Leitlinien & Arzneimittelsicherheit

HOS-097094 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The adverse reactions described in this section are derived from clinical studies data and post-marketing experience of Oncaspar in ALL patients. The safety profile is based on randomised, controlled, prospective, open label multicentre studies using Oncaspar at a dose of 2500 U/m2 administered intravenously as a comparative treatment (studies DFCI 11-001 and AALL07P4). In addition, the safety profile included data from other Oncaspar studies such as the study comparing the pharmacokinetics of the liquid and lyophilized formulations of pegaspargase (CL2-95014-002), its roll over study (CL2-95014-003) and studies using the intramuscular route of administration (studies CCG-1962 and CCG-1991) were also considered to determine the safety profile (see section 5.1 for CCG-1962 and CCG-1991). The most common adverse reactions with Oncaspar (observed in at least 2 studies with a frequency of >10%) included: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, activated partial thromboplastin time prolonged, hypertriglyceridaemia, hyperglycaemia, and febrile neutropenia. The most common, severe adverse reactions with Oncaspar (graded 3 or 4) observed in studies DFCI 11-001 and AALL07P4 with a frequency of >5% included: alanine aminotransferase increased, 7 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 Adverse reaction class Infections and infestations Common: Infections, sepsis Very common: Febrile neutropenia Blood and lymphatic system Common: Anaemia, coagulopathy disorders Not known: Bone marrow failure

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HOS-097090 · has-contraindication-information · PDF-Seite 3

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).

HOS-097089 · has-indication-information · PDF-Seite 2

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.

HOS-097092 · has-interaction-information · PDF-Seite 6

The decrease in serum proteins caused by pegaspargase can increase the toxicity of other medicinal products that are protein bound. In addition, by inhibiting protein synthesis and cell division, pegaspargase can disturb the mechanism of action of other substances which require cell division for their effect, e.g., methotrexate. Methotrexate and cytarabine can interact differently with Oncaspar: their prior administration can increase the action of pegaspargase synergistically. If these substances are given subsequently, the effect of pegaspargase can be weakened antagonistically. Pegaspargase can interfere with metabolism and clearance of other medicinal products, based on its effects on protein synthesis and hepatic function, as well as from its combined use with other chemotherapy products known to interact with CYP enzymes. The use of Oncaspar can lead to fluctuation in coagulation factors. This can promote the tendency to bleeding and/or thrombosis. Caution is therefore needed when anticoagulants such as coumarin, heparin, dipyridamole, acetylsalicylic acid or non-steroidal anti-inflammatory medicinal products are given concomitantly, or when concomitant chemotherapy regimen including methotrexate, daunorubicin, corticosteroids is administered. When glucocorticoids (e.g., prednisone) and pegaspargase are given at the same time, alterations in coagulation parameters (e.g., fall in fibrinogen and antithrombin III deficiency, ATIII) can be more pronounced. Pegaspargase may increase the risk of glucocorticoid-induced osteonecrosis in children and adolescents when both treatments are given simultaneously, with a higher incidence seen in girls, through a potential increase in exposure of dexamethasone. (see sections 4.4 and 4.8). Immediately preceding or simultaneous treatment with vincristine can increase the toxicity of pegaspargase. Administration of Oncaspar before vincristine may increase the neurotoxicity of vincristine. Therefore, vincristine should be given at least 12 hours prior to administration of Oncaspar in order to minimise toxicity. An indirect interaction cannot be ruled out between pegaspargase and oral contraceptives due to pegaspargase hepatotoxicity that may impair the hepatic clearance of oral contraceptives. Therefore, the concomitant use of Oncaspar with oral contraceptives is not recommended. Another method than oral contraception should be used in women of childbearing potential (see sections 4.4 and 4.6). Simultaneous vacc

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HOS-097093 · has-pregnancy-information · PDF-Seite 7

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.

HOS-097091 · has-warning-information · PDF-Seite 3

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. 3 Asparaginase antibodies The presence of anti-asparaginase antibodies may be associated with low asparaginase activity levels due to potential neutralising activity of these antibodies. In such cases, a switch to a different asparaginase preparation should be considered. Measurement of the asparaginase activity level in serum or plasma may be undertaken in order to rule out an accelerated reduction of asparaginase activity. Hypersensitivity Hypersensitivity reactions to pegaspargase, including life-threatening anaphylaxis, can occur during therapy, including in patients with known hypersensitivity to E. coli derived asparaginase formulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye swelling, erythema, decreased blood pressure, bronchospasm, dyspnoea, pruritus and rash (see sections 4.3 and 4.8). Premedicate patients 30-60 minutes prior to administration of Oncaspar (see section 4.2). As a routine precautionary measure, the patient should be monitored for an hour after administration; resuscitation equipment and other appropriate means for the treatment of anaphylaxis should be available (epinephrine, oxygen, intravenous steroids, etc.). Oncaspar should be discontinued in patients with serious hypersensitivity reactions (see sections 4.3 and 4.8). Depending on the severity of the symptoms, administration of antihistamines, corticosteroids and vasopressors may be indicated as a counter-measure. Pancreatic effects Pancreatitis, including haemorrhagic or necrotising pancreatitis with fatal outcomes, has been reported in patients receiving Oncaspar (see section 4.8). Patients should be informed of the signs and symptoms of pancreatitis which, if left untreated, could become fatal. If pancreatitis is suspected, Oncaspar should be discontinued; if pancreatitis is confirmed, Oncaspar should not be restarted. Serum amylase and/or lipase levels should be monitored frequently to identify early signs of pancreatic inflammation. Blood glucose levels should be monitored, as impaired glucose tolerance may occur with concomitant use of Oncaspar with prednisone. Coagulopathy Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving pegaspargase (see section 4.8). Oncaspar

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