Sprycel

Active material: Dasatinib
When ATH: L01XE06
CCF: Anticancer drug. An inhibitor of protein tyrosine kinase
ICD-10 codes (testimony): C91.0, Q92.1
When CSF: 22.06
Manufacturer: BRISTOL-MYERS SQUIBB Company (United States)

Pharmaceutical form, composition and packaging

Pills, Film-coated white or nearly white, round, lenticular, labeled “BMS” on one side and “527” – another.

Excipients: lactose monohydrate, microcrystalline cellulose, giproloza, Croscarmellose sodium, magnesium stearate, Opadry white (Titanium dioxide, polymer-6cP, macrogol 400).

60 PC. – polyethylene bottles * (1) – packs cardboard.

Pills, Film-coated white or nearly white, Oval, lenticular, labeled “BMS” on one side and “528” – another.

Excipients: lactose monohydrate, microcrystalline cellulose, giproloza, Croscarmellose sodium, magnesium stearate, Opadry white (Titanium dioxide, polymer-6cP, macrogol 400).

60 PC. – polyethylene bottles * (1) – packs cardboard.

Pills, Film-coated white or nearly white, round, lenticular, labeled “BMS” on one side and “524” – another.

Excipients: lactose monohydrate, microcrystalline cellulose, giproloza, Croscarmellose sodium, magnesium stearate, Opadry white (Titanium dioxide, polymer-6cP, macrogol 400).

60 PC. – polyethylene bottles * (1) – packs cardboard.

* in flasks placed a container of desiccant.

Pharmacological action

Anticancer drug, an inhibitor of protein tyrosine kinase. Dasatinib in nanomolar concentrations inhibits the tyrosine kinase inhibitors as follows: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2 and PDGFRβ. (C) the model set, that dasatinib is associated with many forms of ABL kinases.

In vitro, dasatinib has been active in Leukemic cell lines, how sensitive, or resistant to imatinib. Dasatinib inhibits the growth of cell lines, chronic myeloid leukemia and acute lymphocytic leukemia with human tissular kallikrein BCR-ABL. In the face of tests dasatinib overcame resistance to Imatinib, associated with mutations in domain BCR-ABL kinase, activation of alternate signaling pathways, SRC family kinases comprising (LYN, NSK) and multidrug resistance gene overexpression.

Pharmacokinetics

Absorption

After oral administration, C_max dazatiniba in plasma achieved through 0.5-6 no. AUC proportional to dose in the range of doses from 15 to 240 mg / day. When taken in the dose of dazatiniba 100 mg after 30 minutes after a meal high in fat increases the average AUC for 14%. Impact of food had no clinically significant.

Distribution

In Кажущийся_d dazatiniba is 2505 l, that indicates a significant distribution in vnesosudistom space. Linking dazatiniba and its active metabolite in human plasma proteins in vitro is 96% and 93% respectively, regardless of the concentration within the range of 100-500 ng / ml.

Metabolism

Dasatinib actively metabolized in humans, mainly with the participation of CYP3A4 enzyme. CYP3A4 is the major enzyme, participating in the formation of the active metabolite. Flavin-containing monooksigenaza 3 and uridindifosfat-glucuronosyltransferase are also involved in the formation of metabolites dazatiniba. In human liver Ca2 dasatinib demonstrated weak, independent of time, inhibitory activity against CYP3A4. The AUC of the active metabolita dazatiniba is approximately 5% AUC dazatiniba. Probably, the active metabolite is not playing a large role in pharmacological action of dazatiniba. Described and other inactive oxidized metabolites dazatiniba.

Deduction

Off dazatiniba is proportional to dose in the range of doses from 15 to 240 mg / day. T_1/2 dazatiniba is 3-5 no.

Dasatinib write mainly from faeces. After a single oral ¹⁴P-dazatiniba approximately 4% and 85% radioactivity is displayed for 10 days with urine and feces, respectively. Unchanged dasatinib is 0.1% and 19% dose, displayed with urine and feces, respectively, While the rest of the doses represented metabolites.

