Immutin

General characteristics. Structure:

Active ingredient: 119,5 mg of an imatinib месилат that is equivalent to 100 mg of an imatinib.

Excipients: cellulose microcrystallic PH 101, hydroxypropyl cellulose of low density (L-HPC LH 11), cellulose microcrystallic PH 102, кросповидон (Kolidon of CLF), silicon dioxide colloid (Aerosil 200), magnesium stearate.

Structure of a cover: Opadry Brown 20A36650: HPMC of a 2910-Gipromelloz 3 cP (E464), hydroxypropyl cellulose (E463), talc, titanium dioxide (Е 171), ferrous oxide yellow (E172), ferrous oxide red (E172), ferrous oxide black (E 172).

Pharmacological properties:

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

Immutin is strong inhibitor of receptors of a tyrosinekinase for a growth factor of thrombocytes (TFR), and a factor of stem cells (FEK), a transmembrane tyrosinekinase (with-Kit), and also suppresses the cellular reactions mediated by the above-named factors. Immutin inhibits proliferation and induces apoptosis of cells of the stromal tumors of digestive tract expressing kit-mutations.

Considerable activation of TFR or Bcr-Abl of a tyrosinekinase is a consequence of integration with various proteins, or stimulations of synthesis of TFR which are involved in a pathogeny of MDS/MPD (miyelodisplastichesky/miyeloprofelirativny) diseases, HES/CEL (a hyper eosinophilic syndrome / chronic eosinophilic leukemia) and the inoperable recurrent and/or metastasizing dermatofibrosarcomas of grumous (DFSP). a |konstruktivna, an ustanovcha | | Immutin inhibits a signal to proliferation of cells which accompanies the deactivated TFR and activity of Bcr-Abl of a tyrosinekinase.

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

Pharmacokinetics. Action of an imatinib at single use is studied in the range of doses from 25 to 1000 mg. Pharmacokinetic profiles were studied in the 1st day of use, and also for the 7th and 28th day i.e. when equilibrium concentration in a blood plasma was reached.

Absorption. Bioavailability of drug averages 98%. Coefficient of variation for an area indicator under a curve "concentration time" (AUC) makes 40 - 60%. At purpose of drug with food with the high content of fats, in comparison with reception on an empty stomach, insignificant decrease in extent of absorption is noted.

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

Removal. In not changed look about 25% of a dose are removed (20% - with a stake and 5% - with urine). Other amount of drug is removed in the form of metabolites.

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

Indications to use:

- for the first time the diagnosed myelosis at children and adults;

- a myelosis at children and adults in a phase of acceleration, blast crisis, and also in a chronic phase at failure of the previous therapy by interferon alpha;

- for the first time diagnosed positive (with presence at leukocytes of the Philadelphian chromosome) an acute lymphoblastoid leukosis at adult patients (as a part of chemotherapy);

- an acute lymphoblastoid leukosis at adult patients in a stage of a recurrence or at resistant tolerance to chemotherapy as monotherapy;

- миелодиспластические/миелопролиферативные the diseases at adult patients connected with activation of a receptor of a platelet growth factor;

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

- a hyper eosinophilic syndrome and/or chronic eosinophilic leukemia at adults;

- nonresectable and/or metastatic malignant stromal tumors of bodies of the digestive tract (DT) at adult patsent;

- inoperable and/or metastatic dermatofibrosarcomas grumous.

Route of administration and doses:

Immutin is appointed in a dose of 400 mg or 600 mg once a day. For patients (including children is more senior than 2 years), who cannot swallow a tablet, it can be dissolved in a glass of water or apple juice. Necessary quantity of tablets place in the corresponding volume of liquid (about 50 ml for one tablet of 100 mg and 200 ml for 4 tablets on 100 mg) and stir. Suspension has to be accepted right after preparation.

At a myelosis (HML) the recommended Immutin's dose depends on a disease phase. In a chronic phase the dose makes 400 mg/days; in a phase of acceleration and at blast crisis - 600 mg/days. Drug should be accepted during food once a day, washing down with a full glass of water.

