Филахромин® FS

General characteristics. Structure:

Active ingredient: 50 mg or 100 mg of an imatinib of a mezilat in terms of иматиниб.

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

Structure of the capsule: case: titanium dioxide of 2%, gelatin to 100%; lid: dye indigo carmine of 0,3%, titanium dioxide of 1%, dye ferrous oxide of yellow 1,7143%, gelatin to 100%.

Pharmacological properties:

Pharmacodynamics. Иматиниб selectively inhibits 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. Иматиниб selectively suppresses proliferation and causes apoptosis of the cellular lines expressing Bcr-Abl-tirozinkinazu, and also unripe leukemic cells at a myelosis with a positive Philadelphian chromosome and at an acute lymphoblastoid leukosis. At patients with a myelosis иматиниб selectively inhibits Bcr-Abl-positive colonies, has antineoplastic activity at monotherapy.

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

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

Activation of a s-Kit-retseptora 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.

Иматиниб inhibits proliferation and induces apoptosis of cells of the gastrointestinal stromal tumors expressing a tyrosinekinase with a s-Kit-retseptora mutation.

Pharmacokinetics. Absorption. After intake bioavailability of an imatinib averages 98%. 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 and delay of speed of absorption is noted. Коэффицент variations for an indicator the area under a curve "concentration time" makes 40 – 60%.

Distribution. Linkng with proteins of plasma makes about 95% (mainly with albumine and acid alpha glycoproteins, in insignificant degree – with lipoproteins).

Metabolism. Иматиниб it is metabolized generally in a liver. The main metabolite of an imatinib circulating in a circulatory bed is N-demetilirovannoye piperazinovy derivative which in vitro has the pharmacological activity similar to that of initial drug.

Removal. Иматиниб it is removed preferential in the form of metabolites within 7 days after reception of one dose (intestines – 68%, kidneys – 13%). 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 hours. At use of the repeated doses appointed once a day the pharmacokinetics of an imatinib does not change. Value of equilibrium concentration exceeds value initial by 1,5 – 2,5 times.

Indications to use:

For the first time the revealed chronic myeloid leukosis, positive on the Philadelphian chromosome (Ph+), at children and adults.

Chronic myeloid leukosis, positive on the Philadelphian chromosome (Ph+), 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+), at adult patients in a combination with chemotherapy.

Recurrent or refractory acute lymphoblastoid leukosis positive on the Philadelphian chromosome (Ph+) at adult patients as monotherapy.

Миелодиспластические/миелопролиферативные the diseases connected with gene reorganizations of a receptor of a growth factor of thrombocytes at adult patients.

System mastocytosis at adult patients with lack of D816V-Kit from a mutation or the unknown with-Kit the mutational status.

Hyper eosinophilic syndrome and/or chronic eosinophilic leukosis at adult patients from positive or negative abnormal FIP1L1-PDGRF an alpha tyrosinekinase.

Adjuvant therapy of gastrointestinal stromal tumors (GISO) positive on with-Kit (CD 117) at adult patients.

Nonresectable and/or metastatic malignant gastrointestinal stromal tumors (GISO) positive on with-Kit (CD 117) at adult patients.

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

Route of administration and doses:

Филахромин® FS should be accepted inside, during meal, washing down with a full glass of water. Doses of 400 and 600 mg a day 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.

For patients (including children) who cannot swallow the capsule entirely, part contents of the capsule with water or apple juice. The turned-out suspension should be accepted inside right after preparation.

At a myelosis (HML) the recommended dose of Filakhromina® of FS depends on a disease phase.

In chronic phase HML the dose for adults makes 400 mg a day; in a phase of acceleration and at blast crisis – 600 mg a day. 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 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 the surface area of a body (mg/sq.m). The dose of 340 mg/sq.m a day is recommended to children with a chronic phase and a phase of acceleration of HML. 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.

There are no data on use of drug for children is younger than 2 years. At an acute lymphoblastoid leukosis with (Ph+) the recommended dose of Filakhromina® of FS makes 600 mg a day.

At миелодиспластичеких / myeloproliferative diseases (MDS/MPZ) the recommended dose of Filakhromina® of FS makes 400 mg a day.

At inoperable and/or metastatic GISO the recommended dose of Filakhromina® of FS makes 400 mg a day. In the absence of side effects of drug and the insufficient answer increase in a daily dose of Filakhromina® of FS from 400 mg to 600 mg or to 800 mg is possible.

Treatment of Filakhrominom® of FS is carried out to the first signs of progressing of a disease. At use of drug as adjuvant therapy at patients with GISO the recommended dose makes 400 mg a day. The optimum duration of adjuvant therapy is not established.

