Спрайсел®

General characteristics. Structure:

Active ingredient: 20 mg, 50 mg or 70 mg of a dazatinib.

Excipients: lactoses monohydrate, cellulose microcrystallic, hypro rod, croscarmellose sodium, magnesium stearate, опадрай white (titanium dioxide, gipromelloza-6sr, macrogoal-400).

Pharmacological properties:

Pharmacodynamics. Дазатиниб in nanomolar concentration inhibits the following tyrosinekinases: BCR ABL, the SRC family (SRC, LCK, YES, FYN), with-KIT, EPHA2 and PDGFRβ. By means of modeling it is established what дазатиниб contacts many ABL forms of a kinase.

In vitro дазатиниб showed activity in leukemic cellular lines, both sensitive, and resistant to an imatinib. Дазатиниб inhibits growth of cellular lines of a myelosis and an acute lymphoblastoid leukosis with BCR-ABL hyper expression. In the conditions of tests дазатиниб overcame the resistance to an imatinib connected with kinase BCR-ABL domain mutations, activation of the alternative alarm paths including kinases of the SRC family (LYN, HCK) and a hyper expression of a gene of medicinal polyresistance.

Pharmacokinetics. Absorption. The maximum concentration (Cmax) of a dazatinib was observed in 0.5–6 hours (Tmax) after intake. The area under a curve "concentration time" (AUC) and elimination are proportional to a dose in the range of doses from 15 to 240 mg/days. The elimination half-life of a dazatinib makes 3-5 hours.

At reception of 100 mg of a dazatinib in 30 minutes after meal with the high content of fat increase in average AUC by 14% is noted. Influence of food was not clinically significant.

Distribution. The seeming volume of distribution of a dazatinib makes 2505 l that demonstrates considerable distribution in extravasated space. Дазатиниб and its active metabolite in vitro contacted proteins of plasma of the person for 96% and 93%, respectively, irrespective of concentration in the range of 100-500 ng/ml.

Metabolism. Дазатиниб it is actively metabolized at people, mainly by means of enzyme 3A4 of P450 cytochrome. CYP3A4 is the main enzyme participating in formation of an active metabolite. The flavin-containing monooxygenase 3 and uridinediphosphate-glyukuronoziltransferaza also participate in formation of metabolites of a dazatinib. In microsomes of a liver of the person дазатиниб showed a weak inhibiting effect, independent of time, concerning CYP3A4. AUC of an active metabolite of a dazatinib makes about 5% of AUC of a dazatinib. Possibly, the active metabolite does not play a large role in pharmacological action of a dazatinib. Also other inactive oxidized metabolites of a dazatinib are described.

Removal. Drug is emitted mainly with a stake. After a single dose inside [14C] - the dazatiniba about 4% and 85% of radioactivity is removed with urine and a stake, respectively, in 10 days. Not changed дазатиниб makes 0,1% and 19% of the dose removed with urine and a stake, respectively, and other part of a dose is presented by metabolites.

Indications to use:

• A myelosis in a chronic phase or a phase of acceleration, lymphoid or myeloid blast crisis at resistance or intolerance of the previous therapy, including иматиниб.

• An acute lymphoblastoid leukosis with a positive Philadelphian chromosome at resistance or intolerance of the previous therapy.

Route of administration and doses:

Tablets should be swallowed entirely. The recommended initial dose of SPRAYSELA at a chronic phase of a myelosis makes 100 mg once a day in the morning or in the evening irrespective of meal.

In other cases it is recommended to accept SPRAYSEL inside in a dose of 70 mg twice a day in the morning and in the evening during food or on an empty stomach (140 mg a day).

In case of lack of the hematologic or cytogenetic answer increase in a dose of SPRAYSELA up to 140 mg (is possible once a day at a chronic phase of a myelosis) or 100 mg 2 times a day (at far come myelosis and an acute limboflastny leukosis with a positive Philadelphian chromosome).

Recommendations about correction of a dose of drug. In case of decrease in absolute number of neutrophils less than 0,5 x 109/l and/or numbers of thrombocytes less than 50 x 109/l at a myelosis in a chronic phase it is necessary to take a break in treatment by drug SPRAYSEL before achievement of absolute number of neutrophils 1,0 x 109/l and numbers of thrombocytes ≥ 50 x 109/l. Then therapy is resumed in a former dose. If the number of thrombocytes less than 25 x 109/l and/or absolute number of neutrophils becomes less than 0,5 x 109/l within more than 7 days - do a break in treatment and, after achievement of initial indicators, therapy renew in a reduced dose 80 mg once a day (the second episode) or stop treatment (the third episode).

