Иматиб

General characteristics. Structure:

Active ingredient: 59,75 mg or 119,5 mg of an imatenib of a mezilat (50 mg and 100 mg of an imatinib).

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

Structure of the capsule: titanium dioxide, gelatin, indigo carmine.

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 has a selective inhibiting effect on Bcr-Abl-tirozinkinazu enzyme, formed at merge of the site of a gene of Bcr (breakpoint cluster region) and Abl (Abelson) protooncogene, at the cellular level, selectively suppresses proliferation and causes apoptosis of the cellular lines expressing Bcr-Abl-tirozinkinazu including the unripe leukemic cells which are formed at patients with myeloses and an acute lymphoblastoid leukosis, positive on the Philadelphian chromosome.

Иматиниб selectively inhibits the Bcr-Abl-positive colonies received from cells sick by a myelosis.

Иматиниб inhibits proliferation and induces apoptosis of cells of the stromal tumors of digestive tract expressing a tyrosinekinase with a mutation
-Kit from a receptor.

Activation of receptors to growth factors of thrombocytes or an Abl-fragment of a tyrosinekinase can be the cause of development as миелодиспластических/миелопролиферативных diseases, and a hyper eosinophilic syndrome and a chronic eosinophilic leukosis and an eminating dermatofibrosarcoma.

Activation-Kit from a receptor of a tyrosinekinase and receptors to growth factors of thrombocytes can be the cornerstone of a pathogeny of a system mastocytosis.

Иматиниб inhibits signal transmission in cells and cellular proliferation, the resulting disturbances of regulation of activity of growth factors of thrombocytes and stem cells,-Kit from a receptor and an Abl-fragment of a tyrosinekinase.

At use of an imatinib for patients with nonresectable and/or metastatic malignant gastrointestinal stromal tumors reliable increase in the general survival of patients (48,8 months) and survival without symptoms of a disease was noted (21 month).

Adjuvant therapy by drug of gastrointestinal stromal tumors during 1 year reduces risk of development of a recurrence by 89%, increases survival without symptoms of a disease (38 months of Imatinib in comparison with 20 months of placebo).

Adjuvant therapy by drug of gastrointestinal stromal tumors within 3 years leads to significant increase in the general survival and survival without signs of progressing of a disease in comparison with therapy during 1 year.

Pharmacokinetics. Pharmacokinetic parameters of an imatinib were estimated in the range of doses from 25 mg to 1000 mg. Pharmacokinetic profiles were analyzed in the first day, and also at achievement of equilibrium concentration of an imatinib in plasma for the 7 or 28 day.

Absorption. After intake bioavailability of drug averages 98%. Coefficient of variation for an indicator the area under a curve "concentration time" (AUC) makes 40-60%. In the range of doses from 25 to 1000 mg direct linear dependence of AUC value on dose size is noted.

At administration 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 the maximum concentration of an imatinib in a blood plasma (Cmax) for 11%, AUC – for 7,4%) and delay of speed of absorption is noted (increase in time of achievement of the maximum concentration of an imatinib in a blood plasma (Tmax) on 1,5 h).

Distribution. About 95% of an imatinib contact proteins of plasma (mainly with albumine and acid alpha glycoproteins, in insignificant degree – with lipoproteins).

Metabolism. Иматиниб it is metabolized, mainly, in a liver with formation of the main metabolite (N-demetilirovannogo of the piperazinovy derivative) circulating in a blood channel. In vitro a metabolite of an imatinib has the pharmacological activity similar to activity of initial substance. AUC value of a metabolite makes 16% of AUC of an imatinib. Linkng of a metabolite with proteins of plasma is similar to that for an imatinib.

Removal. It is removed preferential in the form of metabolites within 7 days after reception of one dose: 68% - intestines and 13% - kidneys. In an invariable look about 25% of a dose are removed (20% - intestines and 5% - kidneys). The elimination half-life of an imatinib makes about 18 hours.

At repeated administrations of drug of 1 times a day, pharmacokinetic parameters do not change, and equilibrium concentration of an imatinib exceeds initial by 1,5-2,5 times.

Pharmacokinetics in different groups. At patients 65 years are more senior the volume of distribution increases slightly (by 12%). 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 essential and do not demand correction of a drug dosing depending on the body weight of the patient. The pharmacokinetics of an imatinib does not depend on a floor. Changes of indicators of clearance and volume of distribution of an imatinib at simultaneous use with other medicines are insignificant and do not demand change of a dose.

