatty liver
Rare: Hepatic necrosis, jaundice, cholestasis, hepatic failure
Very common: Hypersensitivity, urticaria, anaphylactic reaction
Not known: Toxic epidermal necrolysis*
Common: Infections, sepsis
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
Very common: Decreased appetite, hyperglycaemia
Common: Hyperlipidaemia, hypercholesterolaemia
Not known: Diabetic ketoacidosis, hypoglycaemia
Common: Pain in extremities
Common: Seizure, peripheral motor neuropathy, syncope
Rare: Posterior reversible leukoencephalopathy syndrome
Not known: Somnolence, tremor*
Not known: Confusional state
Not known: Renal failure acute*
Common: Hypoxia
Very common: Rash
Very common: Embolism**
Common: Thrombosis***
Not known: Cerebrovascular accident, haemorrhage, superior sagittal sinus thrombosis
* 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
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:
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.
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.
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.
Acute renal failure may develop in rare cases during treatment with L-asparaginase-containing regimens.
Allergic reactions can manifest in the skin. One case of toxic epidermal necrolysis (Lyell’s syndrome) has been described in association with L-asparaginase.
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.
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.
Pyrexia can occur after the injection, which usually subsides spontaneously.
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).
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 type of adverse reactions of Oncaspar is similar with that of native non-pegylated L-asparaginase (e.g., native E. coli asparaginase).
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.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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