Иматиниб

General characteristics. Structure:

Active ingredient: 100 mg of an imatinib.

Excipients: кросповидон, silicon dioxide colloid anhydrous, cellulose microcrystallic, magnesium stearate.

Structure of a cover of the capsule: titanium dioxide (Е 171), gelatin.

Antileukemic cytostatic drug, one of representatives of a new class of the targetny tsitostatik which are selectively influencing cells, genetic defects, having this or that characteristic of tumors.

Pharmacological properties:

Pharmacodynamics. Иматиниб effectively inhibits Bcr-Abl-tirozinkinazu enzyme at the cellular level. Иматиниб selectively suppresses proliferation and causes apoptosis of cellular lines, positive on Bcr-Abl, and also unripe leukemic cells at a myelosis with a positive Philadelphian chromosome (Ph+) and at an acute lymphoblastoid leukosis. Иматиниб selectively inhibits the Bcr-Abl-positive colonies received from blood cells at patients with a myelosis

Drug has antineoplastic activity at monotherapy.

Besides, иматиниб is strong inhibitor of receptors of a tyrosinekinase for a growth factor of thrombocytes (PDGF) and a factor of stem cells (SCF), with-Kit, and also suppresses the cellular reactions mediated by the above-named factors. In vitro иматиниб inhibits proliferation and induces apoptosis of cells of the stromal tumors of digestive tract expressing Kit-mutations.

Considerable activation of PDGF or Bcr-Abl-tirozinkinazy is a consequence of integration with various proteins, or stimulations of synthesis of PDGF which are involved in MDS/MPD pathogeny (miyelodisplasticheskikh/myeloproliferative) diseases, HES/CEL (a hyper eosinophilic syndrome / chronic eosinophilic leukemia) and the inoperable recurrent and/or metastasizing dermatofibrosarcomas of grumous (DFSP). Иматиниб inhibits a signal to proliferation of cells which accompanies the inactivated PDGF and activity of Bcr-Abl-tirozinkinazy.

Efficiency of drug is caused by the general speed of the hematologic and cytogenetic answer at patients with HML, an acute lymphoblastoid leukosis (Ph+ OLL), MDS/MPD, DFSP and objective speed of response at patients with malignant tumors of a stroma of bodies of a digestive tract.

Pharmacokinetics. Absorption. After intake of capsules of drug bioavailability averages 98%. The maximum concentration in a blood plasma is reached in 2-4 h. Coefficient of variation for an indicator the area under a curve "concentration time" makes 40–60%. At purpose of drug with food with the high content of fats, in comparison with reception on an empty stomach, insignificant decrease in extent of absorption (reduction of Cmax by 11%, AUC – for 7,4%) and delay of speed of absorption is noted (lengthening of tmax on 1,5 h).

Distribution. At clinically significant concentration of an imatinib its linkng with proteins of a blood plasma makes about 95% (mainly with albumine and acid alpha glycoproteins, in insignificant degree - with lipoproteins).

Metabolism. It is metabolized in a liver with the participation of CYP3A4 enzyme of system of P450 cytochrome. The main circulating metabolite at the person – derivative N-demetilirovannogo of piperazin which shows the same activity, as well as his predecessor. AUC value in plasma for this metabolite makes only 16% of AUC for an imatinib.

Removal. About 81% of a dose eliminirutsya in 7 days with excrements (68% of a dose) and urine (13% of a dose). In not changed look about 25% of a dose are removed (20% — with a stake and 5% — with urine). Other amount of drug is removed in the form of metabolites.

The elimination half-life of an imatinib makes about 18 h. In the range of doses from 25 to 1000 mg direct linear dependence of AUC value on dose size is noted.

Pharmacokinetics in special groups. Patients of senile age. At patients 65 years are more senior the volume of distribution increases by 12% that clinically not significantly.

For patients with the body weight of 50 kg the average size of clearance of an imatinib makes 8,5 l/h, and for patients with the body weight of 100 kg – 11,8 l/h. However these distinctions are not so essential that change of a dose of drug depending on the body weight of the patient was required.

