Pegaspargase interacts in the following cases:
Simultaneous vaccination with live vaccines may increase the risk of severe infections attributable to the immunosuppressive activity of pegaspargase, the presence of the underlying disease and combination chemotherapy. Vaccination with live vaccines should therefore be given no earlier than 3 months after termination of the entire antileukaemic treatment.
Combination therapy with pegaspargase and hepatotoxic products can result in severe hepatic toxicity.
Caution is required when pegaspargase is given in combination with hepatotoxic products, especially if there is pre-existing hepatic impairment. Patients should be monitored for changes in liver function parameters.
The use of pegaspargase can lead to fluctuation in coagulation factors. This can promote the tendency to bleeding and/or thrombosis. Caution is therefore needed when anticoagulants such as coumarin, heparin, dipyridamole, acetylsalicylic acid or non-steroidal anti-inflammatory medicinal products are given concomitantly, or when concomitant chemotherapy regimen including methotrexate, daunorubicin, corticosteroids is administered.
An indirect interaction cannot be ruled out between pegaspargase and oral contraceptives due to pegaspargase hepatotoxicity that may impair the hepatic clearance of oral contraceptives. Therefore, the concomitant use of pegaspargase with oral contraceptives is not recommended. Another method than oral contraception should be used in women of childbearing potential.
When glucocorticoids (e.g., prednisone) and pegaspargase are given at the same time, alterations in coagulation parameters (e.g., fall in fibrinogen and antithrombin III deficiency, ATIII) can be more pronounced.
By inhibiting protein synthesis and cell division, pegaspargase can disturb the mechanism of action of other substances which require cell division for their effect, e.g., methotrexate. Methotrexate and cytarabine can interact differently with pegaspargase: their prior administration can increase the action of pegaspargase synergistically. If these substances are given subsequently, the effect of pegaspargase can be weakened antagonistically.
Immediately preceding or simultaneous treatment with vincristine can increase the toxicity of pegaspargase. Administration of pegaspargase before vincristine may increase the neurotoxicity of vincristine. Therefore, vincristine should be given at least 12 hours prior to administration of pegaspargase in order to minimise toxicity.
There may be an increased risk of hepatotoxicity in Philadelphia chromosome positive patients, for whom treatment with tyrosine kinase inhibitors (e.g., imatinib) is combined with L-asparaginase therapy. This should be taken into account when considering the use of pegaspargase in these patient populations.
There are limited data on the use of L-asparaginase and no data on the use of pegaspargase in pregnant women. No reproduction studies in animals with pegaspargase were performed but studies in animals with L-asparaginase have shown teratogenicity. Therefore and due to its pharmacological properties, pegaspargase should not be used during pregnancy unless the clinical conditions of the woman require treatment with pegaspargase.
It is not known whether pegaspargase is excreted into breast milk. Based on its pharmacological properties, any risk to the breast-fed newborns/infants cannot be excluded. As a precautionary measure, breast-feeding should be discontinued during treatment with pegaspargase and should not be restarted until after discontinuation of pegaspargase.
Men and women should use effective contraception during treatment and for at least 6 months after pegaspargase discontinuation. Since an indirect interaction between oral contraceptives and pegaspargase cannot be ruled out, oral contraceptives are not considered sufficiently safe in such clinical situation. A method other than oral contraception should be used in women of childbearing potential.
No studies investigating the effect of pegaspargase on fertility have been performed.
Pegaspargase has major influence on the ability to drive and use machines. The following adverse reactions have been reported in patients treated with pegaspargase along with other chemotherapy medicinal products: somnolence, confusion, dizziness, syncope, seizure.
Patients should be advised not to drive or operate machines while receiving pegaspargase if they experience these or other adverse reactions which can impair their ability to drive or operate machines.
The adverse reactions described in this section are derived from clinical trial data and post-marketing experience of pegaspargase in ALL patients. The safety profile is based on randomised, controlled, prospective, open label multicentre studies using pegaspargase at a dose of 2500 U/m 2 administered intravenously as a comparative treatment (studies DFCI 11-001 and AALL07P4). In addition, pegaspargase studies using the intramuscular route of administration (studies CCG-1962 and CCG-1991) were also considered to determine the safety profile.
The most common adverse reactions with pegaspargase (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 pegaspargase (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.
Adverse reactions and their frequencies are reported below. 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.
Adverse reactions reported with pegaspargase therapy:
Very common: Febrile neutropenia
Common: Anaemia, coagulopathy
Not known: Bone marrow failure
Very common: Pancreatitis, diarrhoea, abdominal pain, nausea
Common: Vomiting, stomatitis, ascites
Rare: Pancreatitis necrotising, pancreatitis haemorrhagic
Not known: Pancreatic pseudocyst, parotitis*
Not known: Pyrexia
Common: Hepatotoxicity, fatty liver
Rare: Hepatic necrosis, jaundice, cholestasis, hepatic failure
Very common: Hypersensitivity, urticaria, anaphylactic reaction
Not known: Toxic epidermal necrolysis*
Common: Infections, sepsis
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 bilirubin increased
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, neutrophil count decreased, platelet count decreased, hyperammonaemia
Very common: Decreased appetite, hyperglycaemia
Common: Hyperlipidaemia, hypercholesterolaemia
Not known: Diabetic ketoacidosis, hypoglycaemia
Common: Pain in extremities
Common: Seizure, peripheral motor neuropathy, syncope
Rare: Posterior reversible leukoencephalopathy syndrome
Not known: Somnolence, tremor*
Not known: Confusional state
Not known: Renal failure acute*
Common: Hypoxia
Very common: Rash
Very common: Embolism**
Common: Thrombosis***
Not known: Cerebrovascular accident, haemorrhage, superior sagittal sinus thrombosis
* 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
The following adverse reactions have been observed in association with asparaginase therapy. Although they have not been specifically associated with the use of pegaspargase, they may occur with the use of pegaspargase:
Pegaspargase 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.
Pegaspargase 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.
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 pegaspargase therapy.
Acute renal failure may develop in rare cases during treatment with L-asparaginase-containing regimens.
Allergic reactions can manifest in the skin. One case of toxic epidermal necrolysis (Lyell’s syndrome) has been described in association with L-asparaginase.
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.
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.
Pyrexia can occur after the injection, which usually subsides spontaneously.
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 pegaspargase, including life-threatening anaphylaxis, angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnoea, pruritus and rash, can occur during therapy.
Alteration of liver parameters is common. A dose-independent rise in serum transaminases, and serum bilirubin is commonly observed.
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 type of adverse reactions of pegaspargase is similar with that of native non-pegylated L-asparaginase (e.g., native E. coli asparaginase).
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