Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The adverse reactions described in this section are derived from clinical studies data and post-marketing experience of Oncaspar in ALL patients. The safety profile is based on randomised, controlled, prospective, open label multicentre studies using Oncaspar at a dose of 2500 U/m2 administered intravenously as a comparative treatment (studies DFCI 11-001 and AALL07P4). In addition, the safety profile included data from other Oncaspar studies such as the study comparing the pharmacokinetics of the liquid and lyophilized formulations of pegaspargase (CL2-95014-002), its roll over study (CL2-95014-003) and studies using the intramuscular route of administration (studies CCG-1962 and CCG-1991) were also considered to determine the safety profile (see section 5.1 for CCG-1962 and CCG-1991).

The most common adverse reactions with Oncaspar (observed in at least 2 studies with a frequency of >10%) included: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, activated partial thromboplastin time prolonged, hypertriglyceridaemia, hyperglycaemia, and febrile neutropenia.

The most common, severe adverse reactions with Oncaspar (graded 3 or 4) observed in studies DFCI 11-001 and AALL07P4 with a frequency of >5% included: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, febrile neutropenia, hyperglycaemia, lipase increased, and pancreatitis.

Tabulated list of adverse reactions
Adverse reactions and their frequencies are reported in Table 1. Frequencies are defined by 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Adverse reactions reported with Oncaspar therapy
MedDRA standard
Adverse reaction system organ class
Infections and infestations Common: Infections, sepsis
Very common: Febrile neutropenia
Blood and lymphatic system disorders            Common: Anaemia, coagulopathy
Not known: Bone marrow failure
Very common: Hypersensitivity, urticaria, anaphylactic reaction
Immune system disorders
Not known: Anaphylactic shock
Very common: Decreased appetite, hyperglycaemia
Metabolism and nutrition
Common: Hyperlipidaemia, hypercholesterolaemia disorders
Not known: Diabetic ketoacidosis, hypoglycaemia
Psychiatric disorders       Not known: Confusional state
Common: Seizure, peripheral motor neuropathy, syncope
Nervous system disorders Rare: Posterior reversible leukoencephalopathy syndrome Not known: Somnolence, tremor*
Very common: Embolism**

Vascular disorders           Common: Thrombosis***
Not known: Cerebrovascular accident, haemorrhage, superior sagittal sinus thrombosis
Respiratory, thoracic and
Common: Hypoxia mediastinal disorders
Very common: Pancreatitis, diarrhoea, abdominal pain, nausea

Gastrointestinal disorders   Common: Vomiting, stomatitis, ascites
Rare: Pancreatitis necrotising, pancreatitis haemorrhagic
Not known: Pancreatic pseudocyst, parotitis*
Common: Hepatotoxicity, fatty liver
Hepatobiliary disorders      Rare: Hepatic necrosis, jaundice, cholestasis, hepatic failure Not known: Veno-occlusive disease
Skin and subcutaneous        Very common: Rash tissue disorders             Not known: Toxic epidermal necrolysis*
Musculoskeletal and          Common: Pain in extremities connective tissue
Not known: Osteonecrosis (see sections 4.4 and 4.5) disorders
Renal and urinary
Not known: Renal failure acute* disorders
General disorders and administration site          Not known: Pyrexia conditions
Very common: Weight decreased, hypoalbuminaemia, alanine aminotransferase increased, aspartate aminotransferase increased,
hypertriglyceridaemia, blood fibrinogen decreased, lipase increased,
amylase increased, activated partial thromboplastin time prolonged, blood Investigations               bilirubin increased antithrombin III decreased****, neutrophil count decreased****
Common: Prothrombin time prolonged. international normalised ratio increased, hypokalaemia, blood cholesterol increased,
hypofibrinogenaemia, gamma-glutamyl transferase increased


Not known: Blood urea increased, anti-pegaspargase antibodies, platelet count decreased, hyperammonaemia

*Adverse reactions observed with other asparaginases in the class
**Cases of pulmonary embolism, venous thrombosis, venous thrombosis limb, and thrombophlebitis superficial were observed in DFCI 11-001
***Legend: CNS thrombosis
**** Cases of antithrombin III and neutrophil count decreased were observed in CL2-95014-002 and CL2-95014-003 studies

Description of selected adverse reactions
The following adverse reactions have been observed in association with asparaginase therapy.
Although they have not been specifically associated with the use or pegaspargase, they may occur with the use of Oncaspar:

Blood and lymphatic system disorders
Oncaspar can cause mild to moderate myelosuppression, and all three blood cell lines can be affected.
About half of all serious haemorrhages and thromboses affect cerebral vessels and can lead to e.g., stroke, seizure, headache or loss of consciousness.

Nervous system disorders
Oncaspar may cause central nervous system dysfunctions manifesting as convulsions, and less frequently confusional state and somnolence (mildly impaired consciousness).
In rare cases, a reversible posterior leukoencephalopathy syndrome (RPLS) may occur.
In very rare cases, mild tremor in the fingers has been described.

Gastrointestinal disorders
About half of patients develop mild to moderate gastrointestinal reactions such as loss of appetite, nausea, vomiting, abdominal cramps, diarrhoea and weight loss.
Acute pancreatitis can occur commonly. There have been isolated reports of formation of pseudocysts (up to four months after the last treatment).

Haemorrhagic or necrotising pancreatitis occurs rarely. One case of pancreatitis with simultaneous acute parotitis has been described with L-asparaginase treatment. In single cases, haemorrhagic or necrotising pancreatitis with fatal outcome has been reported.
Serum amylase can rise during and also after the conclusion of Oncaspar therapy.

Renal and urinary disorders
Acute renal failure may develop in rare cases during treatment with L-asparaginase-containing regimens.

Skin and subcutaneous tissue disorders
Allergic reactions can manifest on the skin. One case of toxic epidermal necrolysis (Lyell‘s syndrome) has been described in association with L-asparaginase.

Endocrine disorders
Alterations in endocrine pancreatic function are observed commonly and are expressed mainly in the form of abnormal glucose metabolism. Both diabetic ketoacidosis and hyperosmolar hyperglycaemia have been described, which generally respond to administration of insulin.

Metabolism and nutrition disorders
An alteration in serum lipid levels was observed and changes in serum lipid values, in most cases without clinical symptoms, are very common.
A rise in serum urea occurs regularly, is dose-independent and nearly always a sign of pre-renal metabolic imbalance.

General disorders and administration site conditions
Pyrexia can occur after the injection, which usually subsides spontaneously.

Immune system disorders
Specific antibodies to pegaspargase have been detected; uncommonly they were associated with hypersensitivity reactions. Neutralising antibodies reducing clinical efficacy were also recorded.

Hypersensitivity reactions to Oncaspar, including life-threatening anaphylaxis, angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnoea, pruritus and rash, can occur during therapy (see sections 4.3 and 4.4).

Hepatobiliary disorders
Alteration of liver parameters is common. A dose-independent rise in serum transaminases, and serum bilirubin is commonly observed.

A rapid weight gain, fluid retention with ascites, hepatomegaly, associated with rapid increase of serum bilirubin and persistent thrombocytopenia might indicate a risk of developing a severe VOD, which if left untreated, can be fatal (see section 4.4).

Fatty liver can be observed very frequently. There have been rare reports of cholestasis, icterus, hepatic cell necrosis and hepatic failure with fatal outcome.

Impaired protein synthesis can lead to a decline in the serum proteins. There is a dose-independent decrease in serum albumin in the majority of patients during the treatment.

The types of adverse reactions with Oncaspar are similar to those observed with native non-pegylated L-asparaginase (e.g., native E. coli asparaginase).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il