Patients with damage of a liver. At patients with various degree of an abnormal liver function average AUC values did not increase in comparison with patients with normal function of a liver.

The pharmacokinetics of an imatinib does not depend on a floor.

Indications to use:

- for treatment of adults and children with for the first time the diagnosed chronic myeloid leukosis with a fildelfiysky chromosome (PH + HML);

- for treatment of the adults and children suffering from PH + HML in a phase of blast crisis or a phase of acceleration and also for treatment of a chronic phase after unsuccessful therapy by interferon an alpha;

- for treatment of the adult patients having for the first time the diagnosed acute lymphoblastoid leukosis with a fildelfiysky chromosome  (PH + OLL) as a part of chemotherapy;

- for treatment of adult patients with recurrent or refractory PH + OLL (as monotherapy);

- миелодиспластические/миелопролиферативные diseases (MDS/MPD) at adult patients connected with activation of a receptor of a platelet growth factor;

- the system mastocytosis (SM) with lack of D816V-Kit from mutations or in the absence of data on the mutational status with-Kit at adult patients;

- a hyper eosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CEL) at adults;

- an inoperable, recurrent and/or metastatic eminating dermatofibrosarcoma (DFSP) at adults;

- nonresectable and/or metastatic stromal tumors of digestive tract (GIST) at adults;

- adjuvant therapy after GIST resection at adults.

Route of administration and doses:

It is recommended to accept orally during food, washing down with a full glass of water. The dose of drug 400/600 of mg is accepted once a day whereas it is necessary to use drug in a daily dose of 800 mg on 400 mg 2 times a day, in the morning and in the evening.

Treatment can be continued if signs of an exacerbation of a disease or undesirable toxicity are not shown.

The recommended dosage of Imatiniba. At a myelosis: the recommended dose for treatment of patients with HML in a chronic phase makes 400 mg a day, for patients with HML in a phase of activation or blast crisis - 600 mg a day.

At a myelosis for patients in a chronic phase of a disease increase in a dosage from 400 mg to 600 mg or for patients in a phase of activation or at blast crisis - increase in a dosage from 600 mg to 800 mg (on 400 mg twice a day) is shown only in the absence of heavy side effects and in the absence of the neutropenia which is not connected with leukemia or thrombocytopenia. Such increase in a dose can be necessary in the following cases: progressing of a disease (at any stage), lack of the satisfactory hematologic answer in 3 months after an initiation of treatment, lack of the cytogenetic answer after 12 months of therapy, loss of earlier reached hematologic and/or cytogenetic answer.

At an acute lymphoblastoid leukosis the recommended dose for treatment of patients with Ph + makes OLL 600 mg a day.

At миелодиспластических/миелопролиферативных diseases the recommended dose for treatment of patients with MDS/MPD makes 400 mg a day.

At a system mastocytosis the recommended dose for treatment of patients with CM with lack of D816V-Kit from mutations makes 400 mg a day. For patients with the CM associated with an eosinophilia when clonal hematologic pathology is connected with synthesis of kinases of FIP1L1-PDGFRα, the recommended dose makes 100 mg a day. Increase in a dose from 100 mg to 400 mg can be considered in the absence of side effects and in case of the insufficient response to therapy.

At a hyper eosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CEL) the recommended dose for treatment of patients with HES/CEL makes 400 mg a day. For patients at whom the level of activity of tyrosinekinases FIP1L1-PDGFRα is increased, the initial dose of 100 mg a day is recommended. Increase in a dose from 100 mg to 400 mg can be considered in the absence of side effects and in case of the insufficient response to therapy.

At an eminating dermatofibrosarcoma (DFSP) the recommended initial dose of an imatinib at adult patients with DPSP makes 400 mg/days. If necessary the dose is increased to 800 mg a day.

At stromal tumors of digestive tract (GIST): the recommended dose for treatment of patients with inoperable and/or metastatic GIST makes 400 mg a day. Increase in a dose from 400 mg to 600 and 800 mg can be considered for patients at whom side reactions are not observed or if the response to treatment is insufficiently effective.

The recommended dose for adjuvant treatment of adult patients after a resection of GIST makes 400 mg a day. The optimum duration of adjuvant therapy is not established.

