Иматиниб

General characteristics. Structure:

The operating veshchstvo: 50 mg or 100 mg of an imatinib (in the form of an imatinib of a mezilat).

Excipients: the hypro rod low-replaced povidone, carboxymethylstarch of sodium, silicon dioxide colloid, magnesium stearate, опадрай yellow (dye ferrous oxide yellow, a macrogoal, talc, a gipromelloz), опадрай red (dye ferrous oxide red, a macrogoal, talc, a gipromelloz).

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 Vsg-Abl a tyrosinekinase including the unripe leukemic cells which are formed at a myelosis at patients with a positive Philadelphian chromosome (Ph+) and at an acute lymphoblastoid leukosis.

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 a GIT expressing a tyrosinekinase with a mutation of c-K.it of 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, with - a Kit-receptor and an Abl-fragment of a tyrosinekinase.

Pharmacokinetics. Absorption. After intake bioavailability of drug averages 98%. Coefficient of variation for 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 observed.
 
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 for 11%, AUC - for 7,4%) and delay of speed of absorption is noted (increase in time up to achievement of the maximum concentration of an imatinib in a blood plasma on 1,5 h).
 
Distribution. About 95% of an imatinib contact proteins of plasma (mainly with albumine and acid and - 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 system blood-groove. 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. After reception of one dose drug is removed from an organism within 7 days, is preferential in the form of metabolites (68% - intestines and 13% - kidneys). In not changed look about 25% of a dose are removed (20% - intestines and 5% - kidneys). The elimination half-life of an imatinib makes about 18 h.
 
At repeated administrations of drug 1 р / days pharmacokinetic parameters do not change, and concentration of an imatinib in an equilibrium state exceeds initial by 1,5 - 2,5 times.
 
Pharmacokinetics at special groups of patients. 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 represented so essential that change of a dose of drug depending on the body weight of the patient was required. The pharmacokinetics of an imatinib does not depend on a floor.

At children and teenagers aged up to 18 years, as well as at adults, иматиниб it is quickly soaked up after intake. AUC in the range of doses of 260 and 340 mg/m is similar to that at adults in the range of doses of 400 mg and 600 mg respectively. When comparing AUC(o_24) values for the 1st and 8th days after repeated administration of drug in a dose of 340 mg/m 1 р / days note 1,7-fold cumulation of an imatinib.
 
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 (the clearance of creatinine (CC)> of 30 ml/min.) the increase in exposure of drug in plasma by 1,5 - 2,0 times corresponding to increase in concentration acid and - 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 myelosis (HML), positive on the Philadelphian chromosome (Ph+), at children and adults;

- Ph + 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 (OLL), positive on the Philadelphian chromosome (Ph+), at adult patients in a combination with chemotherapy;

- Recurrent or refractory Ph + OLL at adult patients as monotherapy;

- The Miyelodisplastichesky and myeloproliferative diseases (MDS/MPZ) connected with gene reorganizations of a receptor of a growth factor of thrombocytes at adult patients;

- A hyper eosinophilic syndrome and/or a chronic eosinophilic leukosis (Hydroelectric power station/HEL) at adult patients from positive or negative abnormal FIP1L1-PDGFR an alpha tyrosinekinase;

- Adjuvant therapy of stromal tumors of the digestive tract (DT), positive on with-Kit (CD117) at adult patients;

- An inoperable, recurrent and/or metastatic eminating dermatofibrosarcoma at adults.

Route of administration and doses:

Иматиниб accept inside, during food, washing down with a full glass of water. Doses of 400 and 600 mg/days should be accepted 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 a tablet entirely, for example, to children, it is possible to accept drug in a divorced look; tablets part with water or apple juice. Necessary quantity of tablets place in a glass, fill in with liquid (50 - 100 ml) and stir a spoon; suspension is as a result formed. The turned-out suspension should be accepted inside right after preparation.