Treatment by drug is carried out until the effect remains. The question of increase in a dose from 400 mg to 600 mg or 800 mg for patients with a chronic phase of a disease and from 600 mg to the maximum 800 mg a day for patients with the accelerated phase or a phase of blast crisis, can be considered on condition of lack of heavy side effects and in the absence of the neutropenia or thrombocytopenia which are not connected with a basic disease. Such increase in a dose can be necessary in the following cases: progressing of a disease (at any stage); lack of the satisfactory hematologic answer after 3 months of treatment; the insufficient cytogenetic answer after 12 months of therapy; loss of the reached earlier hematologic and/or cytogenetic answer. Calculation of the mode of dosing at children are based on body surface area (mg/m ²). Doses of 260 mg/m ² in days are recommended at chronic phase HML and 340 mg/m ² in days at HML in an acceleration phase respectively. The general daily dose at children should not exceed equivalent doses for adult 400 mg and 600 mg. Treatment has to be appointed once a day or alternatively divided into two receptions - one reception in the morning, other reception in the evening.

At an acute lymphoblastoid leukosis with a positive Philadelphian chromosome (Ph+-OLL). The recommended drug dose Immutin makes 600 mg/day for patients with an acute lymphoblastoid leukosis (Ph+-OLL). At миелодиспластических/миелопролиферативных diseases (MDS/MPD)

The recommended drug dose Immutin makes 400 mg/day for patients with миелодиспластическими/миелопролиферативными diseases (MDS/MPZ).

At dermatofibrosarcomas of grumous (DFSP). The recommended Immutin's dose makes 800 mg/day for patients with inoperable and/or metastatic dermatofibrosarcomas (DFSP).

At nonresectable and/or metastatic stromal tumors of a GIT (GIST) the recommended Immutin's dose makes 400 mg a day. Increase in a dose of Immutin up to 600 or 800 mg in the absence of side reactions and in case of the insufficient response to therapy is possible.

Treatment by drug is carried out until signs of progressing of a disease are observed.

Doses at positive nonresectable and/or metastatic malignant tumors (HES and/or CEL) make 400 mg/day.

For patients at whom the level of activity of kinases FIP1L1-PDGFRα is increased, the initial dose of-100 mg a day is recommended. Increase in a dose can be considered in the absence of side effects and in case of the insufficient response to therapy.

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

Individual selection of a dose at side reactions at patients with a myelosis (HML) and patients with a digestive tract stroma tumor.

Not hematologic side effects. In case of heavy not hematologic by-effects treatment needs to be suspended before settlement of an undesirable condition of the patient. Besides, it is necessary to estimate risk of a by-effect and to make the decision concerning treatment continuation.

At increase in level of bilirubin is 3 times higher than the upper bound of norm or increase in level of hepatic transaminases, more than by 5 times, Immutin it is necessary to cancel before decrease in concentration of bilirubin to value less than 1,5 and before decrease in concentration of hepatic transaminases to value less than 2,5. Treatment by Immutin can be continued in the reduced daily doses. For adults the dose decreases from 400 to 300 mg a day, or from 600 to 400 mg a day, or from 800 to 400 mg a day. For children - from 260 to 200 mg/sq.m a day or from 400 to 260 mg/sq.m.

Hematologic side effects. The recommended reduction of dosing depending on extent of development of a neutropenia or thrombocytopenia is presented in the table.

