Spectrila · 4.8 Undesirable effects · 1

HOS-096548 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The primary toxicity of asparaginase results from immunologic reactions caused by exposure to the bacterial protein. Hypersensitivity reactions range from transient flushing or rash and urticaria to bronchospasm, angioedema and anaphylaxis. In addition, treatment with asparaginase can result in disturbances in organ systems which exhibit a high level of protein synthesis. Decreased protein synthesis can predominantly lead to liver impairment, acute pancreatitis, decreased insulin production with hyperglycaemia, decreased production of clotting factors (especially fibrinogen and antithrombin III) leading to coagulation disorders (thrombosis, bleeding), and decreased production of lipoproteins resulting in hypertriglyceridaemia. Most serious adverse reactions of Spectrila include severe hypersensitivity reactions such as anaphylactic shock (rare), thromboembolic events (common), acute pancreatitis (common), and severe hepatotoxicity, e.g. jaundice, hepatic necrosis, hepatic failure (rare). Most frequently (very common) observed adverse reactions of Spectrila include hypersensitivity reactions, hyperglycaemia, hypoalbuminaemia, nausea, vomiting, diarrhoea, abdominal pain, oedema, fatigue, and change in laboratory parameters (e.g. transaminases, bilirubin, blood lipids, coagulation parameters). Since Spectrila is usually used in combination therapy with other antineoplastic agents, the demarcation from undesirable effects of other medicinal products is often difficult. Tabulated list of adverse reactions The following adverse reactions, listed in table 1, have been accumulated from clinical trials with Spectrila in 125 children with newly diagnosed acute lymphoblastic leukaemia as well as post-marketing experience with other E. coli-derived asparaginase preparations in children and adults. Adverse reactions are ranked under headings of frequency, the most frequent first. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequencies in this table are defined using 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); not known (cannot be estimated from the available data). Table 1 System organ class Frequency and adverse reaction Infections and infestations Not known Infections Blood and lymphatic syst

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HOS-096544 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to the active substance, any native (non-pegylated) E. coli-asparaginase preparation or to any of the excipients listed in section 6.1. • Pancreatitis. • Severe hepatic impairment (bilirubin > 3 times upper limit of normal [ULN]; transaminases > 10 times ULN). • Pre-existing known coagulopathy (e.g. haemophilia). • History of pancreatitis, serious haemorrhage or serious thrombosis with prior asparaginase therapy. 3

HOS-096543 · has-indication-information · PDF-Seite 2

Spectrila is indicated as a component of antineoplastic combination therapy for the treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients from birth to 18 years and adults.

HOS-096546 · has-interaction-information · PDF-Seite 6

General Asparaginase may increase the toxicity of other medicinal products through its effect on liver function, e.g. increased hepatotoxicity with potentially hepatotoxic medicinal products, increased toxicity of medicinal products metabolised by the liver or bound to plasma proteins and altered pharmacokinetics and pharmacodynamics of medicinal product bound to plasma proteins. Therefore, caution should be exercised in patients receiving other medicinal products metabolised by the liver. Hepatic parameters should be monitored when potentially hepatotoxic medicinal products are given concomitantly with asparaginase (see sections 4.4 and 4.8). Myelosuppressive agents During treatment with asparaginase-containing regimens, myelosuppression, potentially affecting all three myeloid cell lineages (erythrocytes, leukocytes, thrombocytes), and infections can occur. Concomitant treatment with myelosuppressive medicinal products and those known to cause infections are major contributing factors and patients should be carefully monitored for signs and symptoms of myelosuppression and infection (see section 4.8). Vincristine The toxicity of vincristine may be additive with that of asparaginase if both agents are administered concomitantly. Therefore, vincristine should be given 3 to 24 hours before administration of asparaginase in order to minimise toxicity. Glucocorticoids and/or anticoagulants Concomitant use of glucocorticoids and/ or anticoagulants with asparaginase may increase the risk of a change in coagulation parameters (see section 4.4). This can promote tendency to bleeding (anticoagulants) or thrombosis (glucocorticoids). Caution is therefore needed when anticoagulants (e.g. coumarin, heparin, dipyridamole, acetylsalicylic acid or nonsteroidal anti-inflammatory medicinal products) or glucocorticoids are given at the same time. 6 Methotrexate (MTX) Inhibition of protein synthesis secondary to the asparaginase-induced depletion of asparagine has been shown to attenuate the cytotoxic effect of MTX which requires cell replication for its antineoplastic activity. This antagonism is observed if asparaginase is administered prior to or concurrently with methotrexate. Conversely, the antitumour effects of methotrexate are enhanced when asparaginase is administered 24 hours following methotrexate treatment. This regimen has been shown to reduce the gastrointestinal and haematological effects of methotr