The mode of dosing depends on the diagnosis and a stage of a disease. Иматиниб only the doctors having experience of treatment of patients with the corresponding diseases can appoint. Treatment by drug is carried out until the clinical effect remains.

Ph + a myelosis at adults - the recommended dose of an imatinib depends on a disease phase. In chronic phase HML the dose makes 400 mg/days, in a phase of acceleration of HML and at blast crisis - 600 mg/days. It is necessary to accept drug 1 time a day. Treatment by drug is carried out until the clinical effect remains. 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/days to 600 mg/days or to 800 mg/days at patients in a chronic phase of a disease, and from 600 mg/days to 800 mg/days 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.

Ph + a myelosis at children is more senior than 2 years - the dose is calculated depending on body surface area. At children with chronic phase HML and a phase of acceleration the dose of 340 mg/m/days is recommended. The general daily dose at children should not exceed 600 mg. The daily dose of drug can be accepted in one step or to divide into 2 equal receptions - in the morning and in the evening.

Acute Ph + a lymphoblastoid leukosis at adults - the recommended dose of an imatinib makes 600 mg/days.

Miyelodisplastichesky and myeloproliferative diseases at adults - the recommended dose of an imatinib makes 400 mg/days.

Adjuvant therapy of stromal tumors of a GIT at adults - the recommended dose of an imatinib of 400 mg/days. The minimum duration of treatment makes 3 years. The optimum maximum duration of adjuvant therapy is not established. At emergence of signs of progressing therapy by drug should be stopped. Inoperable, recurrent and/or metastatic eminating a dermatofibrosarkomaa of adults - the recommended dose makes 800 mg/days. The hyper eosinophilic syndrome and/or chronic eosinophilic leukemia at adults - the recommended dose makes 400 mg/days. At patients from hydroelectric power stations/HEL caused by abnormal FIP1L1-PDGFR and - a tyrosinekinase, the recommended initial dose makes 100 mg/days. At insufficient efficiency and lack of the expressed side effects increase in a dose to 400 mg/days is possible.

Correction of the mode of dosing. Patients with an abnormal liver function. As иматиниб it is metabolized mainly in a liver, patients with easy, moderate or heavy abnormal liver functions иматиниб should appoint 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, however patients with easy or moderate renal failures have a treatment imatiniby it is necessary to begin with a minimal effective dose - 400 mg/days. Though experience of use of an imatinib for patients with heavy renal failures or when holding a regular procedure of a hemodialysis is limited, at this category of patients therapy with drug can also be begun with 400 mg/days, being careful. At bad portability of therapy imatiniby 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.

Not hematologic side effects. 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 increase in activity of "hepatic" transaminases in blood serum in 3 and 5 times above the upper bound of norm (UBN) respectively, treatment by drug it is necessary to suspend temporarily before decrease in concentration of bilirubin to value less 1,5khvgn and activities of "hepatic" transaminases up to value less 2,5khvgn.

Therapy imatiniby is resumed from the reduced daily dose: at adults the dose is reduced from 400 mg to 300 mg/days or from 600 mg to 400 mg/days, or from 800 mg to 600 mg/days; at children - from 340 to 260 mg/m/days Hematologic side effects

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 hyper eosinophilic syndrome and/or chronic eosinophilic leukemia caused by abnormal FIP1L1-PDGFR and - a tyrosinekinase (an initial dose of an imatinib of 100 mg), in case of decrease in absolute number of neutrophils <1> <109/l and/or numbers of thrombocytes <50x109/l it is recommended:

- to cancel иматиниб until the absolute number of neutrophils does not become> 1,5khyu9/l And thrombocytes> 75khyu9/l;

- to resume treatment imatiniby in the dose applied before therapy interruption. At the chronic phase XMJI at children and adult, stromal tumors of a gastro intestinal path (GIST), MDS/MPZ and hydroelectric power station/HEL at adult patients (an initial dose for adults - 400 mg, for children - 340 mg/sq.m) in case of decrease in absolute number of neutrophils <1x10/l and/or numbers of thrombocytes <50x109/l it is recommended:

- to cancel иматиниб until the absolute number of neutrophils does not become> 1,5x109/l and thrombocytes> 75 x 109/l;

- to resume treatment imatiniby in the dose applied before therapy interruption.