Pharmacokinetics at children. At children and teenagers 18 years, as well as at adults are younger, there is a bystry absorption of drug at intake. AUC at this group of patients in the range of doses of 260 and 340 mg/sq.m is similar to that at adults in the range of doses of 400 mg and 600 mg, respectively. When comparing at children and teenagers of AUC (0-24) values for the first and eighth days after repeated administration of drug on 340 mg/sq.m of 1 times a day increase of size of this indicator by 1,7 times, testimonial of cumulation of an imatinib is noted.

Pharmacokinetics at a renal failure. At patients with various degree of an abnormal liver function average AUC values do not increase.

At use of an imatinib for patients with easy or moderate renal failures (clearance of creatinine> of 30 ml/min.) the increase in exposure of drug in plasma by 1,5 – 2,0 times corresponding to increase in concentration of acid alpha glycoproteins (the main proteins of plasma communicating with imatiniby) is noted. As drug is slightly removed by kidneys, the clearance of a free imatinib was identical to healthy volunteers and patients with renal failures.  Correlation between exposure of drug and weight of renal disturbances is not revealed.

Indications to use:

- For the first time the revealed chronic myeloid leukosis, positive on the Philadelphian chromosome (Ph + HML) at children and adults;
- Positive on the Philadelphian chromosome (Ph+) of HML in a chronic phase at failure of the previous therapy by interferon an alpha or in an acceleration phase, or blast crisis at children and adults;
- For the first time the diagnosed acute lymphoblastoid leukosis, positive on the Philadelphian chromosome (Ph + OLL) at adult patients in a combination with chemotherapy;
- Recurrent or refractory Ph + OLL at adult patients as monotherapy;
- Миелодиспластические/миелопролиферативные a disease (MDS/MPZ), connected with gene reorganizations of a receptor of a growth factor of thrombocytes at adult patients;
- The System Mastocytosis (SM) at adult patients with lack of D816V-Kit from a mutation or with the unknown with-Kit the mutational status;
- A hyper eosinophilic syndrome and/or a chronic eosinophilic leukosis at adults from positive or negative abnormal FIP1L1-PDGRF an alpha tyrosinekinase;
- Nonresectable and/or metastatic malignant gastrointestinal stromal tumors positive on with-Kit (CD 117) at adult patients;
- Adyyuvantny therapy of gastrointestinal stromal tumors positive on with-Kit (CD 117) at adult patients;

Inoperable, recurrent and/or metastatic eminating dermatofibrosarcoma at adult patients.

Route of administration and doses:

Inside during meal, washing down with a full glass of water to reduce risk of development of gastrointestinal frustration.

Doses of 400 mg and 600 mg a day accept in 1 reception; it is necessary to divide a daily dose of 800 mg into 2 receptions – on 400 mg in the morning and in the evening.

To the patients who do not have an opportunity to swallow the capsule entirely, for example to children, it is possible to accept drug in a divorced look; contents of capsules are parted with water or apple juice. The received suspension is accepted inside right after preparation. After opening of capsules it is necessary to wash up hands at once.

Treatment by drug is carried out until the clinical effect remains.

At a myelosis (HML) the recommended dose of drug of Imatib depends on a disease phase. In chronic phase HML the dose makes 400 mg/days; in a phase of acceleration and at blast crisis – 600 mg/days. It is necessary to accept drug 1 time a day.

In the absence of the expressed side effects and a neutropenia or the thrombocytopenia which is not connected with a leukosis increase in a dose from 400 mg to 600 mg or to 800 mg at patients in a chronic phase of a disease, and from 600 mg to 800 mg a day at patients in a phase of acceleration is possible and at blast crisis. Such increase in a dose can be necessary when progressing HML (at any stage), in the absence of the satisfactory hematologic answer after 3 months of treatment, the cytogenetic answer in 12 months of therapy or when losing of earlier reached hematologic and/or cytogenetic answer.

Calculation of the mode of dosing at children is more senior than 2 years is based on body surface area. Doses of 340 mg/sq.m a day are recommended at children with chronic phase HML and a phase of acceleration. The general daily dose at children should not exceed 600 mg. The daily dose of drug can be accepted at the same time or to divide into 2 equal receptions – in the morning and in the evening.

At PH + OLL the recommended dose of drug of Imatib makes 600 mg a day.