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HOS-096547 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential/Contraception in males and females Women of childbearing potential have to use effective contraception and avoid becoming pregnant while being treated with asparaginase-containing chemotherapy and for 7 months following completion of treatment. Since an indirect interaction between components of the oral contraception and asparaginase cannot be ruled out, oral contraceptives are not considered sufficiently safe in such clinical situation. A method other than oral contraceptives should be used in women of childbearing potential (see section 4.4). Men should use effective contraceptive measures and be advised to not father a child while receiving asparaginase and for 4 months following completion of treatment. Pregnancy There are no data on the use of asparaginase in pregnant women. No reproduction studies in animals with asparaginase were performed but studies with asparaginase preparations in mice, rats, chicken and rabbits have shown embryotoxic and teratogenic effects (see section 5.3). Based on results from animal studies and its mechanism of action, Spectrila should not be used during pregnancy unless the clinical condition of the woman requires treatment with asparaginase. Breast-feeding It is unknown whether asparaginase is excreted into human breast milk. Because potential serious adverse reactions may occur in breast-feeding infants, Spectrila should be discontinued during breast-feeding. Fertility No human data on the effect of asparaginase on fertility are available. 7

HOS-096545 · has-warning-information · PDF-Seite 4

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should clearly be recorded. General information and monitoring The following life-threatening situations may arise during asparaginase treatment in patients of all age groups: • acute pancreatitis, • hepatotoxicity, • anaphylaxis, • coagulation disorders including symptomatic thrombosis related to the use of central venous catheters, • hyperglycaemic conditions. Before initiating therapy bilirubin, hepatic transaminases and coagulation parameters (e.g. partial thromboplastin time [PTT], prothrombin time [PT], antithrombin III and fibrinogen) should be determined. After administration of any asparaginase preparation, close monitoring of bilirubin, hepatic transaminases, blood/urinary glucose, coagulation parameters (e.g. PTT, PT, antithrombin III, fibrinogen and D-dimer), amylase, lipase, triglycerides and cholesterol is recommended. Acute pancreatitis Treatment with asparaginase should be discontinued in patients developing acute pancreatitis. Acute pancreatitis has developed in less than 10% of patients. In rare cases, haemorrhagic or necrotising pancreatitis occurs. There have been isolated reports of fatal outcomes. Clinical symptoms include abdominal pain, nausea, vomiting and anorexia. Serum amylase and lipase are usually elevated, although in some patients they can be normal due to impaired protein synthesis. Patients with severe hypertriglyceridaemia are at increased risk of developing acute pancreatitis. These patients should no longer be treated with any asparaginase preparation (see also sections 4.3 and 4.8). Hepatotoxicity In rare cases severe liver impairment has been described, including cholestasis, icterus, hepatic necrosis and hepatic failure with fatal outcome (see sections 4.8 and 4.5). Liver parameters should be monitored closely before and during treatment with asparaginase. Treatment with asparaginase should be interrupted if patients develop severe hepatic impairment (bilirubin > 3 times the upper limit of normal [ULN]; transaminases > 10 times ULN), severe hypertriglyceridaemia, hyperglycaemia or coagulation disorder (e.g. sinus vein thrombosis, severe bleeding). Allergy and anaphylaxis Because of the risk of severe anaphylactic reactions asparaginase should not be administered as a bolus intravenous injection. A previous intracutaneous test or a small intra

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