In case of repeated decrease in number of neutrophils <1x10/l and/or numbers of thrombocytes <50kh107l it is necessary to cancel иматиниб again until the absolute number of neutrophils does not become> 1,5x10/l and thrombocytes> 75x10%, and then to resume treatment imatiniby in the reduced dose of 300 mg (children have 260 mg/m).

In a phase of acceleration and blast crisis of XMJI at children and adults and at (Ph+) - at adult patients (an initial dose for adults - 600 mg, for children - 340 mg/m) in case of decrease in absolute number of neutrophils <0,5x10/l and/or numbers of thrombocytes <10x10/l after one and more months of treatment it is recommended to OJIJI:

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

- if the cytopenia is not connected with a leukosis, to reduce a dose of an imatinib to 400 mg (children have 260 mg/m);

- if the cytopenia remains within 2 weeks, to reduce a dose to 300 mg (children have 200 mg/sq.m);

- if the cytopenia remains within 4 weeks and its communication with a leukosis is not confirmed, to cancel иматиниб until the absolute number of neutrophils does not become> 1x10/l and thrombocytes> 20x10%; then to resume treatment imatiniby 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 an imatinib of 800 mg) in case of decrease in absolute number of neutrophils <1khyu9/l and/or numbers of thrombocytes <50x10/l it is recommended:

- to cancel иматиниб until the absolute number of neutrophils does not become> 1,5x10% and thrombocytes> 75х10%;

- to resume treatment imatiniby in a dose of 600 mg.

In case of repeated decrease in number of neutrophils <1x10/l and/or numbers of thrombocytes <50kh 10% should be cancelled иматиниб again until the absolute number of neutrophils does not become> 1,5x10% and thrombocytes> 75x10%, and then to resume treatment imatiniby in the reduced dose of 400 mg.

Features of use:

Pregnancy and lactation. Purpose of drug is contraindicated. Women of childbearing age during therapy imatiniby and at least within 3 months later should apply effective methods of contraception.

Treatment imatiniby 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 hit it on skin and in eyes, and also drug powder inhalations.

Efficiency and safety of use of an imatinib for children with HML are younger than 2 years is not established yet. Experience of use of an imatinib according to other indications is limited at patients 18 years are younger. Long-term effects of long impact of an imatinib on growth at children are unknown. But as there are messages on growth inhibition cases, it is recommended to make careful control of growth at the children accepting иматиниб.

Hemopoiesis oppression. Frequency of oppression of a hemopoiesis and degree of its expressiveness at use of an imatinb were maximum in case of use of drug in high doses and, apparently, depended on HML stage. In general, oppression of a hemopoiesis against the background of use of an imatinib for sick HML was reversible and in most cases did not demand drug withdrawal or reduction of its dose. Drug withdrawal требоваласьв small number of cases. Also such phenomena as a pantsitpeniya, a lymphopenia and oppression of a hemopoiesis were noted.

At use of an imatinib it is recommended to carry out regular clinical blood test and control of function of a liver ("hepatic" transaminases, bilirubin, an alkaline phosphatase).

Hypostases and delay of liquid. Hypostases are frequent side effect of an imatinib. Frequency of developing of hypostases at the patients receiving иматиниб on all показаням makes more than 50%. Frequency and degree of manifestation of hypostases depends on a dose and, apparently, correlates with concentration of drug in a blood plasma. Most often there are periorbital hypostases, with a little smaller frequency - hypostases of the lower extremities. Specific treatment usually is not required. At patients with hypostases and a delay of liquid heart failure is noted seldom. Despite it, it is necessary to provide careful observation of patients with heart diseases. At patients with late stages of HML the frequency of heart failure was higher, than at patients of other categories that it is possible to explain them with the weakened state in general. The largest frequency of development of a delay of liquid is noted at elderly patients with the accompanying serdechnoksosudisty diseases. The same tendency was observed concerning a renal failure at patients with hypostases and a delay of liquid. Most of patients with hypostases and a delay of liquid were elderly people (> 65 years). For early detection of a delay of liquid 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 imatiniby and/or to appoint diuretics.