The CM associated with an eosinophilia (initial dose of 100 mg)	Absolute quantity of neutrophils (ANC) <1,0 x109/l and/or thrombocytes <50 x109/l	1. To suspend treatment by Immutin 2. to ANC ³ 1,5 x109/l and thrombocytes ³ 75 x109/l. 3. To continue treatment by Immutin in an initial dose.
HES and CEL with synthesis of kinases of FIP1L1-PDGFRα (initial dose of 100 mg)	Absolute quantity of neutrophils (ANC) <1,0 x109/l and/or thrombocytes <50 h109/l		4. To suspend treatment by Immutin to ANC ³ 1,5 x109/l and thrombocytes ³ 75 x109/l. To continue treatment by Immutin in an initial dose.
Chronic phase HML, MDS/MPD and GIST (starting dose of 400 mg)	Absolute quantity of neutrophils (ANC) <1,0 x109/l and/or thrombocytes <50 x109/l		1. To suspend treatment by Immutin to ANC ³ 1,5 x109/l and thrombocytes ³ 75 x109/l. 2. To continue treatment by Immutin in a dose of 400 mg. 3. In case of ANC recurrence <1,0 x109/l and/or thrombocytes <50 x109/l to repeat a step 1 and to resume treatment in a dose of 300 mg.
Phase of acceleration and blast crisis of HML, (Ph+-OLL) Starting dose 600 мгв	Absolute quantity of neutrophils (ANC) and <0,5 x109/l and/or thrombocytes <10 h109/l		1. To check communication of a cytopenia with leukemia (biopsy). 2. In case of communication of a cytopenia with leukemia to reduce a dose to 400 мгб. 3. In case the cytopenia remains for 2 weeks, to reduce a dose to 300 мгб. 4. In case the cytopenia remains for 4 weeks and is not connected with leukemia, to suspend treatment by Immutin to ANC ³ 1 x109/l and thrombocytes ³ 20 x109/l, then to reduce a dose to 300 mg.
(DFSP) Starting dose of 800 mg	Absolute quantity of neutrophils (ANC) <1,0 x109/l and/or thrombocytes <50 x109/l		1. To suspend treatment by Immutin to ANC ³ 1,5 x109/l and thrombocytes ³ 75 x109/l. 2. To continue treatment by Immutin in a dose 600 mg2. 3. In case of ANC recurrence <1,0 x109/l and/or thrombocytes <50 x109/l to repeat a step 1 and to resume treatment in a dose of 400 mg.
and - appeared after 1 month of treatment beat with 260 mg/sq.m at children twisted 340 mg/sq.m at children - or 200 mg/sq.m are at children

Children. Clinical experience of treatment of children aged up to 2 years is limited.

Liver failure. As иматиниб it is metabolized mainly in a liver, patients with insignificant, moderate or heavy abnormal liver functions should appoint minimum recommended dose of 400 mg a day. The dose can be reduced if at the patient the unacceptable toxic effect develops.

Renal failure. As the renal clearance of Immutin insignificant, at patients with a renal failure decrease in the general clearance of an organism is not expected. However at a heavy renal failure it is recommended to be careful.

Elderly patients. At patients of old age the pharmacokinetics was fully not investigated.

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

Features of use:

For the purpose of reduction of risk of emergence of the undesirable phenomena from a GIT it is necessary to accept drug during food, washing down with a significant amount of water.

It is necessary to be careful at Immutin's appointment to patients with an abnormal liver function as strengthening of expressiveness of its action is possible. It is regularly necessary to carry out analyses of peripheral blood and enzymes of a liver. At a combination therapy Immutin with high doses of himiopreparat at patients with (Ph+-OLL) observed manifestations of a tranzitorny abnormal liver function in the form of increase in level of transaminases and a hyperbilirubinemia.

Because at Immutin's use in 1-2% of cases the expressed liquid delay was noted, (a pleural exudate, peripheral hypostases, a fluid lungs, ascites), it is regularly recommended to weigh patients. In case of bystry unexpected increase in body weight it is necessary to conduct examination of the patient and if necessary to appoint the corresponding maintenance therapy and leaving.

The isolated cases of cardiogenic shock, left ventricular failure connected with use of system steroids against the background of therapy by Immutin were observed. Миелодиспластические/миелопрофилератив-ные diseases, can be associated with the high level of eosinophils.

At (5,4%) patients hemorrhages of a GIT and at 2,7% of patients of a hemorrhage in the place of tumoral metastasises were noted. Both intra belly, and intra hepatic tumoral hemorrhages, depending on anatomic localization of a tumor were noted.

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

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

Kidneys do not play an essential role in Immutin's removal and his metabolites. Nevertheless, as special researches at patients with a renal failure were not conducted, now it is not possible to make specific recommendations about the mode of dosing of Immutin at patients with a renal failure.

Use in pediatrics. Sufficient experience of purpose of drug aged up to 2 years is not available for children.

Pregnancy and period of a lactation. There are no data on use of an imatinib for pregnant women now. Toxic impact on reproductive function is revealed, however the potential risk for a fruit is still unknown. Immutin it is not necessary to appoint during pregnancy unless it is vital, however in these cases it is necessary to warn the patient about existence of potential risk for a fruit. Women of childbearing age during therapy by Immutin should apply effective methods of contraception.