Dosing in special groups of patients. Children. For treatment of children 2 years suffering from a myelosis are aged younger than clinical experiment on use of an imatinib, is not available. Experiment on use of drug for treatment of children according to other indications is practically not available.

Calculation of the mode of dosing at children is more senior than 2 years is based on body surface area (mg/m ²). Doses of 260 mg/m ² in days are recommended at chronic phase HML and 340 mg/m ² in days at HML in an acceleration phase respectively. The general daily dose at children should not exceed equivalent doses for adult 400 mg and 600 mg. Treatment has to be appointed once a day or alternatively divided into two receptions - one reception in the morning, other reception in the evening.

Patients with an abnormal liver function. As иматиниб it is metabolized mainly in a liver, patients with insignificant, moderate abnormal liver functions should appoint the minimum recommended dose of 400 mg/days or it is less, depending on the recommended dose for treatment according to the indication. At patients with heavy dysfunction of a liver the dose lower than 100 mg/days is recommended, increase by 100 mg/days to 400 mg/days is admissible in the absence of side effects.

 Patients with a renal failure. Considerable allocation of an imatinib and its metabolites through kidneys does not happen. To patients with a renal failure or to the patients who are on dialysis, drug appoint 400 mg in the minimum initial dose. Nevertheless, at treatment of this category of patients it is necessary to be careful. At intolerance the dose of drug can be reduced. At good tolerance and insufficient efficiency the dose can be raised.

Dosing in special cases. Change of a dosage at a hepatotoxic and other pathological reactions not - hematologic character.

In case of development of heavy not hematologic side reactions (such as severe form of damage of a liver or delay of liquid) it is necessary to stop use of Imatiniba before disappearance of these phenomena then treatment by drug can be resumed taking into account the shown reaction.

At increase in level of bilirubin is 3 times higher than the upper bound of norm or increase in level of hepatic transaminases more than by 5 times, reception of Imatiniba needs to be suspended until concentration of bilirubin does not decrease to the level which exceeds the upper bound of norm no more than by 1,5 times, and the level of hepatic transaminases will not decrease to the level which exceeds the upper bound of norm no more than by 2,5 times. After that treatment by Imatinib can be continued in the reduced daily doses. For adults the dose decreases from 400 to 300 mg a day or from 600 to 400 mg a day, or from 800 to 400 mg a day. For children - from 260 to 200 mg/sq.m a day or from 340 to 260 mg / m2v days.

Hematologic pathological reactions. At emergence of a neutropenia and thrombocytopenia temporary drug withdrawal or reduction of its dose as it is specified in the table is required. 

The CM associated with an eosinophilia, and HES/CEL with synthesis of FIP1L1-PDGFR α-tyrosinekinases (initial dose of 100 mg)	Absolute Quantity of Neutrophils (AQN) <1,0 x 109/l and/or thrombocytes <50 x 109/l	1.  To suspend treatment until the absolute number of neutrophils does not become ≥1,5 x 109/l and thrombocytes ≥75 x 109/l. 2.  To resume treatment in an initial dose.
Chronic phase HML, MDS/MPD, CM, HES/CEL and GIST (initial dose of 400 mg)	AKN <1,0 x 109/l and/or thrombocytes <50 x 109/l	1. To suspend treatment until the absolute number of neutrophils does not become ≥ 1,5 x 109/l and thrombocytes ≥75 x 109/l. 2. To resume treatment in an initial dose. 3. In case of repeated decrease in number of neutrophils <1,0 x 109/l and/or thrombocytes <50 x 109/l to repeat a step 1 and to resume treatment in a dose of 300 mg.
Phase of acceleration and blast crisis of HML, (Ph + - OLL) (initial dose 600 мгб)	AKN and <0,5 x 109/l and/or thrombocytes <10 x 109/l	1. To check communication of a cytopenia with leukemia (a marrow research). 2. If the cytopenia is not connected with leukemia, to reduce a dose to 400 мгв. 3. If the cytopenia remains within 2 weeks, to reduce a dose to 300 мгв. 4. If the cytopenia remains within 4 weeks and its communication with leukemia is not confirmed, to suspend treatment until the absolute number of neutrophils does not become ≥ 1,0 x 109/l and thrombocytes ≥20 x 109/l, then to resume treatment in a dose of 300 mg.
DFSP (initial dose of 400 mg)	AKN <1,0 x 109/l and/or thrombocytes <50 x 109/l	1.                 To suspend treatment until the absolute number of neutrophils does not become ≥ 1,5 x 109/l and thrombocytes ≥75 x 109/l. 2.                 To resume treatment in an initial dose. 3.                 In case of repeated decrease in number of neutrophils <1,0 x 109/l and/or thrombocytes <50 x 109/l to repeat a step 1 and to resume treatment in a dose of 300 mg.
and - appeared after 1 month of treatment beat with 340 mg/sq.m at children twisted 260 mg/sq.m at children - or 200 mg/sq.m are at children