At an inoperable, recurrent and/or metastatic eminating dermatofibrosarcoma the recommended dose of Filakhromina® of FS makes 800 mg in
days.

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

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

At a system mastocytosis in the absence of D816V-Kit from a mutation the recommended dose of Filakhromina® of FS 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 system mastocytosis caused by abnormal FIP1L1-PDGFR the alpha 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. Increase in a dose from 100 mg to 400 mg can be considered at insufficient efficiency and lack of side effects.

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

Patients with a renal failure. Kidneys do not play an essential role in removal of an imatinib and its metabolites. At patients with easy or moderate renal failures treatment should be begun with a minimal effective dose - 400 mg of 1 times a day.

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 it is also possible to begin with drug with a dose 400 mg of 1 times a day. 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 from patients of advanced age.

Correction of the mode of dosing at development of not hematologic side effects of drug. Treatment has to be suspended at development of any serious not hematologic side effect connected with administration of drug before resolving the situation. Then treatment can be resumed depending on weight of the observed serious 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, treatment by drug should be suspended temporarily before decrease in concentration of bilirubin to value less than 1,5 x VGN and activities of transaminases of a liver to value less than 2,5 x VGN.

Therapy of Filakhrominom® of FS should be resumed from the reduced daily dose: at
adults a dose are 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 – from 340 to 260 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 is required temporary drug withdrawal or reduction of its dose, depending on degree of manifestation of these side effects.

Recommendations about reduction of a dose according to development of a neutropenia and thrombocytopenia are presented in the table:

Indications for use	Dynamics of number neutrophils and thrombocytes in blood	Correction of the mode of dosing
The System Mastocytosis (SM) and hyper eosinophilic syndrome and/or chronic eosinophilic leukosis (Hydroelectric power station/HEL) caused by abnormal FIP1L1-PDGFR an alpha tyrosinekinase (an initial dose of Filakhromina® of FS of 100 mg).	Decrease in absolute number of neutrophils <1000/mkl and/or numbers of thrombocytes <50000/mkl.	1. To cancel Filakhromin® of FS, before recovery of absolute number of neutrophils 1500/mkl and thrombocytes 75000/mkl. 2. To resume treatment of Filakhrominom® of FS in the dose applied before therapy interruption.
Chronic phase HML at children and adults, malignant GISO, to miyelodisplasticheskiye/miyeloprolifa rativny diseases, CM and hydroelectric power station/HEL at adult patients (initial dose of Filakhromina® of FS for adults - 400 mg, for children - 340 mg/sq.m).	Decrease in absolute number of neutrophils <1000/mkl and/or numbers of thrombocytes <50000/mkl.                 In case of repeated decrease in number of neutrophils <1000/mkl and/or numbers of thrombocytes <50000/mkl.	1. To cancel Filakhromin® of FS, before recovery of absolute number of neutrophils 1500/mkl and thrombocytes 75000/mkl. 2. To resume treatment Филахромином® FS in a dose, the therapy applied before interruption.       It is necessary to repeat actions, specified in point 1, and then to resume treatment Филахромином® FS in to the reduced dose of 300 mg (children have 260 mg/sq.m).
Phase of acceleration and blast crisis HML at children and adults and at Ph + acute lymphoblastoid leukosis at adult patients (initial dose for adults – 400 mg, for children – 340 mg/sq.m).	Decrease in absolute number of neutrophils <500/mkl and/or numbers of thrombocytes <10000/mkl after one and more months of treatment.	1. To check whether the cytopenia is a consequence of a leukosis (a marrow research). 2. If the cytopenia is not connected with a leukosis, to reduce a dose Филахромина® FS to 400 mg (children have 260 mg/sq.m). 3. If the cytopenia remains within 2 weeks, to reduce a dose to 300 mg (children have 200 mg/sq.m). 4. If the cytopenia remains within 4 weeks and its communication with a leukosis is not confirmed, it is necessary to cancel Filakhromin® of FS until the absolute number of neutrophils does not become ≥ 1000/mkl and thrombocytes ≥ 20000/mkl; then to resume treatment of Filakhrominom® of FS in a dose of 300 mg (children have 260 mg/sq.m).
Inoperable, recurrent and/or metastatic eminating dermatofibrosarcoma (initial dose of Filakhromina® of FS of 800 mg).	Decrease in absolute number of neutrophils <1000/mkl and/or numbers of thrombocytes <50000/mkl. In case of repeated decrease in number of neutrophils <1000/mkl and/or numbers of thrombocytes <50000/mkl.	1. To cancel Filakhromin® of FS until the absolute number of neutrophils does not become ≥ 1500/mkl and thrombocytes ≥ 75000/mkl; 2. To resume treatment Филахромином® FS in a dose of 600 mg. It is necessary to repeat the actions specified in point 1 and then to resume treatment of Filakhrominom® of FS in the reduced dose of 400 mg.

