Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Lipomed GmbH, Hegenheimer Strasse 2, D-79576, Weil/Rhein, Germany
Pharmacotherapeutic group: Purine analogues
ATC code: L01BB04
Cladribine is a purine nucleoside analogue acting as an antimetabolite. The single substitution of hydrogen for chlorine at position 2 distinguishes cladribine from its natural counterpart 2'-deoxyadenosine and renders the molecule resistant to deamination by adenosine deaminase.
Cladribine is a prodrug which is taken up rapidly in cells after parenteral administration, and is phosphorylated intracellularly to the active nucleotide 2-chlorodeoxyadenosine-5'-triphosphate (CdATP) by deoxycytidine kinase (dCK). An accumulation of active CdATP is observed predominantly in cells with a high dCK activity and a low deoxynucleotidase activity, particularly in lymphocytes and in other haematopoietic cells. The cytotoxicity of cladribine is dose-dependent. Non-haematologic tissues seem to be unaffected, explaining the low incidence of non-haematopoietic toxicity of cladribine
Unlike other nucleoside analogues, cladribine is toxic in rapidly proliferating cells as well as in resting cells. No cytotoxic effect of cladribine could be observed in cell lines of solid tumours. The mechanism of action of cladribine is attributed to the incorporation of CdATP into DNA strands: the synthesis of new DNA in dividing cells is blocked and the DNA repair mechanism is inhibited, resulting in an accumulation of DNA strand breaks and a decrease of NAD (nicotinamide adenine dinucleotide) and ATP concentration, even in resting cells. Furthermore, CdATP inhibits ribonucleotide reductase, the enzyme responsible for the conversion of ribonucleotides into deoxyribonucleotides. Cell death occurs from energy depletion and apoptosis.
In the clinical trial using LITAK subcutaneously, 63 patients with hairy cell leukaemia (33 newly diagnosed patients and 30 patients with relapsed or progressive disease) were treated. The overall response rate was 97% with long-lasting remission, with 73% of patients staying in complete remission after four years follow-up time.
Cladribine shows complete bioavailability after parenteral administration; the mean area under the plasma concentration versus time curve (AUC) is comparable after continuous or intermittent 2-hour intravenous infusion and after subcutaneous injection.
After subcutaneous bolus injection of a 0.14 mg/kg cladribine dose, a Cmax of 91 ng/ml is reached on average after 20 minutes only. In another study using a dose of 0.10 mg/kg body weight/day, the maximum plasma concentration Cmax after continuous intravenous infusion was 5.1 ng/ml (tmax: 12 hours) compared to 51 ng/ml after subcutaneous bolus injection (tmax: 25 minutes).
Intracellular concentration of cladribine exceeds its plasma concentration by 128 to 375 times.
The mean volume of distribution of cladribine is 9.2 l/kg. Plasma protein binding of cladribine is 25% on average, with a wide interindividual variation (5-50%).
The prodrug cladribine is metabolised intracellularly, predominantly by deoxycytidine kinase, to 2-chlorodeoxyadenosine-5'-monophosphate, that is further phosphorylated to the diphosphate by nucleoside monophosphate kinase and to the active metabolite 2-chlorodeoxyadenosine-5'-triphosphate (CdATP) by nucleoside diphosphate kinase.
Pharmacokinetic studies in humans showed that the plasma concentration curve of cladribine fits a 2- or 3-compartment model with α- and β-half-lives of on average 35 minutes and 6.7 hours, respectively. The biexponential decline of the serum concentration of cladribine after subcutaneous bolus injection is comparable to elimination parameters after 2-hour intravenous infusion with an initial and terminal half-life of approximately 2 hours and 11 hours, respectively. The intracellular retention time of cladribine nucleotides in vivo is clearly prolonged as compared to the retention time in the plasma: Half-lives t1/2 of initially 15 hours and subsequently more than 30 hours were measured in leukaemic cells.
Cladribine is eliminated mainly by the kidneys. The renal excretion of unmetabolised cladribine occurs within 24 hours and accounts for 15% and 18% of the dose after 2-hour intravenous and subcutaneous administration, respectively. The fate of the remainder is unknown. The mean plasma clearance amounts to 794 ml/min after intravenous infusion and to 814 ml/min after subcutaneous bolus injection at a dose of 0.10 mg/kg body weight/day.
There are no studies available using cladribine in patients with renal or hepatic impairment (see also section 4.2 and section 4.4). Clinical experience is very limited and safety of LITAK in these patients is not well established. LITAK is contraindicated in patients with moderate to severe renal impairment or with moderate to severe hepatic impairment (see section 4.3).
The use of LITAK in children has not been investigated (see section 4.2).
Experience with patients older than 65 years is limited. Elderly patients should be treated by individual assessment and careful monitoring of the blood counts and of the renal and hepatic function.
Cladribine is moderately acutely toxic to mice, with an LD50 of 150 mg/kg by intraperitoneal administration.
In 7- to 14-day continuous intravenous infusion studies in cynomolgus monkeys, the target organs were the immune system (≥0.3 mg/kg/day), bone marrow, skin, mucous membranes, nervous system and testes (≥0.6 mg/kg/day) and kidneys (≥1 mg/kg/day). Unless fatal, indications were that most or all of these effects would be slowly reversible upon cessation of exposure.
Cladribine is teratogenic in mice (at doses of 1.5-3.0 mg/kg/day, given on gestation days 6-15). Effects on sternal ossification were seen at 1.5 and 3.0 mg/kg/day. Increased resorptions, reduced live litter sizes, reduced foetal weights and increased foetal malformations of the head, trunk and appendages were seen at 3.0 mg/kg/day. In rabbits, cladribine is teratogenic at doses of 3.0 mg/kg/day (given on gestation days 7-19). At this dose, severe limb anomalies were seen as well as a significant decrease in the mean foetal weight. Reduced ossification was observed at 1.0 mg/kg/day.
Long-term studies in animals to evaluate the carcinogenic potential of cladribine have not been conducted. On the basis of available data, no evaluation can be made of the carcinogenic risk of cladribine to humans.
Cladribine is a cytotoxic medicinal product, which is mutagenic to cultured mammalian cells. Cladribine is incorporated into DNA strands and inhibits DNA synthesis and repair. Exposure to cladribine induces DNA fragmentation and cell death in various normal and leukaemic cells and cell lines at concentrations of 5 nM to 20 µM.
The effects of cladribine on fertility have not been studied in animals. However, a toxicity study conducted with cynomolgus monkeys has shown that cladribine suppresses maturation of rapidly generating cells, including testicular cells. The effect on human fertility is unknown. Antineoplastic agents, such as cladribine, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on human gametogenesis (see sections 4.4 and 4.6).
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