In case of decrease in absolute number of neutrophils less than 0,5 x 109/l and/or numbers of thrombocytes less than 10 x 109/l at a myelosis and an acute lymphoblastoid leukosis with a positive Philadelphian chromosome it is necessary to be convinced of a phase of acceleration or blast crisis at first that the cytopenia is not caused by a leukosis (aspiration or a biopsy of marrow). If the cytopenia is not connected with a leukosis, treatment should be interrupted before achievement of absolute number of neutrophils ≥ 1,0 x 109/l and numbers of thrombocytes ≥ 20 x 109/l and to resume therapy in a former dose. In case of a recurrence it is necessary to be convinced of the nature of a cytopenia again and to resume therapy in a reduced dose of 50 mg 2 times a day (the second episode) or 40 mg 2 times a day (the third episode). If the arisen cytopenia is connected with a leukosis, it is necessary to consider a question of increase in a dose up to 100 mg 2 times a day.

Clinically significant distinctions in pharmacokinetics at elderly patients are not revealed. Change of a dose of drug at appointment is not required to elderly patients.

Features of use:

Oppression of marrow. At treatment of SPRAYSELOM there can be heavy (3 and 4 degrees on NCI CTC classification) thrombocytopenia, anemia and a neutropenia. More often they are registered at patients with far come phase of a myelosis or an acute lymphoblastoid leukosis with a positive Philadelphian chromosome, than at patients with a chronic phase of a myelosis. Full clinical blood test it is necessary to spend weekly the first 2 months of treatment, and then monthly or more often, according to clinical indications. Oppression of marrow is usually reversible and takes place at temporary cancellation or a dose decline of SPRAYSELA.

Bleedings. The majority of cases of bleedings were connected with heavy thrombocytopenia. Heavy hemorrhages in a brain, including fatal, are registered at less than 1% of the patients receiving SPRAYSEL. Heavy gastrointestinal bleedings are noted at 4% of patients; they usually demanded temporary drug withdrawal and hemotransfusions. Other heavy bleedings are registered at 2% of patients.

Liquid delay. At reception of SPRAYSELA the liquid delay can be observed. The delay of liquid of heavy degree was registered at 7% of patients, including the expressed pleural and pericardiac exudate at 4% and 1% of patients, respectively. The expressed ascites and generalized hypostasis developed at less than 1% of patients. At 1% of patients the heavy fluid lungs is registered. At emergence of an asthma or dry cough radiological control of bodies of a thorax is necessary. The delay of liquid is usually stopped at use of a maintenance therapy with inclusion of diuretics or a short course of glucocorticosteroids. At the expressed pleural exudate the oxygenotherapy and a thoracocentesis were required.

Lengthening of an interval of QT. Дазатиниб it is necessary to use with care at patients with the extended interval of QTc or with risk of lengthening of this interval (a hypopotassemia, a hypomagnesiemia, an inborn syndrome of the extended QT interval, at therapy by the antiarrhytmic and other drugs capable to extend QT interval, the previous therapy with high doses of anthracyclines). Before purpose of SPRAYSELA it is necessary to carry out correction of a hypopotassemia and hypomagnesiemia.

Deviations in laboratory indicators. Increase in activity of transaminases or level of bilirubin 3 or 4 of degree and a hypocalcemia and a hypophosphatemia 3 or 4 degrees were observed more often at patients with a phase of myeloid or lymphoid blast crisis of a myelosis and an acute lymphoblastoid leukosis with a positive Philadelphian chromosome. Normalization of activity of transaminases and/or level of bilirubin usually occurred after a dose decline of drug or a break in treatment. Stopping of a hypocalcemia 3 or 4 degrees was observed at purpose of drugs of calcium for intake.

Side effects:

By-effects at use of SPRAYSELA are presented on the frequency of their registration: often (≥1/100 – <10/100 patients) and infrequently (≥1/1000 – <1/100 patients).

From system of digestion: often – diarrhea, nausea, vomiting, locks, an abdominal cavity pains, an inflammation of mucous membranes (including мукозит / stomatitis), gastritis, colitis, a coloenteritis, cracks in an anus, a dysphagy, appetite disturbances; infrequently – an esophagitis, ulcers of upper parts of digestive tract, impassability of intestines, pancreatitis, cholecystitis, hepatitis, a cholestasia, increase in activity of transaminases, bilirubin level, ascites.

From skin and hypodermic cellulose: often – a liquid delay (superficial hypostases), an alopecia, a xeroderma, eels, a small tortoiseshell, dermatitis (including eczema), a photosensitization, changes of nails, pigmentation disturbances; infrequently – skin ulcers, an acute febrile neutrophylic dermatosis, a violent dermatosis, a syndrome of a palmar and bottom eritrodizesteziya.