Features of use:

Treatment of Filakhrominom® of FS should be carried out only under observation of the doctor having experience with antineoplastic drugs.

It is recommended to be careful at the address with capsule contents in order to avoid contact with skin, with a mucous membrane of eyes or accidental inhalation of powder of drug. After opening of capsules it is necessary to wash up hands at once.

It is regularly recommended to carry out clinical blood tests and control of function of a liver (transaminases, bilirubin, an alkaline phosphatase).

At purpose of drug patients with diseases of a liver should carry out regularly clinical analyses of peripheral blood and liver enzymes.

Careful observation of patients with heart diseases is recommended.

At elderly patients with cardiovascular diseases it is regularly necessary to determine the body weight as at use of an imatinib the expressed liquid delay is often noted.

At bystry unexpected increases in body weight it is necessary to conduct examination of the patient and if necessary temporarily to stop therapy of Filakhrominom® of FS and/or to appoint diuretics. In some cases the expressed delay of liquid can have a heavy current with a lethal outcome.

At patients with malignant GISO gastrointestinal bleedings and bleedings from a tumor are possible. Both intra belly, and intra hepatic bleedings, depending on anatomic localization of a tumor are noted.

At patients with MDS/MPZ and high level of eosinophils it is necessary to conduct an ECG research 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.

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

Efficiency and safety of use of Filakhromina® of FS for children are younger than 2 years is not established yet.

To patients the sodium left thyroxine which transferred a thyroidectomy and receiving replacement therapy, it is regularly necessary to carry out definition of concentration of thyritropic hormone as development of a hypothyroidism is possible.

Patients with a syndrome have hypereosinophilia and heart diseases at the beginning of therapy imatiniby, in some cases, development of cardiogenic shock / left ventricular failure which were stopped by introduction of system glucocorticosteroids, actions directed to maintenance of blood circulation and temporary cancellation of an imatinib was noted.

Kidneys do not play an essential role in removal of an imatinib and its metabolites. Patients with a renal failure have no specific recommendations about the mode of dosing Filakhromina® of FS.

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

Use at pregnancy and during breastfeeding. There are no data on use of an imatinib for pregnant women now. Иматиниб makes toxic impact on reproductive function, however the potential risk for a fruit is still unknown. Иматиниб it is not necessary to appoint during pregnancy unless it is vital, at the same time it is necessary to warn the patient about existence of potential risk for a fruit. Women of childbearing age during therapy imatiniby should apply effective methods of contraception.

It is known that not changed иматиниб and/or its metabolites in significant amounts are allocated with milk. The women accepting Filakhromin® of FS should refuse feeding by a breast.

Possible influence of medicine on ability to manage vehicles, mechanisms. Now data on possible influence of Filakhromina® of FS on ability to manage vehicles and mechanisms are absent. Nevertheless, considering that use of drug can lead to development of such side effects as dizziness, the syncope and misting of sight, is recommended to be careful during the driving of the car or work with mechanisms.

Side effects:

In the developed stage of HML or GISO patients can have the multiple accompanying disturbances complicating assessment of side effects of an imatinib because of a number of the symptoms connected with associated diseases, their progressing and reception of various medicines.

It is known that daily long reception of an imatinib inside at adults and children with HML in general is transferred well. At most of patients at a certain stage of treatment side effects easily or moderately expressed are possible.

Side effects are similar at the patients receiving иматиниб according to various indications. At patients with malignant GISO the miyelosupressiya is less often noted, and intra tumoral bleedings are characteristic only of this group.

Frequency of development of side effects and the general frequency of side effects of varying severity are similar at the patients receiving therapy imatiniby in a dose of 400 mg a day and 800 mg a day.

The most frequent side effects connected with administration of drug - the passing slight nausea, vomiting, diarrhea, abdominal pains, increased fatigue, mialgiya and muscular spasms, rash, peripheral hypostases preferential in periorbital area and the lower extremities. All these phenomena are easily stopped.

The combined side effects, such as pleural exudate, ascites, fluid lungs and bystry increase of body weight with peripheral hypostases or without them can be qualified in general as "a liquid delay". For elimination of the above-stated side effects it is necessary to stop for a while therapy imatiniby, to appoint diuretic means. In certain cases these phenomena can reach degree serious and even life-threatening.

