Spectrila

Spectrila should be prescribed and administered by physicians and healthcare personnel experienced in the use of antineoplastic products. It should only be given in a hospital setting where appropriate resuscitation equipment is available.

5). Adults and children older than 1 year The recommended intravenous dose of asparaginase is 5,000 units per square metre (U/m²) body surface area (BSA) given every third day. Treatment may be monitored based on the trough serum asparaginase activity measured three days after administration of Spectrila.

4). Children 0 – 12 months old Based on limited data, the recommended dose in infants is as follows: - age less than 6 months: 6,700 U/m² BSA, - age 6 – 12 months: 7,500 U/m² BSA. 3 Data on efficacy and safety of Spectrila in adults are limited.

Data on efficacy and safety of Spectrila in the post-induction treatment phases are very limited. Special populations Renal impairment No dose adjustment is necessary in patients with renal impairment. Hepatic impairment No dose adjustment is necessary in patients with mild to moderate hepatic impairment.

3). Elderly Limited data are available for the treatment of patients older than 65 years of age. Method of administration Spectrila is for administration by intravenous infusion only. 9%) solution for infusion. 5 to 2 hours. Asparaginase must not be administered as a bolus dose.

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.

g. jaundice, hepatic necrosis, hepatic failure (rare). 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 system disorders Common Disseminated intravascular coagulation (DIC), anaemia, leukopenia, thrombocytopenia Immune system disorders Very common Hypersensitivity including flushing, rash, hypotension, oedema/angioedema, urticaria, dyspnoea Common Hypersensitivity including bronchospasm 9 Rare Anaphylactic shock Endocrine disorders Very rare Secondary hypothyroidism, hypoparathyroidism Metabolism and nutrition disorders Very common Hyperglycaemia, hypoalbuminaemia Common Hypoglycaemia, decreased appetite, weight loss Uncommon Hyperuricaemia, hyperammonaemia Rare Diabetic ketoacidosis Psychiatric disorders Common Depression, hallucination, confusion Nervous system disorders Common Neurological signs and symptoms including agitation, dizziness and somnolence Uncommon Headaches Rare Ischaemic stroke, reversible posterior leukoencephalopathy syndrome (RPLS), convulsion, disturbances in consciousness including coma Very rare Tremor Vascular disorders Common Thrombosis especially cavernous sinus thrombosis or deep vein thrombosis, haemorrhage Gastrointestinal disorders Very common Diarrhoea, nausea, vomiting, abdominal pain Common Acute pancreatitis Rare Haemorrhagic pancreatitis, necrotising pancreatitis, parotitis Very rare Pancreatitis with fatal outcome, pancreatic pseudocyst Hepatobiliary disorders Rare Hepatic failure with potentially fatal outcome, hepatic necrosis, cholestasis, jaundice Not known Hepatic steatosis General disorders and administration site conditions Very common Oedema, fatigue Common Pain (back pain, joint pain) 10 Investigations Very common Increase in transaminases, blood bilirubin, blood alkaline phosphatase, blood cholesterol, blood triglyceride, very low density lipoprotein (VLDL), lipoprotein lipase activity, blood urea, ammonia, blood lactate dehydrogenase (LDH), Decrease in antithrombin III, blood fibrinogen, blood cholesterol, low density lipoprotein (LDL), total protein Common Increase in amylase, lipase, abnormal electroencephalogram (EEG) (reduced alpha wave activity, increased theta and delta wave activity) Description of selected adverse reactions Immune system disorders Spectrila can induce antibodies of different immunoglobulin classes (IgG, IgM, IgE).

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.

g. partial thromboplastin time [PTT], prothrombin time [PT], antithrombin III and fibrinogen) should be determined. 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. 8). 5). Liver parameters should be monitored closely before and during treatment with asparaginase.

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 intravenous test dose can be used.

Both procedures, however, do not allow for predicting accurately which patients will experience an allergic reaction. If allergic symptoms occur, administration of asparaginase must be discontinued immediately and appropriate treatment given, which may include antihistamines and corticosteroids.

• Hypersensitivity to the active substance, any native (non-pegylated) E. 1. • Pancreatitis. • Severe hepatic impairment (bilirubin > 3 times upper limit of normal [ULN]; transaminases > 10 times ULN). g. haemophilia). • History of pancreatitis, serious haemorrhage or serious thrombosis with prior asparaginase therapy.

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