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

Hepatotoxic. Drug can have toxic effect on a liver. Disturbance of biochemical indicators of function of a liver, as a rule, consists in slight increase of activity of "hepatic" transaminases and increase in concentration of bilirubin in blood serum. Toxic action on a liver is usually shown within the first two months of treatment, however in some cases it is shown also 6-12 months later after an initiation of treatment. As imparted, after drug withdrawal biochemical indicators of function of a liver are normalized within 1 - 4 weeks. The expressed increase in activity of "hepatic" transaminases or bilirubin was noted at less, than 3% of patients with XMJI and were usually controlled by a dose decline of drug or temporary interruption of treatment (the average duration of such episodes made about 1 week). At use of drug for patients with diseases of a liver it is regularly necessary to carry out clinical blood test and control of function of a liver ("hepatic" transaminases, bilirubin, an alkaline phosphatase).

Hemorrhage/bleeding. Bleedings from a GIT were significant bleedings most frequent clinically at use of an imatinib. Most often they arose at patients with late stages of XMJI and at patients with malignant stromal tumors of a GIT at which they can be a consequence of a basic disease (the bleeding from a tumor caused by a tumor necrosis).

At patients with malignant stromal tumors of a GIT gastro intestinal bleedings and bleedings from a tumor are possible. At the same time, both intra belly, and intra hepatic hemorrhages, depending on anatomic localization of a tumor are noted.

At sick HML at which a hemopoiesis was oppressed already prior to treatment during treatment hemorrhages in the central nervous system or a GIT were quite often noted. It is established that patients with leukoses with acute development of a disease quite often have bleedings/hemorrhages caused by thrombocytopenia or a trombotsitopatiya.

Rash and heavy skin undesirable phenomena. At a number of the patients receiving иматиниб generalized erythematic, spotty and papular and pruritic rash which could pass independently, despite drug use continuation was noted. Some patients had an itch which is not followed by rash, in some cases there was an erythrosis. Rash was noted approximately at a third of all patients receiving иматиниб according to all indications. Often rash is followed by an itch and is, as a rule, shown in the form of erythematic, spotty and papular defeats on a forearm, a trunk and a face. Though in most cases rash easy also passes without treatment, in more hard cases temporary or full drug withdrawal can be required. As a rule, expressiveness of rash decreases after purpose of antihistaminic drugs and glucocorticosteroids for topical administration. In certain cases it is required to use corticosteroid drugs for system use. Impassability, perforation or stomach ulcer or intestines

At a small part of the patients receiving иматиниб the GIT ulceration which in some cases can be a consequence of local irritative action of an imatinib was noted. The hemorrhagic necrosis of a tumor, and also impassability and perforation of a GIT were most often observed at patients with malignant stromal tumors of a GIT. In case of metastatic malignant stromal tumors of a GIT the necrosis of a tumor can arise against the background of the tumoral answer that in rare instances leads to perforation. Impassability of a GIT arose at patients more often with malignant stromal tumors of a GIT at which the metastasises or commissures resulting from earlier performed GIT operation can serve as its reason (in case of use of drug as adjuvant therapy).

Other special instructions. 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 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 cancellation of an imatinib.

At patients with MDS/MPZ and high level of eosinophils it is necessary to carry out an electrocardiography and to define serumal concentration of a 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.

During therapy imatiniby and at least within 3 months later it is necessary to use reliable ways of contraception.

Influence on ability to manage vehicles and mechanisms. Some side reactions of drug, such as dizziness and illegibility of sight, can negatively influence ability of driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. In this regard, the patients receiving иматиниб should show 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 undesirable phenomena (UP). The most frequent NYa (> 10%) connected with reception of an imatinib 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 XMJI 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 depending on NYa degree of manifestation is possible, up to drug withdrawal.