At nonresectable and/or metastatic malignant gastrointestinal stromal tumors, MDS/MPZ the recommended dose of drug of Imatib makes 400 mg a day. In the absence of side effects of drug and the insufficient answer increase in a daily dose of drug of Imatib from 400 mg to 600 mg or to 800 mg is possible.

At emergence of signs of progressing of a disease therapy of drug of Imatib should be stopped.

At use of drug as adjuvant therapy at patients with gastrointestinal stromal tumors the recommended dose makes -
400 mg/days. The minimum duration of treatment is 3 years. The optimum duration of adjuvant therapy is not established.

At an inoperable, recurrent and/or metastatic eminating dermatofibrosarcoma the recommended dose of drug of Imatib makes 800 mg a day.

At CM in the absence of D816V-Kit from a mutation the recommended dose of drug of Imatib makes 400 mg a day. At the unknown mutational status and insufficient efficiency of the previous therapy the recommended dose makes
400 mg a day.

At the CM caused by abnormal FIP1L1-PDGFR the α-tyrosinekinase which is formed as a result of merge of genes of Fip like1 and PDGFR, the recommended initial dose makes 100 mg a day. At insufficient efficiency and lack of the expressed side effects increase in a dose to 400 mg/days is possible.

At a hyper eosinophilic syndrome and/or a chronic eosinophilic leukosis (Hydroelectric power station/HEL) at adult patients the recommended dose makes 400 mg/days.

At patients from hydroelectric power stations/HEL caused by abnormal FIP1L1-PDGFR a α-tyrosinekinase, the recommended initial dose makes 100 mg a day. At insufficient efficiency and lack of the expressed side effects increase in a dose to 400 mg/days is possible. Treatment by drug is carried out until the clinical effect remains.

Patients with an abnormal liver function. As иматиниб it is metabolized mainly in a liver, patients with easy, moderate or heavy disturbances of a liver should appoint drug of Imatib in the minimum daily dose - 400 mg. At development of undesirable toxic effects the dose of drug needs to be reduced. It is necessary to appoint with care drug to patients with a heavy liver failure.

Patients with a renal failure. Kidneys do not play an essential role in removal of an imatinib and its metabolites. At patients with renal failures or at patients who need systematic carrying out a hemodialysis treatment with drug of Imatib should be begun with a minimal effective dose - 400 mg of 1 times a day, being careful.

At intolerance of drug of Imatib the initial dose of drug can be lowered, at insufficient efficiency - is increased.

Patients of advanced age. Correction of the mode of a drug dosing is not required from patients of advanced age.

Correction of the mode of dosing at development of not hematologic side effects of drug. At development of any serious not hematologic side effect connected with administration of drug, therapy should be interrupted before resolving the situation. Then treatment can be resumed in the dose depending on weight of the observed side effect.

At increase in concentration of bilirubin and activity of transaminases of a liver in blood serum in 3 and 5 times above the upper bound of norm (UBN), respectively, drug it is necessary to suspend treatment temporarily before decrease in concentration of bilirubin to value less 1,5khvgn and activities of "hepatic" transaminases up to value less 2,5khvgn.

Therapy by drug of Imatib is resumed from the reduced daily dose: at adults the dose is reduced from 400 mg to 300 mg a day or from 600 mg to 400 mg a day, or from 800 mg to 600 mg a day; at children - with 340 do260 mg/sq.m a day.

Correction of the mode of dosing at development of serious side effects from system of a hemopoiesis (heavy thrombocytopenia, a neutropenia). At emergence of a neutropenia and thrombocytopenia temporary drug withdrawal or reduction of its dose, depending on degree of manifestation of these undesirable phenomena is required. At the CM and a hyper eosinophilic syndrome and/or a chronic eosinophilic leukosis (Hydroelectric power station/HEL) caused by abnormal FIP1L1-PDGFR a α-tyrosinekinase (an initial dose of drug of Imatib of 100 mg) in case of decrease in absolute number of neutrophils <1000/mkl and/or numbers of thrombocytes <50000/mkl it is recommended:

1.   to cancel drug of Imatib until the absolute quantity of neutrophils does not become 1500/mkl and thrombocytes 75000/mkl;

2.   to resume treatment by drug of Imatib in the dose applied before therapy interruption.

