L-Asgen 10,000 IU

Each vial of powder contains 10,000 units of asparaginase*.
*Produced in Escherichia coli cells.
Excipients/Inactive Ingredients: Mannitol, Water for Injection.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents. ATC code: L01XX02.
Pharmacology: Pharmacodynamics: Mechanism of action: Asparaginase hydrolyses asparagine to aspartic acid and ammonia. In contrast to normal cells, lymphoblastic tumour cells have a very limited capacity for synthesising asparagine because of a significantly reduced expression of asparagine synthetase. Therefore, they require asparagine which diffuses from the extracellular environment. As a result of asparaginase-induced asparagine depletion in serum, protein synthesis in lymphoblastic tumour cells is disturbed while sparing most normal cells. Asparaginase may also be toxic to normal cells that divide rapidly and are dependent to some degree on exogenous asparagine supply.
Due to the asparagine concentration gradient between the extra- and intravascular space, asparagine levels are subsequently also reduced in the extravascular spaces, e.g. the cerebrospinal fluid.
Pharmacodynamic effects: In a clinical trial in children with de novo ALL (study MC-ASP.4/ALL) it was shown that immediately after the end of infusion of asparaginase mean asparagine concentrations in serum dropped from the pre-dose concentrations of about 40 µM to below the lower limit of quantification of the bioanalytical method (<0.5 µM). The mean asparagine concentrations in serum remained below 0.5 µM from immediately after the end of first infusion of asparaginase until at least three days after the last infusion. Thereafter, asparagine serum levels increased again and returned to normal values within 1-3 weeks.
In addition to asparagine, asparaginase is also able to cleave the amino acid glutamine to glutamic acid and ammonia, however with much less efficiency. Clinical trials with asparaginase have shown that glutamine levels are only moderately affected with a very high interindividual variability. Immediately after the end of infusion of asparaginase, serum levels of glutamine declined by a maximum of 50% from pre-dose levels of about 400 µM but rapidly returned to normal values within a few hours.
Clinical efficacy and safety: Not applicable.
Pharmacokinetics: Absorption: Asparaginase is not absorbed by the gastrointestinal tract, thus L-Asgen 10,000 IU must be given intravenously.
Distribution: Asparaginase is distributed mainly within the intravascular space. The mean (Standard Deviation, SD) of the volume of distribution at steady state (V_dss) was 2.47 L (0.45 L).
Asparaginase does not seem to penetrate the blood-brain barrier in measurable amounts.
Median (range) maximum serum concentrations of asparaginase activity were 2,324 U/L (1,625-4,819 U/L). Peak (C_max) of asparaginase activity in serum was reached with a delay of approximately 2 hours after the end of the infusion.
After repeated administration of asparaginase at a dose of 5,000 U/m² every third day, trough asparaginase activity levels in serum ranged from 108 to 510 U/L.
Biotransformation: The metabolism of asparaginase is not known but thought to occur via degradation within the reticulo-histiocytic system and by serum proteases.
Elimination: The mean ± SD terminal half-life (elimination half-life) of asparaginase activity in serum was 25.8 ± 9.9 h, with a range between 14.2 and 44.2 h.
Pharmacokinetic/pharmacodynamic relationships: In clinical trials with asparaginase, trough asparaginase serum activity levels greater than 100 U/L were achieved in the majority of patients which nearly always correlated with a complete depletion of asparagine in serum and cerebrospinal fluid (CSF). Even those few patients with trough asparaginase serum activity levels of 10-100 U/L usually experienced complete asparagine depletion in serum and CSF.
Paediatric population: Pharmacokinetic parameters after administration of 5,000 U/m² of L-Asgen 10,000 IU were determined in 14 children/adolescents (age 2-14 years) with de novo ALL (study MC-ASP.4/ALL). Results are shown in Table 1. (See Table 1.)

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Median trough serum asparaginase activities were measured in 81 children/adolescents with de novo ALL three days after infusion of asparaginase (just before the next dose had to be given) during induction treatment and ranged from 168 to 184 U/L (study MC-ASP.5/ALL).
Trough serum activity levels were measured in 12 infants (age from birth to 1 year) with de novo ALL (study MC-ASP.6/INF). Median (range) serum trough asparaginase activities on days 18, 25, and 33 were 209 (42-330) U/L, 130 (6-424) U/L, and 32 (1-129) U/L, respectively. The lower median activity level on day 33 compared to the former two measurements was in part due to the fact that this last serum sample was taken 4 days after the last infusion of asparaginase instead of three days on the other occasions.
Toxicology: Preclinical safety data: Non clinical repeat dose toxicity and safety pharmacology studies in rats revealed no special hazard for humans, except a slight but significant saluretic effect at doses below the recommended dose for ALL patients. Additionally, the urinary pH value and the relative weight of kidneys were increased at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Evidence from published data with asparaginase renders the mutagenic, clastogenic and carcinogenic potential of asparaginase negligible.
Asparaginase caused an increase in the incidence of malformations (including those of the central nervous system, heart and skeletal system) and foetal death at doses that are similar to or in excess of those proposed clinically (on a U/m² basis) in a number of species including the mouse, rat and/or rabbit.