The women accepting Immutin should refuse feeding by a breast.

Features of influence on ability to manage vehicles or potentially dangerous mechanisms. Patients have to be informed that they can have undesirable reactions like a faint or an illegibility of sight during treatment by Immutin. Therefore, it is recommended to be careful at control of motor transport or other potentially dangerous mechanisms.

Side effects:

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

Most of patients at a certain stage of treatment had side effects of easy or moderate degree; drug withdrawal in connection with side effects was noted only at 2% of recently diagnosed patients, 4% of patients in a late chronic phase after unsuccessful treatment by interferon, 4% of patients in the accelerated phase after unsuccessful therapy with interferon and at 5% of patients with blast crisis after unsuccessful therapy with interferon. In clinical trials on patients with stromal tumors of a GIT cancellation of appointment because of side effects of drug was required in 4% of cases.

Side effects are similar on both nozologiya behind two exceptions. At patients with stromal tumors of a GIT the miyelosupressiya was not noted, and intra tumoral bleedings were noted only at this group.

Slight nausea, vomiting, diarrhea, abdominal pains, fatigue, mialgiya and myotonia were the most frequent side effects connected with administration of drug, rash which were easily stopped. Peripheral hypostases were often noted, it is preferential in periorbital area or hypostases of the lower extremities. However they seldom had the expressed character and well therapies by diuretics gave in, and at some patients took place after a dose decline of Immutin.

At the combined treatment by Immutin at patients Ph+-OLL manifestations of a tranzitorny abnormal liver function in the form of the increased level of transaminases and a hyperbilirubinemia met high doses of chemotherapeutic drugs.

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 usually for a while stop therapy by Immutin, apply diuretics. Nevertheless, in certain cases these phenomena reached degree serious and even life-threatening. For example, one fatal case at the patient with blast crisis and a complex of such clinical disturbances as a pleural exudate, congestive heart failure and a renal failure is recorded.

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

Determination of frequency: very often (> 1/10), it is frequent (> 1/100 ≤ 1/10), sometimes (≥ 1/1000 ≤ 1/100), is rare (≥1/10000 ≤1/100), is very rare (≤1/10000), including separate cases.

Very often:

- increase in weight

- neutropenia, thrombocytopenia, anemia

- headache

- dyspepsia, abdominal pain, nausea, vomiting, diarrhea

- periorbital hypostasis, dermatitis, eczema, skin rash

- muscular spasms and spasms, musculoskeletal pains (mialgiya,

 arthralgia, bone pains)

- liquid delay, hypostases

- fatigue

Often:

- febrile neutropenia

- anorexia, disturbance of taste, an ulceration in an oral cavity

- dizziness, sleep disorders

- paresthesias

- conjunctivitis, increase in a slezootdeleniye

- epistaksiya, диспноэ

- abdominal distention, meteorism, lock, gastroesophageal reflux

- increase in activity of liver enzymes

- puffiness of the person, century

- itch, erythema, xeroderma, alopecia

- swelling of joints

- fever, weakness, fever, night perspiration

Sometimes:

- pancytopenia

- sepsis, pneumonia

- the herpes simplex, herpes surrounding upper respiratory tract infections

- dehydration

- hyperuricemia, gout

- hypopotassemia, hyperpotassemia, hyponatremia, hypophosphatemia

- appetite disturbances: increase or decrease

- depression, uneasiness, decrease in a libido

- irritation of eyes, hemorrhages in a conjunctiva, a xerophthalmus

- вертиго, sonitus

- heart failure, tachycardia; arterial, hypertensia,

 hypotension, hyperemia of the person

- fluid lungs

- cold snap of extremities

- cough, pleural exudate, pharyngolaryngeal pain

- ascites

- dryness in a mouth, stomach ulcer, gastritis, gastrointestinal hemorrhages, a melena

- jaundice, hepatitis, hyperbilirubinemia

- petechias, bruises, hematomas, hemorrhages

- the increased sweating, injury of nails, reactions of a photosensitization, purple, a hypotrichosis, a cheilitis, a hyperpegmentation, psoriasis, exfoliative dermatitis and violent rash, a small tortoiseshell