The side effects revealed during clinical trials of an imatinib at patients with HML and with nonresectable and/or metastatic malignant stromal tumors of a GIT are listed below on bodies and systems with the indication of their frequency of emergence: very often (> 1/10), it is frequent (> 1/100 <1/10), infrequently (> 1/1000 <1/100), is rare (> 1/10 000 <1/1000), is very rare (<1/10 000, including separate messages).

Infectious diseases: infrequently - the herpes simplex, herpes surrounding, a nasopharyngitis, pneumonia, sinusitis, an inflammation of hypodermic cellulose, an infection of upper parts of respiratory tracts, 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 limfoadenopatiya; seldom - hemolitic anemia.

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

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

Disturbances from an organ of sight: often - the century, increase in a slezootdeleniye, hemorrhage in a conjunctiva, conjunctivitis, a syndrome of "a dry eye", a sight illegibility 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, chronic cordial nedostatochnost3, a fluid lungs, tachycardia, "inflows"; seldom - arrhythmias, fibrillation of auricles, a sudden cardiac standstill, a myocardial infarction, stenocardia, a pericardiac exudate, increase in arterial pressure.

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

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

Disturbances from digestive tract: very often - nausea, vomiting, diarrhea, dyspepsia, pains in zhivote7; often - abdominal distention, a meteorism, a lock, a gastroesophageal reflux, dryness in a mouth, gastritis; infrequently - stomatitis, an ulceration of a mucous membrane of an oral cavity, gastrointestinal bleedings, 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" transaminases; infrequently - jaundice, hepatitis, a hyperbilirubinemia; seldom - a liver failure, a liver necrosis.

Disturbances from skin and hypodermic fabrics: very often - periorbital hypostases, dermatitis, eczema, skin rash; often - puffiness of the person, an itch, a xeroderma, an erythema, 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, 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, a Quincke's disease, a multiformny erythema, a leykoklastichesky vasculitis, Stephens's syndrome - Johnson, an acute generalized pustular dieback.

Disturbances from a musculoskeletal system and connecting fabric: very often - muscular spasms and spasms, musculoskeletal pains (including mialgiya, arthralgias, pains in kostyakh1); often - swelling of joints; infrequently - constraint of muscles and joints; seldom - 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.

Disturbances from generative organs and mammary glands: infrequently - a gynecomastia, erectile dysfunction, a menorrhagia, disturbance 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 data: infrequently - increase in activity of an alkaline phosphatase, kreatinfosfokinaza, lactate dehydrogenase and concentration of creatinine in blood serum; seldom - increase in activity of amylase in a blood plasma.

1. Pneumonia was most often noted at patients with HML in a phase of acceleration, blast crisis and with nonresectable and/or metastatic stromal tumors of a GIT.

2. The headache was most often noted at patients with nonresectable and/or metastatic 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 stromal tumors of a GIT.

5. Bleedings (hematomas, hemorrhages) were most often noted at patients with HML in a phase of acceleration, blast crisis and with nonresectable and/or metastatic stromal tumors of a GIT.

6. The pleural exudate was more often noted at patients with HML in a phase of acceleration and at blast crisis in comparison with HML in a chronic phase (observation duration - 1 year).

7. The abdominal pain was most often noted at patients with nonresectable and/or metastatic stromal tumors of a GIT.

8. Gastrointestinal bleedings were most often noted at patients with nonresectable and/or metastatic stromal tumors of a GIT.

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

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

At use of an imatinib in clinical practice, and also during additional clinical trials 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 (> 1/10 000, <1/1000), is very rare (<1/10 000, including separate messages). The interrelation between use of drug and these undesirable phenomena is not established (the size of population of patients is unknown).

Disturbances from a nervous system: infrequently - wet brain.

Disturbances from an organ of sight: seldom - vitreous hemorrhages.