L-Asgen 10,000 IU 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.

L-Asgen 10,000 IU 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.
Posology: L-Asgen 10,000 IU is usually employed as part of combination chemotherapy protocols with other antineoplastic agents (see also Interactions).
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 L-Asgen 10,000 IU. If asparaginase activity values fail to reach target levels, a switch to a different asparaginase preparation could be considered (see Precautions).
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.
Data on efficacy and safety of L-Asgen 10,000 IU in adults are limited.
Data on efficacy and safety of L-Asgen 10,000 IU 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. However, L-Asgen 10,000 IU should not be used in patients with severe hepatic impairment (see Contraindications).
Elderly: Limited data are available for the treatment of patients older than 65 years of age.
Method of administration: L-Asgen 10,000 IU is for administration by intravenous infusion only.
The daily amount of L-Asgen 10,000 IU needed per patient can be diluted in a final volume of 50-250 mL sodium chloride 9 mg/mL (0.9%) solution for infusion. The diluted solution of asparaginase may be infused over 0.5 to 2 hours.
Asparaginase must not be administered as a bolus dose.

No case of asparaginase overdose with clinical symptoms has been reported. There is no specific antidote. Treatment is symptomatic and supportive.

Hypersensitivity to the active substance, any native (non-pegylated) E. coli-asparaginase preparation or to any of the excipients listed in Description.
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.

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).

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 Precautions). 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 Pharmacology: Toxicology: Preclinical safety data under Actions). Based on results from animal studies and its mechanism of action, L-Asgen 10,000 IU 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, L-Asgen 10,000 IU should be discontinued during breast-feeding.
Fertility: No human data on the effect of asparaginase on fertility are available.

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 L-Asgen 10,000 IU 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 L-Asgen 10,000 IU 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 L-Asgen 10,000 IU 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 2, have been accumulated from clinical trials with L-Asgen 10,000 IU 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). (See Table 2.)

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Description of selected adverse reactions: Immune system disorders: L-Asgen 10,000 IU can induce antibodies of different immunoglobulin classes (IgG, IgM, IgE). These antibodies may induce clinical allergic reactions, inactivate the enzymatic activity or accelerate the elimination of asparaginase.
Allergic reactions can manifest as flushing, rash, pain (joint pain, back pain and abdominal pain), hypotension, oedema/angioedema, urticaria, dyspnoea, bronchospasm up to anaphylactic shock.
The probability of the occurrence of allergic reactions increases with the number of administered doses; however, in very rare cases reactions can occur at the first dose of asparaginase. Most hypersensitivity reactions to asparaginase are observed during subsequent treatment phases (re-induction treatment, delayed intensification).
In a clinical trial in children with newly diagnosed ALL (study MC-ASP.5/ALL), the following frequencies of allergic events were observed (Table 3). (See Table 3.)