 

Features of use:

Treatment by Imatinib should be carried out only under observation of the doctor having experience with antineoplastic drugs.

It is necessary to be careful at purpose of Imatiniba to patients with the broken function of a liver as strengthening of expressiveness of its action is possible.

At the treatment of drug it is necessary to avoid hit it on skin and in eyes, and also drug powder inhalations.

Because at use of Imatiniba the expressed liquid delay (a pleural exudate, peripheral hypostases, a fluid lungs, ascites) is possible, at patients it is recommended to determine body weight regularly. In case of bystry unexpected increase in body weight it is necessary to conduct examination of the patient and if necessary to appoint the corresponding symptomatic therapy.

Laboratory tests. During therapy it is necessary to carry out systematically the integrated clinical analysis of peripheral blood. At use of drug for patients with a myelosis the neutropenia and thrombocytopenia are noted, however their emergence depends on a disease phase. At blast crisis and in an acceleration phase these undesirable phenomena meet more often than in a chronic phase of a disease. At emergence of these undesirable phenomena it is recommended to cancel temporarily drug or to reduce a dose.

During therapy regular control of function of a liver (transaminases, bilirubin, an alkaline phosphatase) is shown. In case of deviations of these laboratory indicators from norm it is recommended to reduce a dose of Imatiniba or to temporarily cancel it.

Patients with heart diseases or a renal failure. It is necessary to control attentively patients with heart diseases, risk factors of developing of heart failure, or with a renal failure in the anamnesis; patients with signs or symptoms of heart failure it is necessary to inspect and appoint treatment. At elderly patients and patients with heart diseases indicators of fraction of emission of a left ventricle (FV LZh) prior to treatment imatiniby have to be defined.

Patients with a syndrome have hypereosinophilia (HES) and separate cases of development of cardiogenic shock / dysfunction of a left ventricle were connected by dysfunction of heart with an initiation of treatment imatiniby. It was reported that at purpose of system steroids, use of systems of maintenance of blood circulation and at the temporary termination of reception of an imatinib such states had reversible character.

Миелодиспластические/миелопролиферативные diseases and a system mastocytosis can be followed by the high level of eosinophils. Therefore at the patients suffering from HES/CEL and also at the patients suffering from MDS/MPD or the CM associated with the high level of eosinophils it is necessary to control an ECG and to determine the level of a troponin in blood serum. If pathological changes are noted, at a stage of an initial phase of treatment the therapy accompanying with imatiniby should consider the possibility of preventive use of system steroids (1-2 mg/kg) for 1-2 weeks as.

Gastrointestinal bleeding. Patients with tumors of a GIT can have gastrointestinal bleedings therefore before therapy at patients it is necessary to control possible development of symptoms from digestive tract.

Syndrome of a lysis of a tumor. At the patients receiving treatment imatiniby cases of the syndrome of a lysis of a tumor (SLT) were observed. In a type of possible development of SLO, before therapy imatiniby it is necessary to carry out correction of clinically significant dehydration and to stop high levels of uric acid.

Hypothyroidism. It was reported about clinical cases of development of a hypothyroidism in the patients receiving replacement therapy by left thyroxine after a thyroidectomy when performing the combined therapy by drug Glivek. At such patients it is necessary to control the level of thyritropic hormone regularly.