At chronic phase HML at children and adults (an initial dose for adults – 400 mg, for children – 340 mg/sq.m), malignant gastrointestinal stromal tumors, to MDS/MPZ, to CM and hydroelectric power station/HEL at adult patients (an initial dose for adults - 400 mg) in case of decrease in absolute number of neutrophils <1000/mkl and/or numbers of thrombocytes <50000/mkl it is recommended:

1.   to cancel drug of Imatib until the absolute quantity of neutrophils does not become 1500/mkl and thrombocytes 75000/mkl;

2.   to resume treatment by drug of Imatib in the dose applied before therapy interruption.

3.   in case of repeated decrease in number of neutrophils <1000/mkl and/or numbers of thrombocytes <50000/mkl it is necessary to repeat the actions specified in point 1 and then to resume treatment by drug of Imatib in the reduced dose of 300 mg (children have 260 mg/sq.m).

In a phase of acceleration and blast crisis of HML at children and adults and at PH + at adult patients (an initial dose for adults - 600 mg, for children - 340 mg/sq.m) in case of decrease in absolute number of neutrophils <500/mkl and/or numbers of thrombocytes <10000/mkl after one and more months of treatment it is recommended to OLL:

1.   to check whether the cytopenia is a consequence of a leukosis (a marrow research);

i. if the cytopenia is not connected with a leukosis, to reduce a dose of drug of Imatib to 400 mg (children have-260 mg/sq.m);
ii. if the cytopenia remains within 2 weeks, to reduce a dose to 300 mg (children have 200 mg/sq.m);
iii. if the cytopenia remains within 4 weeks and its communication with a leukosis is not confirmed, to cancel drug of Imatib until the absolute quantity of neutrophils does not become 1000/mkl and thrombocytes 20000/mkl; then to resume treatment by drug of Imatib in a dose of 300 mg (children have 260 mg/sq.m).

At an inoperable, recurrent and/or metastatic eminating dermatofibrosarcoma (an initial dose of drug of Imatib of 800 mg) in case of decrease in absolute number of neutrophils <1000/mkl and/or numbers of thrombocytes <50000/mkl it is recommended:

i. to cancel drug of Imatib until the absolute quantity of neutrophils does not become 1500/mkl and thrombocytes 75000/mkl;
ii. to resume treatment by drug of Imatib in a dose of 600 mg.

In case of repeated decrease in number of neutrophils less 1000/mkl and/or numbers of thrombocytes less 50000/mkl it is necessary to repeat the actions specified in point 1 and then to resume treatment by drug of Imatib in the reduced dose of 400 mg.

Features of use:

Use of an imatinib at pregnancy and during breastfeeding is contraindicated. Women of childbearing age during therapy imatiniby and within 3 months after treatment should apply effective methods of contraception.

Use at pregnancy and during breastfeeding is possible only if the estimated advantage for mother exceeds potential risk for a fruit and the child, at the same time it is necessary to warn the patient about existence of potential risk for a fruit.

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

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

Experience of treatment by drug of Imatib of children with HML is younger than 2 years is limited, experience of use of drug according to other indications is limited at patients 18 years are younger. Long-term effects of long impact of drug of Imatib on growth at children are unknown. But, as there are messages on growth inhibition cases, it is recommended to carry out careful control of growth at the children applying иматиниб.

At use of drug of Imatib it is regularly recommended to carry out clinical blood tests and to exercise control of function of a liver (transaminases, bilirubin, alkaline a phosphobasin).

It is necessary to provide weight observation of patients with heart diseases and kidneys.

Because at use of drug of Imatib in 1-2% of cases the expressed liquid delay is observed, it is recommended to control the body weight of patients regularly. In case of bystry unexpected increase in body weight, it is necessary to conduct examination of the patient and if necessary temporarily to stop therapy by drug of Imatib and/or to appoint diuretics. The largest frequency of development of a delay of liquid is noted at elderly patients, with the accompanying cardiovascular diseases.

In some cases the expressed delay of liquid can have a heavy current with a lethal outcome. At use of drug the death of the patient with blast crisis and complex symptomatology was noted: pleural exudate, congestive heart and renal failure.

At drug use patients with diseases of a liver should carry out regularly clinical blood test and to define activity of "hepatic" enzymes.

As there are messages on development of a hypothyroidism against the background of use of an imatinib for the patients who transferred a thyroidectomy and receiving replacement therapy by sodium left thyroxine it is regularly necessary to carry out definition of concentration of thyritropic hormone at this category of patients.

Patients with a syndrome have hypereosinophilia and heart diseases at the beginning of therapy imatiniby noted separate cases of development of cardiogenic shock / left ventricular failure. These undesirable phenomena are stopped after introduction of the system glucocorticosteroids, taking measures directed to blood circulation maintenance and temporary drug withdrawal of Imatib.

