LEUCLADINE(injection solution 0.1%)
Solutio Leucladini 0,1 % pro injectionibus
International nonproprietary name (INN)
1 ml of the solution for injections contains 1 mg of leucladine (cladribin).
Leucoladine (2-chlorine-2’-deoxyadenosine) is an analogue of 2’-deoxyadenosine, the component of DNA molecule . lymphoid cells are more sensitive to leucladine than non-lymphoid ones because the former are characterized by higher level of deoxycytidinekinase and lower level of 5’-nucleotidases activity. Leucladine develops cytotoxic action towards dividing and non-dividing cells inhibiting DNA synthesis and repair.
Cytotoxic action is based on active metabolite activity of 5’triphosphate2chlorine-2’- deoxyadenosine.
The drug action is bound to inhibition of ribonucleotide reductase catalyzing reaction of desoxinucleoside triphosphates required for DNA synthesis. DNA synthesis terminates either due to DNA-polymerase inhibition. Further, 5’triphosphate2chlorine-2’- deoxyadenosine activates specific endonuclease that results in single-stranded DNA breakage. Saidconditionscausefurthercellloss.
Possible administration of leucladine in disseminated sclerosis therapy is based on combination of higher immunosuppression activity and rather lower (against other immunosuppressants) toxicity, either towards hemopoietic stem cells. Apparent immunosuppression activity of leucladine is provided, primarily, by its selective and prolonged effect on T-cells. Inhibiting CD4 antigen expression under sparing effect on CD8, leucladine reduces significantly (by 4 times) and for a long period (several months) their ratio.
Leucladine in disseminated sclerosis stabilizes patient state (blocks depression of stem disorder, coordinative disorder, favors stabilization of functional conditions of pyramidal system), and in certain cases enhances the reduction of invalidation. Against drug course of treatment there is evidence of the reduction of demyelinization nidus and the extension of oligocloned proliferations in samples of cerebrospinal fluid.
I.v.injectionТ1/2 — 5.7 – 19.7 h. Drugconcentrationincerebrospinalfluidis 25% ofitsplasmaconcentration. The drug is mainly excreted with urine, insignificantly (less 1%) with faeces.
The drug undergoes intracellular metabolism. At the initial phase deoxycytidinekinase is responsible for phosphorylation to 5’-monophosphate. Since the activity degree of deoxycytidinekinase in lymphocytes is higher than for 5’- nucleotidase, and due to leucladine resistance to adenosine deaminase , three phosphorylated forms of 2-chlorine-2’- deoxyadenosine, 5’triphosphate2chlorine-2’- deoxyadenosine inclusive, are rapidly accumulated in the cell.
Indications for usage
· Chronic lymphatic leukemia (progressive and resistant to the drugs of the first series of polychemotherapy form);
· Non-Hodgkin's lymphoma of lower and intermediate degree of malignancy;
· Recurrent disseminated sclerosis
· Chronic progressive disseminated sclerosis.
Administration and dosage
Dosage and period of treatment is fixed by a doctor subject to peculiarities of the disease and the degree of severity.
The drug is introduced i.v. by drops in the dose of 0.09 mg/kg/day. Higherdosesareofrisktoxicaction. In hair-cellular leukemia introduce permanently during 7 days (24 h. i.v.infusion), 1 course of infusion, in chronic lymphatic leukemia during 5 days (2 h. i.v.infusion), 1-6 courses with interval 28-48 days; in non-Hodgkin's lymphoma, lower and intermediate degree of malignancy – 5 days (2 h. i.v.infusion), 1-6 courses with interval 28.
In recurrent remittent disseminated sclerosis the drug is introduced s.c., single dose of 0.07—0.09 mg/kg/day for 5 days, 1-6 courses with interval 28 days; in chronic progressive disseminated sclerosis i.v. by drops, dose of 0.09 mg/kg/day for 5 days (2 h. i.v.infusion), 1-6 courses with interval 28 days. In the treatment of disseminated sclerosis it is recommended to administer leuclodine in combination with basis symptomatic supportive therapy.
The drug in the form of saline is stable for a 24 h.
Thetreatmentisadministeredundercarefulclinicalandhematologiccontrol. The control is obligatory either the first 4-8 weeks after leucladine administration as mielosuppression may provoke the retard activity.
In leuclodine therapy possible side effects: depression of marrow function, leucopenia, granulopenia, thrombocytopenia, anemia, fever, peripheral sensory neuropathy, skin peeling, itch, depression of immunity, propensity for infections, opportunistic infection caused by Herpes simplex, Herpes zoster, Cytomegalovirus. In certain cases pneumonia (pneumonitis), moderate reversible increase of transaminase, alkaline phosphatase, and bilirubin. In recurrent injections possible moderate pain in the injection points.
The majority of non-hematologic side effects are of transient nature and do not require intensive therapy. Mielosuppression in treatment with conventional doses is reversible.
Contraindications for leuclodine therapy are: hypersensitivity, apparent marrow depression, acute infections, pregnancy, lactation (breast feeding should be cancelled during treatment).
The patient should be informed of the toxicity of the drug and acknowledge the treatment only under doctor’s coordination. Administer with care leucladine after cytotoxic therapy or radiation, in patients with liver and renal dysfunction. In the phase of induction of the remission be very careful if lacking of cells is expected, take preventive measures to avoid hyperuricemy and hyperuricosuria (risk of acute hepatic deficiency). To avoid hyperuricemy abundant drink is recommended, if necessary, allopurinol and alkali drink.
If leucocytes and thrombocytes exceed the lower level, in susceptibility to bleeding, apparent nephro- and hepatotoxic conditions (anuria, oliguria, hepatitis and others), cancel the drug.
Interaction with other drugs
Concurrentadministrationimmediatelyaftermielotoxicdrugsmaycauseadditivedepressionofmarrow. If leucladine is administered in higher doses (more than conventional) in combination with cyclophosphamide and radio therapy, the risk of neurotoxicity (non-reversible para- and tetraparesis) and nephrotoxicity (acute renal deficiency) is more elevated. Combination with allopyrinole and antibiotics provokes skin eruption.
No evidence revealed on unfavorable interaction of leucladine and drugs of symptomatic therapy in the treatment of disseminated sclerosis (pentoxyfilline, cinnarisine, pyracetam, ibuprofen, aminophylline, baclophen, thiamine).
To prepare infusions, 5% glucose solution is not recommended due to the higher degradation of leucladine.
Irreversible disorder of central nervous system (para- and tetraparesis, paralysis), nephrotoxic action and severe mielosuppression.
Treatment: cancel leucladine therapy. Symptomatic remedies (no effective antidote).
0.1% injection solution in vials of 10 ml.