Children and teenagers. There are messages on the growth inhibition observed among children and children of preadolescent age receiving иматиниб. Long-term effects of long administration of drug on growth at children are not established. Therefore at the children receiving therapy imatiniby it is recommended to control dynamics of growth carefully.

Sufficient experience of use of drug for children with HML aged up to 2 years is not available.

Иматиниб and its metabolites are excreted through kidneys in insignificant quantity. It is known that the clearance of creatinine (Klkr) decreases with age, and the age does not influence substantially drug kinetics. At patients with a renal failure the level of an imatinib in a blood plasma is slightly higher, than at patients with normal function of kidneys (it is possible in connection with the increased level of an acid alpha glycoprotein which is an imatinibsvyazyvayushchy protein at such patients). At patients with easy (clearance of creatinine of 40-59 ml/min.) and heavy (the clearance of creatinine <20 ml/min.) degree of a renal failure of interrelation between the size of exposure of an imatinib and degree of a renal failure determined by the level of clearance of creatinine is not available. However at bad portability initial doses of drug can be lowered as it is specified in the section "Route of Administration and Doses".

Use during pregnancy or feeding by a breast. During therapy by Imatinib women of reproductive age should apply effective methods of contraception. In case of use of Imatiniba during pregnancy the patient needs to be warned about possibility of potential threat for a fruit.

Иматиниб and its active metabolite are capable to get into breast milk at the feeding women. The women accepting Imatinib should refuse feeding by a breast.

Use in geriatrics. 65 years are more senior than special recommendations about dosing for patients it is not required.

Influence on ability to manage motor transport and potentially dangerous mechanisms. Some side effects of drug, such as dizziness and illegibility of sight, can negatively influence ability to manage motor transport and to carry out potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. Therefore it is recommended to be careful at control of motor transport or other mechanisms.

Side effects:

At the developed stage of a myelosis or stromal tumors of a GIT patients can have the multiple accompanying disturbances complicating assessment of side effects because of a number of the symptoms connected with associated diseases, their progressing and reception of various medicines.

Иматиниб in general it is transferred well at long daily intake at patients with HML, including at children. Most of patients had side effects, is more often from lungs to moderately expressed. Cancellation of administration of drug because of development of side reactions was observed at less than 5% of patients.

Slight nausea, vomiting, diarrhea, mialgiya, muscular spasms, rash which were easily controlled were the most frequent undesirable phenomena connected with administration of drug. Peripheral hypostases of preferential periorbital areas or hypostases of the lower extremities were often noted. However they seldom had the expressed character and well therapies by diuretics gave in; at some patients hypostases passed after a dose decline of Imatiniba.

Various undesirable phenomena, such as pleural exudate, ascites, fluid lungs and bystry increase in body weight with peripheral hypostases or without them can be qualified in general as a liquid delay. For elimination of the above-stated undesirable phenomena usually temporarily interrupt therapy by Imatinib and/or apply diuretics.

The undesirable phenomena are listed below on bodies and systems with the indication of frequency of their emergence.

Determination of frequency: very often (from 1/10), it is frequent (from 1/100 to 1/10), infrequently (from 1/1000 to 1/100), is rare (from 1/10000 to 1/1000), is very rare (to 1/10000).

Infectious and parasitic diseases: infrequently – the herpes simplex, herpes surrounding, a nasopharyngitis, pneumonia, sinusitis, phlegmon, upper respiratory tract infections, flu, infections of an urinary path, a gastroenteritis, sepsis; seldom - mycoses.

Disturbances from blood and lymphatic system: very often - a neutropenia, thrombocytopenia, anemia; often - a pancytopenia, a febrile neutropenia; infrequently - a trombotsitemiya, a lymphopenia, oppression of function of marrow, an eosinophilia, a lymphadenopathy; seldom - hemolitic anemia.

Disturbances from a metabolism and food: often - anorexia; infrequently - a hypopotassemia, increase in appetite, a hypophosphatemia, a loss of appetite, dehydration, gout, a hyperuricemia, a hyperglycemia, a hypercalcemia, a hyponatremia; seldom - a hyperpotassemia, a hypomagnesiemia.