At patients with MDS/MPZ and high level of eosinophils it is necessary to carry out
ECG research and to define serumal concentration of a cardiospecific troponin. At identification of aberrations, at the beginning of therapy it is necessary to consider the possibility of preventive use of system glucocorticosteroids (1-2 mg/kg) within 1-2 weeks along with imatiniby.

At patients with nonresectable and/or metastatic malignant gastrointestinal stromal tumors in clinical trials of bleeding of various localization were noted in 12,9% of cases; gastrointestinal bleedings were noted at 8 patients (5,4%), bleeding from the tumoral centers – at 4 patients (2,7%).

Bleedings were observed both in abdominal organs, and in a liver, depending on localization of the tumoral centers.

It is necessary to control a condition of a GIT at patients with metostatichesky malignant gastrointestinal stromal tumors at the beginning of therapy imatiniby.

During therapy by drug of Imatib and, at least, within 3 months later, it is necessary to use reliable ways of contraception.

The expressed increase in activity of "hepatic" transaminases or bilirubin was noted at less than 3% of patients with HML and was usually controlled by a dose decline of drug or temporary interruption of treatment (the average duration of such episodes made about 1 week).

Owing to risk of development of a syndrome of a lysis of a tumor before purpose of drug of Imatib it is necessary to correct if necessary clinically expressed dehydration and the increased level of uric acid at patients.

 Influence of medicine on ability to manage vehicles, mechanisms
Some side effects of drug, such as dizziness and illegibility (misting) of sight, can negatively influence ability to control of vehicles and to performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

In this regard, the patients accepting drug of Imatib should show special attention and care at control of vehicles and performance of potentially dangerous types of activity.

Side effects:

The profile of safety of an imatinib is well studied. Most of patients at use of drug test these or those NYa. The most frequent NYa (> 10%) connected with administration of drug were: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, hypostases, increase in body weight, nausea, vomiting, diarrhea, mialgiya, muscular spasms, rash, weakness, abdominal pain. Generally these NYa were easy or moderately expressed. Only 2-5% of patients stopped therapy imatiniby because of development of NYa.

Miyelosupressiya, NYa from a GIT, hypostases and rash arise at use of an imatinib both at HML, and at malignant stromal tumors of a GIT. At patients with HML the miyelosupressiya develops more often, and patients with malignant stromal tumors of a GIT have gastrointestinal and intra tumoral bleedings more often. Other disturbances from a GIT, such as obstruction of a GIT, perforation and ulceration, meet more often at stromal tumors of a GIT. Other serious NYa at use of an imatinib are a hepatotoxic, an acute renal failure, a hypophosphatemia, disturbances from respiratory system, a syndrome of a lysis of a tumor and a growth inhibition at children.

Dose adjustment of drug depending on NYa degree of manifestation is possible, up to drug withdrawal.

At patients with HML and with nonresectable and/or metastatic malignant stromal tumors of a GIT the following undesirable phenomena which are listed below on bodies and systems with the indication of frequency of their emergence were noted: very often (≥1/10), it is frequent (≥1/100 <1/10), infrequently (≥1/1000 <1/100), is rare (≥1/10000 <1/1000), is very rare (<1/10000), including separate messages:

Infectious and parasitic diseases: infrequently - the herpes simplex, herpes surrounding, a nasopharyngitis, pnevmoniya1, sinusitis, an inflammation of hypodermic cellulose, an upper respiratory tract infection, flu, infections of urinary tract, a gastroenteritis, sepsis; seldom - mycoses.

The high-quality, malignant and not specified new growths (including cysts and polyps): seldom – a syndrome of a lysis of a tumor.

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 a marrowy hemopoiesis, an eosinophilia, a lymphadenopathy; seldom - hemolitic anemia.

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

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

Disturbances from a nervous system: very often - head bol2; often - dizziness, paresthesias, taste disturbance, a hypesthesia; infrequently - migraine, drowsiness, a faint, peripheral neuropathy, memory disturbances, a sciatica, a syndrome of "uneasy" legs, a tremor, a hemorrhagic stroke; seldom - increase in intracranial pressure, a spasm, an optic neuritis.