The side effects registered more often than single observations are listed below on bodies and systems with the indication of frequency of their emergence.

Determination of frequency: very often (> 10%), it is frequent (from> 1% and <10%), infrequently – (> 0,1% and <1%), is rare (> 0,01% and <0,1%), is very rare (<0,01%), including separate messages.

Infectious diseases: infrequently – the herpes simplex surrounding herpes, pnevmoniya1, upper respiratory tract infections, a nasopharyngitis, sinusitis, an inflammation of hypodermic cellulose, 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 disintegration of a tumor.

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

Disbolism and food: often – anorexia; infrequently – a hypopotassemia, the increased appetite or a loss of appetite, gout, a hypophosphatemia, dehydration, a hyperuricemia, a hyponatremia, a hypercalcemia, a hyperglycemia; 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, disturbance of taste, paresthesia, a hypesthesia; infrequently – migraine, drowsiness, a faint, peripheral neuropathy, memory disturbance, a sciatica, a syndrome of "uneasy" legs (Vittmaaka-Ekbom's syndrome), a tremor, a hemorrhagic stroke, wet brain; seldom – increase in intracranial pressure, a spasm, an optic neuritis.

Disturbances from an organ of sight: often – the century, conjunctivitis, increase in a slezootdeleniye, sight "misting", hemorrhage under a conjunctiva, dryness of a conjunctiva swelled; infrequently – irritation of eyes, eye pain, orbital hypostasis, macular hypostasis, papillary hypostasis, retinal hemorrhages, a blepharitis; seldom – a cataract, glaucoma, a papilledema, vitreous hemorrhages.

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

Disturbances from heart: infrequently – heartbeat, congestive cordial nedostatochnost3, a fluid lungs, tachycardia, disturbance of permeability of capillaries, increase in arterial pressure, lowering of arterial pressure, "inflows" to the person, a fibrinferment/embolism; seldom – arrhythmias, a ciliary arrhythmia, fibrillation of auricles, a sudden cardiac standstill, a myocardial infarction, stenocardia, a pericardiac exudate, a pericardis, a cardiac tamponade.

Disturbances from vessels: infrequently – krovoizliyaniya4; seldom – hematomas, a cold snap of extremities, 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, acute respiratory insufficiency, intersticial pneumonia; seldom – pleural pain, pulmonary fibrosis, pleurisy, pulmonary hypertensia, pulmonary bleeding.

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

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

Disturbances from skin and hypodermic fabrics: very often – periorbital hypostasis, dermatitis, eczema, skin rash; often – puffiness of the person, puffiness a century, an itch, an erythema, a xeroderma, an alopecia, night perspiration, reactions of a photosensitization; infrequently – petechias, bruises, the increased sweating, a small tortoiseshell, ecchymomas, easy formation of hematomas, an urtikariya, injury of nails, purple, a hypotrichosis, a hyperpegmentation/hypoxanthopathy, a folliculitis, psoriasis, exfoliative dermatitis, violent rash; seldom – an acute febrile neutrophylic dermatosis (a syndrome It is twisted), a Quincke's disease, discoloration of nails, a multiformny erythema, a leykoklastichesky vasculitis, vesicular rash, Stephens-Johnson's syndrome, acute generalized exanthematic пустулез, a lichenoid keratosis, red flat deprive; very seldom - a toxic epidermal necrolysis.

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 - an ischialgia, constraint of muscles and joints; seldom – muscular weakness, arthritis, an acute necrosis of skeletal muscles (рабдомиолиз), a myopathy, an avaskulyarny necrosis of a head of a femur.

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

Disturbances from reproductive and endocrine systems: infrequently – a gynecomastia, increase in mammary glands, nipple pain, a hydroscheocele, decrease in a potentiality, erectile dysfunction, sexual dysfunction, a menorrhagia, disturbance of a menstrual cycle; very seldom – women have a bleeding from an oothecoma.

General frustration: very often – a delay of liquid and hypostases, increased fatigue; often – weakness, fervescence, a fever, a shiver, an anasarca; infrequently – a febricula, a stethalgia.

Others: very often – increase in body weight; often – decrease in body weight; 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; very seldom – an acute anaphylaxis.

