Chemical formula: C₁₃₇₇H₂₂₀₈N₃₈₂O₄₄₂S₁₇ PubChem compound: 5460875
Asparaginase interacts in the following cases:
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.
Concomitant use of glucocorticoids and/or anticoagulants with asparaginase may increase the risk of a change in coagulation parameters. 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.
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.
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.
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.
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.
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.
During treatment with asparaginase-containing regimens, myelosuppression, potentially affecting all three cell lines, 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.
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.
In rare cases severe liver impairment has been described, including cholestasis, icterus, hepatic necrosis and hepatic failure with fatal outcome. 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).
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.
Reversible posterior leukoencephalopathy syndrome (RPLS) may occur rarely during treatment with any asparaginase. 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.
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.
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. Based on results from animal studies and its mechanism of action, asparaginase should not be used during pregnancy unless the clinical condition of the woman requires treatment with asparaginase.
It is unknown whether asparaginase is excreted into human breast milk. Because potential serious adverse reactions may occur in nursing infants, asparaginase should be discontinued during breast-feeding.
Women of childbearing potential have to use effective contraception and avoid becoming pregnant while being treated with asparaginase-containing chemotherapy. 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. Men should use effective contraceptive measures and be advised to not father a child while receiving asparaginase. The time period following treatment with asparaginase when it is safe to become pregnant or father a child is unknown. As a precautionary measure it is recommended to wait for three months after completion of treatment. However, treatment with other chemotherapeutic agents should also be taken into consideration.
No human data on the effect of asparaginase on fertility are available.
Asparaginase has moderate influence on the ability to drive and use machines, especially through its potential effects on the nervous and gastrointestinal systems.
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 side effects of asparaginase 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 side effects of asparaginase 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 asparaginase is usually used in combination therapy with other antineoplastic agents, the demarcation from undesirable effects of other medicinal products is often difficult.
The following adverse reactions, in list 1, have been accumulated from clinical trials with asparaginase 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 list 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).
List 1:
Not known: Infections
Common: Disseminated intravascular coagulation (DIC), anaemia, leukopenia, thrombocytopenia
Very common: Hypersensitivity including flushing, rash, hypotension, oedema/angioedema, urticaria, dyspnoea
Common: Hypersensitivity including bronchospasm
Rare: Anaphylactic shock
Very rare: Secondary hypothyroidism, hypoparathyroidism
Very common: Hyperglycaemia, hypoalbuminaemia
Common: Hypoglycaemia, decreased appetite, weight loss
Uncommon: Hyperuricaemia, hyperammonaemia
Rare: Diabetic ketoacidosis
Common: Depression, hallucination, confusion
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
Common: Thrombosis especially cavernous sinus thrombosis or deep vein thrombosis, haemorrhage
Very common: Diarrhoea, nausea, vomiting, abdominal pain
Common: Acute pancreatitis
Rare: Haemorrhagic pancreatitis, necrotising pancreatitis, parotitis
Very rare: Pancreatitis with fatal outcome, pancreatic pseudocyst
Rare: Hepatic failure with potentially fatal outcome, hepatic necrosis, cholestasis, jaundice
Not known: Hepatic steatosis
Very common: Oedema, fatigue
Common: Pain (back pain, joint pain)
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)
Asparaginase 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 (list 2).
List 2. Frequency of patients with allergic reactions (MC-ASP.5/ALL; Safety analysis set):
| Treatment group | Asparaginase (study) | Reference asparaginase |
|---|---|---|
| Number of patients | 97 | 101 |
| Allergic reactions within 12 hours after asparaginase infusion during induction treatment | 2 (2.1%) | 5 (5.0%) |
| Any allergic event* within 24 hours after asparaginase infusion during induction treatment | 16 (16%) | 24 (24%) |
* Including all allergic reactions within 12 hours after asparaginase infusion and all adverse events with CTCAE terms syncope (fainting), hypotension, rash, flushing, pruritus, dyspnoea, injection site reaction or airway obstruction within 24 hours after asparaginase infusion
No allergic reactions were observed in any of the 12 infants <1 year of age during treatment with asparaginase (study MC-ASP.6/INF).
In case of occurrence of allergic symptoms, administration of asparaginase should be discontinued immediately.
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 asparaginase 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 (asparaginase 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 asparaginase (study MC-ASP.6/INF).
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.
As a result of impaired protein synthesis, the serum protein level (especially albumin) decreases very commonly in patients treated with asparaginase. As a consequence of hypoalbuminaemia oedema can occur.
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 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.
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.
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, a reversible posterior leukoencephalopathy syndrome (RPLS) has been observed during therapy with asparaginase-containing regimens.
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.
Data on safety of asparaginase in infants <1 year of age is limited.
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