Disturbances from an organ of sight: often - the century, increase in a slezootdeleniye, hemorrhage under a conjunctiva, conjunctivitis, a syndrome of a "dry" eye, an illegibility (zatumanennost) of sight swelled; infrequently - irritation of eyes, eye pain, orbital hypostasis, hemorrhages in an eye sclera, retinal hemorrhages, a blepharitis, macular hypostasis; seldom - a cataract, a papilledema, glaucoma.

Disturbances from an acoustic organ and labyrinth disturbances: infrequently – вертиго, a sonitus, decrease in hearing.

Disturbances from heart: infrequently – a heart consciousness, hronicheskaya3 heart failure, a fluid lungs, tachycardia, "inflows" 4; seldom - arrhythmias, fibrillation of auricles, a sudden cardiac standstill; myocardial infarction, stenocardia, pericardiac exudate, increase in arterial pressure, hematoma.

Disturbances from vessels: infrequently - krovoizliyaniya4; seldom – hematomas, a cold snap of extremities, a lowering of arterial pressure, Reynaud's syndrome.

Disturbances from respiratory system, bodies of a thorax, a mediastinum: often - nasal bleeding, an asthma, cough; infrequently - pleural vypot5, throat or throat pains, pharyngitis; seldom - pleural pain, pulmonary fibrosis, pulmonary hypertensia, pulmonary bleeding.

Disturbances from the alimentary system: very often - nausea, vomiting, diarrhea, dyspepsia, pains in zhivote6; often – abdominal distention, a meteorism, a lock, a gastroesophageal reflux, dryness of a mucous membrane of an oral cavity, gastritis; infrequently - stomatitis, an ulceration of a mucous membrane of an oral cavity, gastrointestinal krovotecheniya7, an eructation, a melena, an esophagitis, ascites, stomach ulcer, vomiting blood, a cheilitis, a dysphagy, pancreatitis; seldom - colitis, paralytic / обтурационная intestinal impassability, an intestines inflammation.

Disturbances from a liver and biliary tract: often - increase in activity of "hepatic" enzymes, infrequently - jaundice, hepatitis, a hyperbilirubinemia, is rare - hepatic nedostatochnost9, a necrosis pecheni9.

Dermatological reactions: very often - periorbital hypostases, dermatitis, eczema, skin rash; often - puffiness of the person, an itch, an erythema, a xeroderma, an alopecia, night perspiration, reactions of a photosensitization; infrequently - pustular rash, petechias, the increased sweating, a small tortoiseshell, ecchymomas, the increased predisposition to formation of hematomas, easy formation of hematomas, a hypotrichosis, a hyperpegmentation/hypoxanthopathy, exfoliative dermatitis, injury of nails, a folliculitis, psoriasis, a purpura, violent rash; seldom - an acute febrile neutrophylic dermatosis (a syndrome It is twisted), discoloration of nails, ангионевротическнй hypostasis, a multiformny erythema, a leykoklastichesky vasculitis, Stephens-Johnson's syndrome, an acute generalized pustular dieback.

Disturbances from musculoskeletal and connecting fabric: very often - muscular spasms and spasms, musculoskeletal pains, including mialgiya, arthralgias, pain in kostyakh8; often – puffiness in joints; infrequently – constraint of muscles and joints, it is rare - muscular weakness, arthritises; frequency is unknown – delay of growth at children;

Disturbances from kidneys and urinary tract: infrequently - kidney pain, a hamaturia, an acute renal failure, a frequent urination.

Disturbance from endocrine system, generative organs and mammary glands: infrequently - a gynecomastia, erectile dysfunction, a menorrhagia, disturbances of a menstrual cycle, sexual dysfunction, nipple pain, increase in mammary glands, a hydroscheocele.

The general frustration and disturbances in an injection site: very often - a delay of liquid and hypostases, increased fatigue, increase in body weight; often - weakness, fervescence, an anasarca, a fever, a shiver, decrease in body weight, infrequently - a stethalgia, a febricula.

Laboratory and tool researches: infrequently - increase in activity of an alkaline phosphatase, kreatinfosfokinaza, lactate dehydrogenase and content of creatinine in blood serum; seldom - increase in activity of amylase in a blood plasma.

