Expiration date: 01/2025
Product form, composition and packaging
Lyophilizate for the preparation of a solution for I / V administration in the form of a porous mass of almost white color.
1 vial:
fludarabine phosphate 50 mg
Excipients: mannitol-50 mg, sodium hydroxide-up to pH 7.6.
Clinico-pharmacological group: Antineoplastic drug
Pharmaco-therapeutic group: Antineoplastic agent, antimetabolite
Pharmacological action
Anticancer drug. Contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent, vidarabine, 9-?-D-arabinofuranosyladenine (Ara-A), which is relatively resistant to deamination by adenozindezaminazy.
In the human body fludarabine phosphate quickly dephosphorylated to 2-fluoro-Ara-A, which is captured by cells, then intracellularly phosphorylated to the active triphosphate (2-fluoro-Ara-ATP). This metabolite inhibits RNA reductase, DNA polymerase (alpha, Delta and Epsilon), DNA primase and DNA ligase, which leads to disruption of DNA synthesis. In addition, RNA polymerase K is partially inhibited, followed by a decrease in protein synthesis.
Pharmacokinetics
Suction
Fludarabine phosphate (2-fluoro-Ara-AMP) is a water-soluble precursor of fludarabine (2-fluoro-Ara-A).
In patients with chronic lymphocytic leukemia after a single infusion of a standard dose of the drug for 30 minutes Cmax fludarabine in plasma equal to 3.5-3.7 microns is achieved by the end of the infusion. After 5 injections of the drug revealed a moderate increase in Cmax to 4.4-4.8 microns at the end of the infusion.
The maximum level of fludarabine triphosphate (2-fluoro-Ara-ATP) in leukemic lymphocytes of patients with chronic lymphocytic leukemia is noted, on average, to 4 hours and is characterized by significant individual variability.
Distribution
Binding to plasma proteins is insignificant.
Accumulation of fludarabine after several cycles of therapy can be excluded. The concentration of fludarabine triphosphate in leukemic cells is much higher than in plasma, indicating its accumulation in tumor cells.
Metabolism
In the human body fludarabine phosphate quickly and completely dephosphorylated to the nucleoside fludarabine, which is transported to leukemic cells, where it is refosforylated to monophosphate and partially to di - and triphosphate - the main intracellular metabolite fludarabine, which has cytotoxic activity.
Breeding
After the end of infusion observed three-phase reduction in the concentration of fludarabine with T1/2 initial phase about 5 min., intermediate - 1-2 h and terminal - about 20 hours T1/2 of fludarabine triphosphate of target cells is, on average, from 15 to 23 h. fludarabine is excreted primarily in the urine (40-60% in/in the dose imposed).
Pharmacokinetics in special clinical cases
In persons with reduced renal function there is a decrease in total clearance, indicating the need to reduce the dose.
There was no clear correlation between the pharmacokinetics of fludarabine and its therapeutic effect in cancer patients, with the frequency of detection of neutropenia and hematocrit changes - dose-dependent.