Disturbances from heart: seldom - a pericardis, a cardiac tamponade.

Disturbances from vessels: infrequently - fibrinferments/embolisms; very seldom - an acute anaphylaxis.

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

Disturbances from digestive tract: infrequently - Ilheus (intestinal impassability), bleedings from a GIT tumor, a GIT tumor necrosis, perforatsiya2 a GIT; 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 a musculoskeletal system and connecting fabric: seldom - an avaskulyarny necrosis / necrosis of a head of a femur, рабдомиолиз / a myopathy.

Disturbances from generative organs and mammary glands: very seldom - women have a bleeding from a cyst of a yellow body / ovary.

1. There are 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.

It was reported about separate cases of development a perforatsy GIT with a lethal outcome.

Interaction with other medicines:

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

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

At simultaneous use of an imatinib and simvastatin increase in Cmax and AUC of a simvastatin in 2 and 3,5 times is noted, respectively, that is a consequence of inhibition of an isoenzyme of CYP3A4 imatiniby. It is recommended to be careful at the simultaneous use of an imatinib and drugs which are substrates of an isoenzyme CYP3A4 and having the narrow range of therapeutic concentration (for example, cyclosporine, Pimozidum).

Иматиниб can increase serumal concentration of other drugs, metabolized CYP3A4 isoenzyme (the triazolobenzodiazepines derivative of dihydropyridine - blockers of "slow" calcium channels, the majority of inhibitors Z-gidroksi-Z-metilglutarilreduktazy of a coenzyme And (GMG-KOA-reduktazy), including statines). Иматиниб also inhibits isoenzymes of CYP2C9 and CYP2C19 in vitro. Lengthening of a prothrombin time was observed at the combined use with warfarin.

At simultaneous use with coumarinic derivatives short-term monitoring of a prothrombin time at the beginning and at the end of therapy imatiniby is necessary, and also at change of the mode of dosing of an imatinib. Alternatively it is necessary to consider a question of use of low-molecular derivatives of heparin.

At a combination of an imatinib 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 CYP2D6 isoenzyme in the same concentration in which it inhibits CYP3A4 isoenzyme.

At use of an imatinib in a dose of 400 mg 2 times a day together with metoprololy, CYP2D6 isoenzyme substrate, are 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-glyukuronidatsiyu 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 or drugs of the St. John's Wort which is made a hole.

Contraindications:

Hypersensitivity to an imatinib or any components of medicine, pregnancy, the feeding period a breast, age up to 2 years (safety and efficiency of use are not established).

With care: Иматиниб patients should appoint with care with a heavy liver failure, heavy renal failures (KK less than 30 ml/min.), 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 an imatinib in the doses exceeding therapeutic is limited. In clinical practice drug overdose cases were noted. In general, the outcome of cases of overdose imatiniby 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 reception of an imatinib in a dose more than 1200 - 1600 mg in knocks within 1-10 days were observed nausea, vomiting, diarrhea, skin rash, an erythema, hypostases, puffiness in joints, muscular spasms, increased fatigue, thrombocytopenia, a pancytopenia, an abdominal pain, a headache, a loss of appetite.

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

At use of an imatinib in a dose of 6400 mg once at the patient nausea, vomiting, an abdominal pain, fervescence, a face edema, decrease in quantity 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 three-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 were observed decrease in quantity of leukocytes in blood and diarrhea.

Storage conditions:

To store in the dry place protected from light at a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets for dosages of 50 mg and 100 mg or 12 tablets for a dosage of 100 mg in a blister strip packaging from aluminum foil and a film of PVC. On 3 blister strip packagings on 10 tablets for a dosage of 50 mg, on 2 or 6 blister strip packagings on 10 tablets for a dosage of 100 mg together with the application instruction in a pack cardboard. On 2, 3, 4, 8, 10 or 15 blister strip packagings on 12 tablets for a dosage of 100 mg together with the application instruction in a pack cardboard.