Expiration date: 04/2025

Pharmacological action

Imatinib selectively inhibits the enzyme veg-Abl-tyrosine kinase, formed at the confluence of the site of the veg gene (breakpoint cluster region) and the proto-oncogene Abl (Abelson) at the cellular level. Imatinib selectively inhibits proliferation and causes apoptosis of cell lines expressing veg-Abl-tyrosine kinase, as well as immature leukemia cells in chronic myeloid leukemia with positive Philadelphia chromosome and acute lymphoblastic leukemia. In patients with chronic myeloid leukemia, imatinib selectively inhibits veg-Abl-positive colonies, has antitumor activity in monotherapy.

Imatinib selectively inhibits veg-Abl-positive colonies obtained from blood cells of patients with chronic myeloid leukemia.

Activation of receptors to platelet growth factors or Abl-fragment tyrosine kinase may be the cause of both myelodysplastic/myeloproliferative diseases, and hypereosinophilic syndrome and chronic eosinophilic leukemia and bulging dermatofibrosarcoma.

Activation of the C-Kit receptor of tyrosine kinase and receptors to platelet growth factors may be the basis of the pathogenesis of systemic mastocytosis.

Imatinib inhibits signal transmission in cells and cell proliferation, resulting from violations of the regulation of activity of growth factors of platelets and stem cells, c-Kit-receptor and Abl-tyrosine kinase fragment.

Imatinib inhibits proliferation and induces apoptosis of gastrointestinal stromal tumor cells expressing tyrosine kinase with C-Kit receptor mutation.

Pharmacokinetics

Suction

After ingestion, the bioavailability of imatinib is on average 98%. When taking the drug with food high in fat, compared with fasting, there is a slight decrease in the degree of absorption and slowing the rate of absorption. The coefficient of variation for the AUC is 40-60%.

Distribution

Binding to plasma proteins is about 95% (mainly with albumin and acidic alpha-glycoproteins, to a small extent - with lipoproteins).

Metabolism

Imatinib is metabolized mainly in the liver. The main metabolite of imatinib, circulating in the bloodstream, is N-demethylated piperazine derivative, which in vitro has pharmacological activity, similar to that of the original drug.

Breeding

Imatinib is excreted mainly in the form of metabolites within 7 days after taking one dose (intestine - 68%, kidneys - 13%). In unchanged form, about 25% of the dose is excreted (20% - by the intestine and 5% - by the kidneys). T1/2 of imatinib is approximately 18 hours When using repeated doses prescribed 1 times/day, the pharmacokinetics of imatinib is not affected. The value of the equilibrium concentration exceeds the value of the initial 1.5-2.5 times.

Pharmacokinetics in special clinical cases

In patients older than 65 years Vd slightly increased (by 12%). The value of imatinib clearance increases with increasing body weight of the patient. However, these changes do not require dose adjustment depending on the body weight and age of the patient.

Pharmacokinetics of imatinib does not depend on gender.

As in adults, in children and adolescents under 18 years there is a rapid absorption of the drug after oral administration. Cumulation of the drug after repeated administration was established.

In violation of liver function serum concentrations of imatinib may increase. When using imatinib in patients with mild or moderate renal impairment (creatinine clearance>, 30 ml / min) there is an increase in

exposure of the drug in plasma 1.5-2 times, corresponding to an increase in the concentration of acidic alpha-glycoproteins (the main plasma proteins associated with imatinib). There was no correlation between the exposure of the drug and the severity of renal disorders.

Dosage

Viagrain FS should be taken inside, during a meal with a full glass of water.

Doses of 400 and 600 mg per day should be taken in 1 dose, a daily dose of 800 mg should be divided into 2 doses - 400 mg in the morning and evening. For patients (including children) who cannot swallow the whole capsule, the contents of the capsule are diluted with water or Apple juice. The resulting "suspension" should be taken inside immediately after preparation.

In chronic myeloid leukemia (was) the recommended dose of Villagrains depends on the phase of the disease. In the chronic phase of CML dose for adults is 400 mg/day, in the phase of acceleration and blast crisis - 600 mg / day. The drug should be taken 1 time / day. Treatment with the drug is carried out as long as the clinical effect remains.