Disturbances of mentality: often - sleeplessness, infrequently - a depression, decrease in a libido, uneasiness; seldom - confusion of consciousness.

Disturbances from a nervous system: very often – a headache, it is frequent - dizziness, paresthesia, disturbance of flavoring feelings, a hypesthesia; infrequently - migraine, drowsiness, a loss of consciousness, peripheral neuropathy, a memory impairment, a sciatica, a syndrome of "uneasy" legs, a tremor, a hematencephalon; seldom – increase in intracranial pressure, a spasm, an optic neuritis.

Disturbances from an organ of sight: often - the century, strengthening of a slezootdeleniye, conjunctival hemorrhages, conjunctivitis, a xerophthalmus, a sight illegibility swelled; infrequently - feeling of irritation in eyes, eye pain, orbital hypostasis, hemorrhages in a sclera, hemorrhages in a retina, a blepharitis, macular hypostasis; seldom - a cataract, glaucoma, a papilloedema.

Disturbances from an acoustic organ and labyrinth disturbances: infrequently - вертиго, a ring in ears, a hearing loss.

Disturbances from heart: infrequently - palpitation, tachycardia, congestive heart failure, a fluid lungs; seldom - arrhythmia, fibrillation of auricles, a cardiac standstill, a myocardial infarction, stenocardia, a pericardiac exudate.

Disturbances from vessels: often - feeling of inflow of blood, a hemorrhage; infrequently - hypertensia, hematomas, a cryesthesia in extremities, arterial hypotension, Reynaud's phenomenon.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: often - диспноэ, nasal bleeding, cough; infrequently - a pleural exudate, pharyngolaryngeal pain, pharyngitis; seldom - pleural pains, a pneumosclerosis, pulmonary hypertensia, pulmonary bleeding.

Disturbances from digestive tract: very often - nausea, diarrhea, vomiting, dyspepsia, abdominal pain; often - a meteorism, abdominal distention, a gastroesophageal reflux, a lock, dryness in a mouth, gastritis; infrequently - stomatitis, ulcers of an oral cavity, bleeding from digestive tract, an eructation, a melena, an esophagitis, ascites, stomach ulcer, vomiting with blood, a cheilitis, a dysphagy, pancreatitis; seldom - colitis, intestinal impassability, inflammatory processes in intestines.

Disturbances from a liver and bile-excreting system: often - increase in level of liver enzymes; infrequently - a hyperbilirubinemia, hepatitis, jaundice; seldom - a liver failure, a liver necrosis.

Disturbances from skin and hypodermic fabrics: very often - periorbital hypostasis, a dermatitis/eczema/rash; often - an itch, a face edema, a xeroderma, an erythema, an alopecia, night perspiration, photosensitivity reaction; infrequently - pustular rash, the increased perspiration, urtikariya, an ecchymoma, the increased tendency to hemorrhages, a hypotrichosis, a hypoxanthopathy, exfoliative dermatitis, fragility of nails, a folliculitis, petechias, psoriasis, a purpura, a skin hyperpegmentation, violent rashes; seldom - an acute febrile neutrophylic dermatosis (a syndrome It is twisted), discoloration of nails, a Quincke's disease, vesicular rash, a multiformny erythema, a leykotsitoklastichesky vasculitis, Stephens-Johnson's syndrome, an acute generalized exanthematous pustular rash.

Disturbances from skeletal and muscular and connecting fabric: very often - a muscular spasm and spasms, muscle and bones pain, including a mialgiya, an arthralgia, an ostealgia, it is frequent - a swelling of joints; infrequently - constraint in joints and muscles; seldom - muscular weakness, arthritis.

Disturbances from kidneys and urinary tract: infrequently - pain in kidneys, a hamaturia, an acute renal failure, the increased frequency of urinations.

Disturbances from generative organs and a mammary gland: infrequently - a gynecomastia, erectile dysfunction, a menorrhagia, disturbance of a menstrual cycle, disturbance of sexual function, nipple pain, increase in mammary glands, a hydroscheocele.