From respiratory system: often – pulmonary infiltrates, pneumonia, asthma, a fluid lungs, a pleural exudate, cough, an asthma; infrequently – a bronchospasm, an acute respiratory distress syndrome, reticular asphyxia.

From the central nervous system: often – a food faddism, drowsiness, a syncope, a tremor, spasms; infrequently – amnesia, disturbance of cerebral circulation, passing ischemic disturbances, a syndrome of a reversible back leukoencephalopathy.

From system of a hemopoiesis: often – thrombocytopenia, anemia, a neutropenia; infrequently – decrease in coagulation, an eritroblastopeniye.

From a musculoskeletal system: often – a miositis, muscular weakness, muscular constraint; infrequent – a tendinitis, рабдомиолиз.

From cardiovascular system: often – heartbeat, stenocardia, a cardiomegaly, a myocardial infarction, heat inflows, decrease or increase in arterial pressure; infrequently – a pericardis, ventricular tachycardia, an acute coronary syndrome, myocarditis, lengthening of an interval of QTcF on an ECG.

From an urinary system: often – the speeded-up urination, a renal failure; infrequently – a proteinuria.

From reproductive system: often – a gynecomastia; infrequently – disturbances of a menstrual cycle, decrease in a libido.

From organs of sight: often - conjunctivitis, a xerophthalmus.

From acoustic organs: often - a sonitus, вертиго.

From laboratory indicators: often – increase in activity of a kreatinfosfokinaza, increase in level of a troponin, a hyperuricemia (a syndrome of a tumoral lysis); infrequently – a hypoalbuminemia, disturbance of aggregation of thrombocytes, a hypocalcemia, a hypophosphatemia.

Others: often – weakness, a herpes infection, sepsis (including fatal); coloenteritis; infrequently – hypersensitivity.

Interaction with other medicines:

CYP3A4 inhibitors: Inhibitors of activity CYP3A4 (for example, кетоконазол, итраконазол, erythromycin, кларитромицин, атазанавир, индинавир, нефазодон, нельфинавир, ритонавир, саквинавир, телитромицин) can increase concentration of a dazatinib in a blood plasma therefore it is necessary to avoid their combined use with dazatiniby. In case of combined use the dose of SPRAYSEL should be reduced by 20-40 mg/days.

Inductors CYP3A4: The inductors CYP3A4 can reduce concentration of a dazatinib in plasma. Patients to whom the inductors CYP3A4 are appointed (for example, dexamethasone, Phenytoinum, carbamazepine, rifampicin, phenobarbital) should appoint drugs with smaller ability to induce this enzyme.

The grass of a St. John's Wort (Hypericum perforatum) can cause decrease in concentration of a dazatinib in a blood plasma therefore it should not be used at treatment of SPRAYSELOM.

Antacids: Simultaneous use of SPRAYSELA and antacids is undesirable. If antacids are necessary, it is recommended to accept them not less than in 2 hours or in 2 hours after reception of SPRAYSELA.

Blockers of H2-histamine receptors and inhibitors of a proton pomp: long suppression of a serkretion of hydrochloric acid blockers of H2-histamine receptors and inhibitors of a proton pomp (for example, famotidine and omeprazoly) can reduce concentration of a dazatinib. Simultaneous use of these drugs and SPRAYSELA is not recommended.

CYP3A4 substrates: CYP3A4 substrates with a narrow therapeutic range, such as alfentanil, астемизол, терфенадин, цизаприд, cyclosporine, fentanyl, Pimozidum, quinidine, сиролимус, такролимус and ergot derivatives (ergotamine, dihydroergotamine) it is necessary to use with care at the patients receiving SPRAYSEL.

Contraindications:

Hypersensitivity to a dazatinib or other components of drug. Pregnancy and period of feeding by a breast. Age up to 18 years (efficiency and safety are not established).

With care: at a liver failure.

Overdose:

One case of reception of 280 mg of drug SPRAYSEL the patient with a myelosis which was not followed by clinical symptoms and laboratory deviations is described.

In case of overdose observation and if necessary symptomatic therapy is required.

Storage conditions:

At a temperature from 15 to 30 °C. To store in the place, unavailable to children! A period of validity - 2 years. Not to use drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, on 20 mg, 50 mg and 70 mg. On 60 tablets in bottles from polyethylene of high pressure with the cover unavailable to opening by children. In a bottle place a container with a dehumidifier (silica gel) on which the precautionary text is applied "is not", the neck of a bottle is closed a cotton plug. On 1 bottle together with the application instruction in a cardboard pack.