1) Pneumonia most often can be noted at patients with HML in a phase of acceleration, blast crisis and with nonresectable and/or metastatic malignant stromal tumors of a GIT;

2) The headache is most often noted at patients with nonresectable and/or metastatic malignant stromal tumors of a GIT;

3) The undesirable phenomena from heart, including chronic heart failure, were more often noted at patients with HML in a phase of acceleration and at blast crisis in comparison with patients with HML in a chronic phase (observation duration 1 year);

4) "Inflows" were most often noted at patients with nonresectable and/or metastatic malignant stromal tumors of a GIT;

- bleedings (hematomas, hemorrhages) are most often noted at patients with HML in a phase of acceleration, blast crisis and with nonresectable and/or metastatic malignant stromal tumors of a GIT;

5) The pleural exudate to a bowl is noted at patients with HML in a phase of acceleration and at blast crisis in comparison with patients with HML in a chronic phase (observation duration 1 year);

6/7) The abdominal pain and gastrointestinal bleedings were most often noted at patients with nonresectable and/or metastatic malignant stromal tumors of a GIT;

8) Musculoskeletal pains, including mialgiya, arthralgias, an ostealgia, were more often noted at patients with HML in comparison with patients with nonresectable and/or metastatic malignant stromal tumors of a GIT.

9) It was reported about separate cases of development of a liver failure and a necrosis of a liver.

At use of an imatinib in clinical practice, and also during additional clinical trials the following NYa which are listed below on bodies and systems with the indication of frequency of their emergence were noted: very often (≥1/10), it is frequent (≥1/100 <1/10), infrequently (≥1/1000 <1/100), is rare (≥1/10000 - <1/1000), is very rare (<1/10000), including separate messages.

Disturbances from a nervous system: infrequently - wet brain.

Disturbances from sense bodys: seldom - vitreous hemorrhages.

Disturbances from heart and vessels: infrequently — fibrinferments/embolisms; seldom - a pericardis; cardiac tamponade; very seldom - an acute anaphylaxis.

Disturbances from respiratory system, bodies of a thorax, a mediastinum: infrequently - acute respiratory nedostatochnost1, intersticial pneumonia.

Disturbances from the alimentary system: infrequently – Ilheus (intestinal impassability), bleedings from a GIT tumor, a GIT tumor necrosis, perforation of ZhKT2; seldom — a diverticulitis.

Disturbances from skin and hypodermic fabrics: infrequently – a palmar and bottom eritrodizesteziya; seldom - a lichenoid keratosis, red flat deprive; very seldom - a toxic epidermal necrolysis.

Disturbances from musculoskeletal and connecting fabric: seldom - an avaskulyarny necrosis / necrosis of a head of a femur, рабдомиолиз / a myopathy.

Disturbances from generative organs: infrequently – decrease in a potentiality, is very rare – women have a bleeding from a cyst of a yellow body / ovary.

1-Imeyutsya separate messages on development of the expressed acute respiratory insufficiency with a lethal outcome at patients with serious infectious diseases expressed by a neutropenia and other serious associated diseases.

2-Soobshchalos about separate cases of development a perforatsy GIT with a lethal outcome.

Interaction with other medicines:

At simultaneous use of drug of Imatib with the drugs inhibiting a P450 cytochrome CYP3A4 isoenzyme (кетоконазол, итраконазол, erythromycin, кларитромицин) delays of metabolism of an imatinib and increase in its concentration in a blood plasma are possible. Care at the combined use of drug of Imatib with drugs-inhibitors of isoenzymes CYP3A4 is necessary.

On the contrary, simultaneous use of the drugs which are CYP3A4 isoenzyme inductors (for example, dexamethasone, rifampicin, antiepileptic drugs: carbamazepine, an okskarbazepin, Phenytoinum, phenobarbital, a fosfenitoin, Primidonum or medicines on the basis of the St. John's Wort which is made a hole) can lead to acceleration of metabolism of an imatinib and, as a result, decrease in its concentration in a blood plasma.

At simultaneous use of an imatinib and simvastatin increase in Cmax and AUC in 2 and 3,5 times respectively is noted that is a consequence of inhibition of an isoenzyme of CYP3A4 imatiniby. It is recommended to be careful at simultaneous use of drug of Imatib and drugs which are substrates of an isoenzyme CYP3A4 and having the narrow range of therapeutic concentration (for example, cyclosporine and Pimozidum). Drug of Imatib can increase concentration in serum of other drugs, metabolized CYP3A4 isoenzyme (triazolobenzodiazepines, dihydropyridine, blockers of "slow" calcium channels, the majority of inhibitors of GMG-KOA-reduktazy, including statines).