Others: very often - a delay of liquid and hypostasis, fatigue, increase in body weight; often - weakness, fervescence, an anasarca, a fever, a shiver, decrease in body weight, infrequently - a stethalgia, an indisposition, increase in creatinine in blood, increase in a kreatinfosfokinaza in blood, increase in a lactate dehydrogenase in blood, increase in an alkaline phosphatase in blood; seldom - increase in amylase in blood.

Interaction with other medicines:

Increase in concentration of an imatinib in plasma is possible at simultaneous use with the drugs inhibiting a P450 cytochrome CYP3A4 isoenzyme (for example, кетоконазол, интраконазол, erythromycin, кларитромицин). On the contrary, simultaneous use of the drugs which are the inductors CYP3A4 (for example, dexamethasone, Phenytoinum, carbamazepine, rifampicin, phenobarbital, or drugs of a St. John's Wort (Hypericum perforatum)), can lead to strengthening of metabolism of Imatiniba and decrease in its concentration in plasma. For patients to whom rifampicin or other inductors CYP3A4 is shown alternative therapeutic means with smaller ability to induce enzymes have to be considered.

Иматиниб increases Cmax and AUC of a simvastatin in 2 and 3,5 times respectively owing to CYP3A4 inhibition imatiniby. It is necessary to be careful at simultaneous use of the Imatiniba and drugs which are CYP3A4 substrates and having the narrow range of therapeutic concentration (for example, cyclosporine or Pimozidum). Иматиниб can increase concentration in plasma of other medicines, metaboliziruyemy CYP3A4 (for example, triazolobenzodiazepines, dihydropyridinic blockers of calcium channels, GMG-KOA-reduktazy inhibitors).

In the conditions of in vitro иматиниб inhibits activity of an isoenzyme of CYP 2D6 of P450 cytochrome in the same concentration which influence activity of CYP 3A4. Иматиниб in a dose of 400 mg 2 times a day the weak inhibiting influence on CYP shows the 2D6-mediated metabolism of a metoprolol with increase in Cmax and AUC of a metoprolol approximately for 23%. Co-administration of an imatinib and CYP 2D6 substrates, such as метопролол, does not lead to emergence of risk factors of interaction between drugs therefore dose adjustment is not required.

In the researches in vitro it was shown that Imatinib inhibits a P450 cytochrome CYP2D6 isoenzyme in the same concentration in which it inhibits CYP3A4. In this regard it is necessary to consider a possibility of strengthening of effects of the drugs which are CYP2D6 isoenzyme substrates at their combined use with Imatinib. Иматиниб inhibits O-glyukuronidatsiyu paracetamol / acetaminophen.

Иматиниб inhibits activity of CYP2C9 and CYP2C19 therefore at the combined use with warfarin lengthening of a prothrombin time is observed. At simultaneous use with coumarinic derivatives short-term monitoring of a prothrombin time at the beginning and at the end of therapy by Imatinib is necessary, and also at change of the mode of dosing of Imatiniba. As an alternative warfarin is recommended to use low-molecular derivatives of heparin.

In the researches in vitro it was shown that Imatinib inhibits a P450 cytochrome CYP2D6 isoenzyme in the same concentration in which it inhibits CYP3A4. In this regard it is necessary to consider a possibility of strengthening of effects of the drugs which are CYP2D6 isoenzyme substrates at their combined use with Imatinib. Иматиниб inhibits O-glyukuronidatsiyu paracetamol / acetaminophen.

In all cases when there is a need to accept any additional drugs together with Imatinib, it is necessary to consult with the doctor.

Contraindications:

Hypersensitivity to an imatinib to a mezilat or any other component of drug.

Children's age up to 2 years.

Pregnancy and period of a lactation.

Overdose:

Symptoms: strengthening of side effects is possible.

Treatment: it is necessary to establish observation of the patient and to appoint the corresponding maintenance therapy.

Storage conditions:

In the place protected from light and moisture, at a temperature not over 25 ºС. List A. To store in the place, unavailable to children. Period of validity 2 years.

Issue conditions:

According to the recipe

Packaging:

On 21 capsules in a blister strip packaging. 3 or 6 blister strip packagings with the instruction on a medical use place in a pack cardboard.