Section 4.8 Undesirable effects has been updated. The following has been added to the frequency table of undesirable effects
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Not known
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Cannot be estimated from the available data
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The following section in the Table has been updated:
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Blood and lymphatic system disorders (see additional information below the table)
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Very common:
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Anaemia, thrombocytopenia.
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Common:
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Leucopenia, coagulation disorders including disseminated intravascular coagulation.
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Rare:
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Agranulocytosis, aplastic anaemia, haemolytic anaemia.
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Not known:
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Eosinophilia (see additional information below the table).
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Capillary leak syndromeCardiac arrhythmias (supraventricular and ventricular), angina pectoris, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, oedema and mental status changes may be associated with capillary leak syndrome (see section 4.4
Severe manifestations of eosinophilia
During treatment most patients experience lymphocytopenia and eosinophilia with a rebound lymphocytosis within 24 to 48 hours following treatment. These may be related to the mechanism of antitumour activity of Proleukin. Severe manifestations of eosinophilia have been reported, involving eosinophilic infiltration of cardiac and pulmonary tissues.
The following has been updated in 5.2 Pharmacokinetic properties
The pharmacokinetic parameters of IL-2, following an intravenous or subcutaneous administration of aldesleukin in metastatic renal cell carcinoma and metastatic malignant melanoma patients is as follows:
The subcutaneous kinetics can be described by a one-compartment model. The IL-2 absorption half-life is 45 minutes, while the elimination half-life is 3-5 hours. The longer half-life estimate, compared with the intravenous result is likely due to continued absorption of IL-2 from the subcutaneous injection site during the plasma elimination phase. Absolute bioavailability of subcutaneous aldesleukin ranges between 31-47%.
Following a continuous intravenous infusion-fixed and continuous intravenous infusion-decrescendo administration of aldesleukin, the mean tmax of IL-2 was 11 hours and 4.4 hours, respectively. Compared to the serum levels following the subcutaneous administration, the observed serum levels following the continuous intravenous infusion-fixed and continuous intravenous infusion-decrescendo administration of aldesleukin are 3.20 and 1.95-fold higher.
Elimination
The kidney is the major clearance route of recombinant IL-2 (rIL-2) in animals, and most of the injected dose is metabolized in the kidney with no biologically active aldesleukin appearing in the urine. A secondary elimination pathway is IL-2 receptor- mediated uptake. This active process is induced after chronic dosing. After an aldesleukin-free period between dosing cycles (9-16 days), the clearance of IL-2 is restored to its original value.
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