Иматиниб also inhibits an isoenzyme of CYP2C9 and an isoenzyme of CYP2C19 in vitro. At the combined use of drug of Imatib with warfarin lengthening of a prothrombin time was observed. At simultaneous use with coumarinic derivatives short-term monitoring of a prothrombin time at the beginning and the end of therapy by drug is necessary, and also at change of the mode of a drug dosing of Imatib. As an alternative warfarin should consider a question of use of low-molecular heparins.

At a combination of drug of Imatib with chemotherapeutic drugs in high doses development of tranzitorny hepatic toxicity in the form of increase in activity of "hepatic" transaminases and a hyperbilirubinemia is possible.

At a combination of an imatinib and the modes of chemotherapy which can potentially cause abnormal liver functions it is necessary to provide control of function of a liver.

In vitro иматиниб inhibits a P450 cytochrome CYP2D6 isoenzyme in the same concentration in which it inhibits CYP3A4 isoenzyme. At use of drug of Imatib in a dose of 400 mg 2 times a day together with metoprololy, CYP2D6 isoenzyme substrate, were noted the moderate decrease in metabolism of a metoprolol which is followed by increase in Cmax and AUC approximately for 21%. Considering moderate strengthening of effects of the drugs which are CYP2D6 isoenzyme substrates (for example, a metoprolola), at their combined use with imatiniby, change of the mode of dosing is not required.

In vitro иматиниб inhibits O-glyukuronirovaniye paracetamol. The case of development in the patient of an acute liver failure with a lethal outcome at simultaneous use of an imatinib and paracetamol is described. It is necessary to be careful at use of an imatinib together with paracetamol.

Contraindications:

- Hypersensitivity to an imatinib or any other component of drug;
- Children's age up to 2 years (efficiency and safety are not established so far);
- Pregnancy and period of breastfeeding.

With care. If at you one of the listed diseases before administration of drug surely consult with the doctor.

It is necessary to appoint with care drug of Imatib to patients with a heavy liver failure, heavy renal failures, cardiovascular diseases or with risk factors of development of heart failure, and also when holding a regular procedure of a hemodialysis.

Overdose:

Experience of use of drug of Imatib in the doses exceeding therapeutic is limited.

In clinical practice cases of overdose of an imatinib were noted. In general the result of overdose was favorable (improvement of a condition of patients was noted). The antidote to an imatinib is not known. At overdose medical observation and symptomatic therapy is recommended.

Overdose at adults. At administration of drug of Imatib in a dose of 1200-1600 mg within 1-10 days nausea, vomiting, diarrhea, rash, an erythema, hypostases, a swelling generally of the person, increased fatigue, muscular spasms, thrombocytopenia, an abdominal pain, a headache, a loss of appetite were observed.

At reception of an imatinib in a dose of 1800-3200 mg (the greatest dose makes 3200 mg a day within 6 days) weakness, a mialgiya, increase in blood of activity of a kreatinfosfokinaza, concentration of bilirubin, gastrointestinal pains were noted.

At use of an imatinib in a dose of 6400 mg once (information from the published source) at the patient nausea, vomiting, an abdominal pain, a hyperthermia, a face edema, decrease in number of neutrophils and increase in activity of "hepatic" transaminases developed.

At reception of an imatinib in a dose of 8-10 g vomiting and gastrointestinal pains were once noted.

Overdose at children and teenagers. At reception of an imatinib in a dose of 400 mg once at the 3-year-old child vomiting, diarrhea and anorexia were noted. In other case at reception of an imatinib in a dose of 980 mg once at the child at the age of 3 years diarrhea and decrease in quantity of leukocytes were observed.

Storage conditions:

In the dry, protected from light place at ^{a temperature not higher than 25 ° C}. To store also the place, unavailable to children. Period of validity 2 years.

Issue conditions:

According to the recipe

Packaging:

Capsules of 50 mg:

- On 10 capsules place in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On the 3rd blister strip packagings place together with the instruction on a medical use in a cardboard pack.

- On 30 capsules place in the bottles from polymeric materials for medicines corked by a plastic cover with control of the first opening or without it. On 1 bottle place together with the instruction on a medical use in a cardboard pack.

Capsules of 100 mg:

- On 12 capsules place in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 2, 3, 4, 8, 10 or 15 blister strip packagings place together with the instruction on a medical use in a cardboard pack.

- On 24, 36, 48, 96, 120 or 180 capsules place in the bottles from polymeric materials for medicines corked by a plastic cover with control of the first opening or without it. On 1 bottle together with the instruction on a medical use place in a cardboard pack.