L-Asgen 10,000 IU Adverse Reactions

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.