- sciatica, joint and muscular constraint

- a renal failure, pain in kidneys, strengthening

 urinations, hamaturia

- gynecomastia, increase in mammary glands, nipple pain, menorrhagia, hydroscheocele, sexual dysfunctions

- strong indisposition

Seldom:

- confusion of consciousness

- hemorrhagic stroke

- syncope

- peripheral neuropathy, giposteziya, drowsiness, migraine

- memory disturbances

- macular hypostasis, a papiloedema, a retinal hemorrhage, hemorrhages in a vitreous, glaucoma, a cataract

- acoustical and vestibular disturbances

- ciliary arrhythmia, pericardiac exudate, pericardis, cardiac tamponade, fibrinferments/embolism, stenocardia, myocardial infarction, cardiac standstill

- pneumofibrosis, intersticial pneumonia, pulmonary hypertensia, pulmonary bleeding

- colitis, diverticulitis, intestinal impassability, tumoral bleedings / tumoral necrosis, perforation of intestines, pancreatitis

- liver failure, necrotic hepatitis

- anginevrotichesky hypostasis, vesicular rash, Stephens-Johnson's syndrome, an acute febrile neutrophylic dermatosis (a syndrome It is twisted)

- aseptic necrosis / osteonecrosis of a hip

- anasarca

Very seldom:

- wet brain, increase in intracranial pressure, convulsion

Interaction with other medicines:

At combined use of IMMUTIN with:

- the drugs inhibiting a P450 cytochrome CYP3A4 isoenzyme (for example кетоконазол, итраконазол, erythromycin, кларитромицин), increase in concentration of an imatinib in a blood plasma is possible. There are data on increase in Cmax for 26% and AUC for 40% at one-time simultaneous use of an imatinib and ketokonazol;

- the drugs which are the inductors CYP3A4 (for example, dexamethasone, Phenytoinum, carbamazepine, rifampicin, phenobarbital, or drugs of a St. John's Wort (hypericum perforatum), action of an imatinib can be weakened. For patients to whom rifampicin or other inductors CYP 3A4 is shown alternative therapeutic means with smaller ability to induce enzymes have to be considered;

- simvastatiny - иматиниб increases Cmax and AUC of a simvastatin in 2 and 3.5 times respectively;

- warfarin - observed lengthening of a prothrombin time.

As an alternative warfarin should consider a question of use of low-molecular derivatives of heparin.

- 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 ИММУТИНа.

IMMUTIN can increase concentration in a blood plasma of other medicines, metabolizirovanny CYP3A4 (for example triazolo-benzodiazepines, dihydropyridines, blockers of calcium channels, GMG-KOA inhibitors - reductases).

IMMUTIN inhibits a P450 cytochrome CYP2D6 isoenzyme in the same concentration in which it inhibits CYP3A4. In this regard it is necessary to consider a possibility of strengthening of effects of the drugs which are CYP2D6 isoenzyme substrates at their combined use with ИММУТИНом. Drug inhibits O-glyukuronidatsiyu paracetamol / acetaminophen.

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 or Pimozidum).

Contraindications:

- hypersensitivity to an imatinib and other components of drug

- pregnancy and period of a lactation

- children's age up to 2 years (efficiency and safety are not established)

Overdose:

Symptoms: nausea, vomiting, diarrhea, an abdominal pain, a headache, reduced appetite, weakness, a hyperthermia, rashes, an erythema, the Eden, hypostasis, fatigue, thrombocytopenia, a pancytopenia, increase in level of creatinine in serum, ascites, increase in activity of hepatic transaminases, increase in level of bilirubin, muscular spasms.

Treatment: medical observation and symptomatic therapy is recommended. Immutin's antidote is unknown.

Storage conditions:

In the dry, protected from light place at a temperature not over 25 ºС. To store in the place, unavailable to children! Period of storage 2 years. Not to apply after the storage expiration.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 100 mg. On 10 tablets in a blister strip packaging from printing aluminum foil. On 1, 6 or 12 planimetric packagings together with the instruction on a medical use in the state and Russian languages place in a pack from a cardboard.