L-Asgen 10,000 IU Special Precautions

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 Contraindications and Adverse Reactions).
Hepatotoxicity: In rare cases severe liver impairment has been described, including cholestasis, icterus, hepatic necrosis and hepatic failure with fatal outcome (see Adverse Reactions and Interactions). 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 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.
Coagulation disorders: Due to the inhibition of protein synthesis (decreased synthesis of factors II, V, VII, VIII, and IX, proteins C and S, antithrombin III [AT III]) caused by asparaginase, coagulation disorders can occur which can manifest either as thrombosis, disseminated intravascular coagulation (DIC), or bleeding. The risk of thrombosis seems to be higher than the risk of bleeding. Symptomatic thromboses related to the use of central venous catheters have been described, too.
Approximately half of the thrombotic events is localised in cerebral vessels. Sinus vein thrombosis can occur. Ischaemic strokes are rare.
Acquired or genetically decreased physiologic coagulation inhibitors (protein C, protein S, antithrombin) are also described in relation to vascular complications.
Frequent evaluation of coagulation parameters is important before and during asparaginase treatment. Expert advice should be sought in cases where AT III is decreased.
Hyperglycaemic conditions: Asparaginase may induce hyperglycaemia as a consequence of decreased insulin production. Additionally it may decrease insulin secretion from pancreatic β-cells and impair insulin receptor function. The syndrome is generally self-limiting. However, in rare cases it can result in diabetic ketoacidosis. Concomitant treatment with corticosteroids contributes to this effect. Serum and urine glucose levels should be regularly monitored and managed as clinically indicated.
Antineoplastic agents: Asparaginase-induced tumour cell destruction may release large amounts of uric acid, resulting in hyperuricaemia. Co-administration of other antineoplastic medicinal products contributes to this effect. Aggressive alkalinisation of the urine and use of allopurinol can prevent urate nephropathy.
Glucocorticoids: A higher risk of thrombosis during induction therapy with asparaginase and prednisone was seen in children with a genetic prothrombotic risk factor (factor V G1691A-mutations, prothrombin G20210A-variation, methylenetetrahydrofolate reductase [MTHFR] T677T-genotype, increased lipoprotein A, hyperhomocysteinaemia).
Contraceptives: Women of childbearing potential should use effective contraceptive measures while being treated with asparaginase 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 (see Use in Pregnancy & Lactation).
Philadelphia chromosome-positive patients: Efficacy and safety of L-Asgen 10,000 IU have not been established in Philadelphia chromosome-positive patients.
Recommended control examinations for patients of all age groups: Asparaginase activity: Measurement of the asparaginase activity level in serum or plasma may be undertaken in order to rule out accelerated reduction of asparaginase activity. Preferably, levels should be measured three days after the last asparaginase administration, i.e. usually directly before the next dose of asparaginase is given. Low asparaginase activity levels are often accompanied by the appearance of anti-asparaginase antibodies. In such cases, a switch to a different asparaginase preparation should be considered. Expert advice should first be sought.
Hypoalbuminaemia: As a result of impaired protein synthesis, the serum protein level (especially albumin) decreases very commonly in patients treated with asparaginase. Since serum protein is important for the binding and transport function of some active substances, the serum protein level should be monitored regularly.
Hyperammonaemia: Plasma ammonia levels should be determined in all patients with unexplained neurologic symptoms or severe and prolonged vomiting. In case of hyperammonaemia with severe clinical symptoms, therapeutic and pharmacological measures that rapidly reduce plasma ammonia levels (e.g. protein restriction and haemodialysis), reverse catabolic states and increase removal of nitrogen wastes should be initiated and expert advice sought.
Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS) may occur rarely during treatment with any asparaginase (see Adverse Reactions). This syndrome is characterised in magnetic resonance imaging (MRI) by reversible (from a few days to months) lesions/oedema, primarily in the posterior region of the brain. Symptoms of RPLS essentially include elevated blood pressure, seizures, headaches, changes in mental state and acute visual impairment (primarily cortical blindness or homonymous hemianopsia). It is unclear whether the RPLS is caused by asparaginase, concomitant treatment or the underlying diseases.
RPLS is treated symptomatically, including measures to treat any seizures. Discontinuation or dose reduction of concomitantly administered immunosuppressive medicinal products may be necessary. Expert advice should be sought.
Effects on ability to drive and use machines: L-Asgen 10,000 IU has moderate influence on the ability to drive and use machines, especially through its potential effects on the nervous and gastrointestinal systems (see Adverse Reactions).