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No allergic reactions were observed in any of the 12 infants <1 year of age during treatment with L-Asgen 10,000 IU (study MC-ASP.6/INF).
In case of occurrence of allergic symptoms, administration of L-Asgen 10,000 IU should be discontinued immediately (see Precautions).
Immunogenicity: In the study in children/adolescents aged 1-18 years with de novo ALL (study MC-ASP.5/ALL), by day 33 of induction treatment 10 patients in the L-Asgen 10,000 IU group (10.3%) and 9 in the reference group (8.9%) were measured positive for anti-asparaginase antibodies at least at one time point.
A comparable proportion of patients in both groups developed anti-asparaginase antibodies before the start of the post-induction treatment phase (L-Asgen 10,000 IU 54.6% vs. reference E. coli-asparaginase 52.5%). The majority of anti-asparaginase antibodies developed in the time gap between the last asparaginase infusion on day 33 and start of post-induction treatment at day 79.
No anti-asparaginase antibodies were detected in any of the 12 infants <1 year of age during treatment with L-Asgen 10,000 IU (study MC-ASP.6/INF).
Hypothyroidism: There have been reports of transitory secondary hypothyroidism probably caused by a decrease in the serum thyroxin-binding globulin due to asparaginase-induced protein synthesis inhibition.
Hypoalbuminaemia: As a result of impaired protein synthesis, the serum protein level (especially albumin) decreases very commonly in patients treated with asparaginase (see Precautions). As a consequence of hypoalbuminaemia oedema can occur.
Dyslipidemia: Mild to moderate changes in blood lipid values (e.g. increased or decreased cholesterol, increased triglyceride, increased VLDL fraction and decreased LDL, increased lipoprotein lipase activity) are very commonly observed in patients treated with asparaginase, which in most cases present without clinical symptoms. Concomitant administration of glucocorticoids may be a contributing factor. However, in rare cases severe hypertriglyceridaemia (triglycerides >1,000 mg/dL) has been reported which increases the risk of development of acute pancreatitis. Asparaginase-associated hyperlipidaemia should be treated depending on its severity and on clinical symptoms.
Hyperammonaemia: Hyperammonaemia has been reported uncommonly in patients treated with asparaginase-containing therapy protocols, especially if patients suffer additionally from hepatic impairment. In very rare cases, severe hyperammonaemia has been reported which may induce neurologic disorders such as seizures and coma.
Hyperglycaemia and hypoglycaemia: Changes in endocrine pancreatic function are observed very commonly during treatment with asparaginase and manifest predominantly as hyperglycaemia. These events are usually transient.
In rare cases, diabetic ketoacidosis has been reported.
Hypoglycaemia mostly without clinical symptoms has been commonly observed in patients treated with asparaginase. The mechanism leading to this reaction is unknown.
Nervous system disorders: Adverse central nervous system reactions observed in patients treated with asparaginase-containing therapy protocols include changes in EEG, seizures, dizziness, somnolence, coma and headache.
The causes of these nervous system disorders are unclear. Hyperammonaemia and sinus vein thrombosis may need to be excluded.
In rare cases, RPLS has been observed during therapy with asparaginase-containing regimens.
Gastrointestinal disorders: Nausea/vomiting are very commonly observed in patients treated with asparaginase-containing treatment regimens but are usually mild. Anorexia, loss of appetite, abdominal cramps, diarrhoea and weight loss have also been reported.
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. A few cases of asparaginase-induced parotitis have been reported in the literature.
Paediatric population: Data on safety of L-Asgen 10,000 IU in infants <1 year of age is limited.
Adults and other special populations: Qualitatively, the same asparaginase-induced adverse drug reactions are observed in adults and children; however, some of these undesirable effects (e.g. thromboembolic events) are known to occur with a higher frequency in adult patients compared to the paediatric population.
Because of a higher frequency of comorbidities such as liver and/or renal impairment, patients >55 years of age usually tolerate asparaginase treatment worse than paediatric patients.

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 Precautions and Adverse Reactions).
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 Adverse Reactions).
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 Precautions).
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.
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 methotrexate.
Cytarabine: Laboratory in vitro and in vivo data indicate that the efficacy of high-dose cytarabine is reduced by prior administration of asparaginase. However, when asparaginase was given after cytarabine a synergistic effect was observed. This effect was most prominent with a treatment interval of about 120 hours.
Vaccination: Concomitant vaccination with live vaccines increases the risk of serious infection. Immunisation with live vaccines should therefore take place at the earliest 3 months after completion of the course of antileukaemic treatment.

Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Special precautions for disposal and other handling: Parenteral drugs products should be inspected visually for particulate matter and discoloration prior to administration.
For Intravenous Use: Reconstitute with sterile water for injection or with sodium chloride injection. The volume for reconstitution is 5 mL for the 10,000 IU unit vial. Ordinary shaking during reconstitution does not inactivate the enzyme. The solution may be used for direct intravenous administration with eight hour period following restoration. For administration by infusion, solutions should be diluted with isotonic solution, sodium chloride injection or dextrose injection 5%. These solutions should be infused within eight hours and only if clear.
The solution should be clear without any visible particles. Fine crystalline or thread-like wisps of protein aggregates may be visible if shaking is excessive. If there are any visible particles or protein aggregates present the reconstituted solution should be rejected.
The solution should be administered within 15 minutes of reconstitution. If a delay of more than 15 minutes between reconstitution and administration is unavoidable, the solution should be withdrawn into a glass or polypropylene syringe for the period of the delay. The solution should be used within 8 hours.
L-asparaginase is not a cytotoxic drug (such as vincristine or methotrexate) and does not require the special precautions needed for manipulating such agents.
It should be handled in the same way as other therapeutic enzymes such as hyaluronidase.
Any unused product or waste material should be disposed of in accordance with local requirements.

Shelf life: Proposed Shelf life (after reconstitution or dilution): The solution should be administered within 15 minutes of reconstitution. If a delay of more than 15 minutes between reconstitution and administration is unavoidable, the solution should be withdrawn into a glass or polypropylene syringe for the period of the delay. The solution should be used within 8 hours.
Proposed Storage Conditions: Store unused or unopened vials and cartons at 36°F to 46°F (2°C to 8°C).
Special precautions for storage: Store in a refrigerator (2°C-8°C).
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see Shelf life as previously mentioned.

Cytotoxic Chemotherapy

L01XX02 - asparaginase ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.

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