1-Pneumonia is most often noted at patients with HML in a phase of acceleration, blast crisis and with inoperable and/or metastatic malignant GISO.
2-The headache is most often noted at patients with inoperable and/or metastatic GISO.
3-By-effects from heart, including congestive heart failure, are 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.
4-"Inflows" are most often noted at patients with inoperable and/or metastatic malignant GISO; bleedings (hematomas, hemorrhages) are most often noted at patients with HML in a phase of acceleration, blast crisis and with inoperable and/or metastatic malignant GISO.
5-Plevralny the exudate is 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.
6/7-The abdominal pain and gastrointestinal bleedings are most often noted at patients with inoperable and/or metastatic malignant GISO.
8-Myshechno-skeletnye pains, including a mialgiya, an arthralgia, an ostealgia are more often noted at patients with inoperable and/or metastatic malignant GISO.
9-Soobshchalos about separate cases of development of a liver failure and a necrosis of a liver.

Interaction with other medicines:

Increase in concentration of an imatinib in a blood plasma is possible at simultaneous use of an imatinib with the medicines inhibiting a P450 cytochrome CYP3A4 isoenzyme (кетоконазол, итраконазол, erythromycin, кларитромицин) owing to delay of metabolism of an imatinib. Care at the combined use of Filakhromina® of FS with drugs is necessary – inhibitors of isoenzymes CYP3A4.

Simultaneous use with the medicines which are the inductors CYP3A4 (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 plasma.

At simultaneous use of an imatinib and simvastatin increase in concentration of a simvastatin in blood is noted that is a consequence of inhibition of CYP3A4 imatiniby. It is recommended to be careful at the simultaneous use of an imatinib and drugs which are CYP3A4 substrates and having the narrow range of therapeutic concentration (for example, cyclosporine and Pimozidum). Иматиниб can increase serumal concentration of other medicines, metabolized CYP3A4 isoenzyme (triazolobenzodiazepines, dihydropyridines, blockers of "slow" calcium channels, the majority of inhibitors of GMG-KOA-reduktazy, including statines).

Иматиниб in vitro inhibits also CYP2C9 and CYP2C19.

At simultaneous use with warfarin increase in a prothrombin time is possible. At co-administration 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 medicines in high doses development of a tranzitorny hepatotoxic in the form of increase in activity of transaminases of a liver and a hyperbilirubinemia is possible.

At a combination of an imatinib and the modes of chemotherapy which can potentially have a hepatotoxic action 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. In this regard it is necessary to consider a possibility of strengthening of effects of the medicines which are CYP2D6 isoenzyme substrates at their combined use with imatiniby.

At use of an imatinib in a dose of 400 mg 2 times a day together with metoprololy, CYP2D6 enzyme 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 medicines which are CYP2D6 isoenzyme substrates (for example, a metoprolola), at their combined use with imatiniby, correction 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 active agent or any other component of drug.
• Children's age up to 2 years (efficiency and safety are not established).
• Pregnancy and period of feeding by a breast.

With care. It is necessary to appoint with care 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:

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 reception of an imatinib in a dose of 1200 - 1600 mg within 1–10 days at the patient with HML in a phase of blast crisis nausea, vomiting, diarrhea, skin rash, an erythema, hypostases, a swelling of joints, increased fatigue, muscular spasms, thrombocytopenia, a pancytopenia, 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 made 3200 mg a day within 6 days) weakness, mialgiya, gastrointestinal pains, increase in concentration in blood of a kreatinfosfokinaza and bilirubin were noted. At use of an imatinib in a dose of 6400 mg once at the patient nausea, vomiting, abdominal pain, a hyperthermia, a face edema, decrease in number of neutrophils and increase in activity of transaminases of a liver 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 number of leukocytes were observed.

Storage conditions:

Period of validity - 2 years. Not to use after the period of validity specified on packaging. In the dry, protected from light place at a temperature from 15 to 25 °C. To store in places unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules of 50 mg, 100 mg. Dosage of 50 mg: on 30 capsules in bottles polymeric. On bottles paste the self-adhesive label. On 10 capsules in a blister strip packaging from a film of polyvinyl chloride and printing aluminum foil. On 1 bottle or on 3 blister strip packagings together with the application instruction place in a cardboard pack. Dosage of 100 mg: on 24, 36, 48, 96, 120 or 180 capsules in bottles polymeric. On bottles paste the self-adhesive label. On 1 bottle together with the application instruction place in a cardboard pack. On 12 or on 6 capsules in a blister strip packaging from a film of polyvinyl chloride and printing aluminum foil. On 2, 3, 4, 8, 10, 15 blister strip packagings (on 12 capsules) or on 4, 6, 8, 16, 20, 30 blister strip packagings (on 6 capsules) together with the application instruction place in a cardboard pack.