In the absence of pronounced side effects and neutropenia or thrombocytopenia, not associated with leukemia, it is possible to increase the dose from 400 mg to 600 mg or up to 800 mg in patients in the chronic phase of the disease and from 600 mg to 800 mg per day in patients in the phase of acceleration and blast crisis. Such an increase in the dose may be necessary in the progression of CML (at any stage), in the absence of a satisfactory hematological response after 3 months of treatment, cytogenetic response after 12 months of therapy or in the loss of a previously achieved hematological and/or cytogenetic response.

The calculation of the dosage regimen in children over 2 years is based on the body surface area (mg/m2).

Children with chronic phase and CML acceleration phase are recommended to take 340 mg/m2/day. The total daily dose in children should not exceed 600 mg Daily dose of the drug can be taken in one stage or divided into 2 equal reception - morning and evening.

There is no data on the use of the drug in children under 2 years.

In acute lymphoblastic leukemia (Ph+) recommended dose Filigrana FS is 600 mg/day.

With myelodysplastic/myeloproliferative diseases (MDS/MPD) the recommended dose Filigrana FS is 400 mg/day.

With unresectable and/or metastatic GISO recommended dose Filigrana FS is 400 mg/day. In the absence of side effects of the drug and inadequate response, may increase daily dose Filigrana FS from 400 mg to 600 mg or 800 mg.

Treatment Filigrana FS is carried out until the first signs of disease progression.

When using the drug as adjuvant therapy in patients with GIS, the recommended dose is 400 mg / day. The optimal duration of adjuvant therapy has not been established.

With unresectable, recurrent and/or metastatic wybuchowa dermatofibrosarcoma recommended dose Filigrana FS 800 mg/day.

In hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/HEL) in adult patients, the recommended dose of Filachromine FS is 400 mg / day. In patients with HES/HEL, due to abnormal FIP1L1-PDGFR alpha-tyrosine kinase, the recommended initial dose is 100 mg/day. In the absence of insufficient effectiveness and pronounced side effects may increase the daily dose to 400 mg.Treatment with the drug is carried out as long as the clinical effect.

In systemic mastocytosis in the absence of the D816V c-Kit mutation recommended dose Filigrana FS is 400 mg/day. With an unknown mutation status and insufficient effectiveness of the previous therapy, the recommended dose is 400 mg/day.

In systemic mastocytosis, due to abnormal FIP1L1-PDGFR alpha-tyrosine kinase, formed as a result of the fusion of genes Fip likel and PDGFR, the recommended initial dose is 100 mg/day. Increasing the dose from 100 mg to 400 mg can be considered with insufficient efficiency and no side effects.

Patients with impaired liver function

Since imatinib is metabolized mainly in the liver, patients with mild, moderate or severe hepatic impairment drug should be prescribed at a minimum daily dose-400 mg. with the development of undesirable toxic effects dose should be reduced. Patients with severe hepatic insufficiency drug should be administered with caution.

Patients with impaired renal function

Kidneys do not play a significant role in the excretion of imatinib and its metabolites. In patients with mild or moderate renal impairment treatment should begin with a minimum effective dose - 400 mg 1 time/day. Although the experience of using imatinib in patients with severe renal impairment or during regular hemodialysis is limited, in this category of patients, drug therapy can also be started with a dose of 400 mg 1 time/day. With poor tolerability of therapy with imatinib, the initial dose of the drug can be reduced, with insufficient effectiveness increased.

Elderly patients

In elderly patients, no correction of the dosage regimen is required.

Correction of dosing regimen in the development of non-hematological side effects of the drug

Treatment should be suspended with the development of any serious non-hematological side effect associated with taking the drug until the situation is resolved. Then treatment can be resumed depending on the severity of the observed serious side effect.

With an increase in the concentration of bilirubin and the activity of liver transaminases in blood serum in 3 and 5 times higher than the upper limit of normal (VGN), respectively, treatment with the drug should be temporarily suspended until the bilirubin concentration drops to a value of less than 1.5 x VGN and the activity of liver transaminases to a value of less than 2.5 x VGN. Therapy with Filachromine FS should be resumed with a reduced daily dose: in adults, the dose is reduced from 400 mg to 300 mg per day or from 600 mg to 400 mg per day, or from 800 mg to 600 mg per day, in children - from 340 to 260 mg/m2 per day.

Correction of dosing regimen in the development of serious side effects from the hematopoietic system (severe thrombocytopenia, neutropenia)

In the event of neutropenia and thrombocytopenia, a temporary withdrawal of the drug or a decrease in its dose, depending on the severity of these side effects.