Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Atnahs Pharma UK Limited., Sovereign House, Miles Gray Road, Basildon, Essex, SS14 3FR, United Kingdom
LEUSTAT Injection (cladribine) is a synthetic antineoplastic agent.
The selective toxicity cladribine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase, deoxynucleotidase and adenosine deaminase. It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by cladribine as toxic deoxynucleotides accumulate intracellularly.
Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks. LEUSTAT Injection can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.
When LEUSTAT Injection was given by continuous intravenous infusion over 7 days the mean steady-state serum concentration was estimated to be 5.7 ng/ml with an estimated systemic clearance of 663.5 ml/h/kg. Accumulation of LEUSTAT over the seven day treatment period was not noted.
Plasma concentrations are reported to decline multi-exponentially after intravenous infusions with terminal half-lives ranging from approximately 3-22 hours. In general, the apparent volume of distribution of cladribine is very large (mean approximately 9l/kg), indicating an extensive distribution of cladribine in body tissues. The mean half-life of cladribine in leukaemic cells has been reported to be 23 hours.
There is little information available on the metabolism or route of excretion of cladribine in man. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumours during a 5-day continuous intravenous infusion of 3.5-8.1 mg/m²/day of LEUSTAT. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.
Cladribine penetrates into cerebrospinal fluid. One report indicates that concentrations are approximately 25% of those in plasma.
Cladribine is bound approximately 20% to plasma proteins.
No animal carcinogenicity studies have been conducted with cladribine. However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of cladribine. Cladribine induced chromosomal effects when tested in both an in vivo bone marrow micronucleus assay in mice and an in vitro assay using CHO-WBL cells. Cladribine is mutagenic in mammalian cells in culture. Cladribine was not mutagenic to bacteria and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures.
Other preclinical safety data has been included in specific sections of SPC.
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