Pharmacokinetics in special clinical situations

Clinically significant differences in pharmacokinetics in elderly patients is not revealed.

Testimony

-chronic myeloid leukemia in chronic phase, accelerated phase or, lymphoid or myeloid blastny Kriz with resistance or intolerance to previous therapy, including as imatinib;

-acute lymphoblastic leukemia with positive Philadelphia chromosome with resistance or intolerance to previous therapy.

Dosage regimen

The tablets should be swallowed whole.

At chronic phase chronic myeloid leukemia The recommended starting dose is 100 mg 1 times/day in the morning or in the evening, regardless of mealtimes.

In other cases, We recommend that you assign the drug dose 70 mg 2 times per day in the morning and in the evening with meals or on an empty stomach (140 mg / day).

In case of absence or Hematology cytogenetic response may increase the dosage if you chronic phase chronic myeloid leukemia to 140 mg 1 time / day, at far before chronic mielolakose and limboflastnom acute leukemia with positive Philadelphia chromosome – to 100 mg 2 times / day.

Recommendations for dose adjustment

In the case of reducing the absolute number of Klebsiella less than 500/MKL and/or the number of platelets less 50 000/MKL with chronic mielolakose in the chronic phase, you should take a break from treatment drug Sprajsel before reaching the absolute number of neutrophils ≥ 1000/µL and the number of platelets ≥ 50000/µl. Then resume therapy at the same dose. If the number of platelets less 25 000/MKL and/or absolute neutrophil count falls below 500/µl for more 7 days – make a break in treatment and, after reaching the benchmarks, therapy resumed at a reduced dose 80 mg 1 time / day (the second episode) or stop treatment (third episode).

In the case of reducing the absolute number of Klebsiella less than 500/MKL and/or the number of platelets less 10 000/MCL accelerated phase or blastic crisis in chronic mielolakose and acute lymphoblastic leukemia with positive Philadelphia chromosome should first be sure, cytopenia that is not due to leukemia (aspirate or biopsy kostnogo mozga). If not cytopenia is associated with leukemia, treatment should be interrupted until reaching the absolute number of neutrophils ≥ 1000/µL and the number of platelets ≥ 200/µl 000000 and resume therapy in the previous dose. In the case of recurrence should again confirm the nature of cytopenia and resume therapy at a reduced dose 50 mg 2 times / day (the second episode) or 40 mg 2 times / day (third episode). If originated cytopenia associated with leukemia, should consider increasing the dose to 100 mg 2 times / day.

Elderly patients dose change is not needed.

Side effect

Determining the frequency of side effects: often (≥1% – <10%); sometimes (≥0.1% – <1%).

From the digestive system: often – diarrhea, nausea, vomiting, constipation, abdominal pain, mucositis (including mucositis / stomatitis), gastritis, colitis, enterocolitis, cracks in the anus, dysphagia, eating disorders; sometimes – esophagitis, upper gastrointestinal ulcers, bowel obstruction, pancreatitis, cholecystitis, hepatitis, cholestasis, increase in transaminases, bilirubin, ascites.

The respiratory system: often – pulmonary infiltrates, pneumonia, asthma, pulmonary edema, pleural effusion, cough, breathlessness; sometimes – bronchospasm, acute respiratory distress syndrome, reticular asphyxia.

CNS: often – dysgeusia, drowsiness, fainting, tremor, convulsions; sometimes – amnesia, cerebrovascular accident, transient ischemic, reversible posterior leukoencephalopathy syndrome.

From the hematopoietic system: often – thrombocytopenia, anemia, neutropenia; sometimes – decrease in coagulation, erythroblastopenia.

On the part of the musculoskeletal system: often – myositis, muscular weakness, muscle stiffness; sometimes – Tendinitis, raʙdomioliz.

Cardio-vascular system: often – heartbeat, angina, kardiomegalija, myocardial infarction, hot flashes, reduction or increase in blood pressure; sometimes – perikardit, ventricular tachycardia, acute coronary syndrome, miokardit, QTcF interval lengthening on ECG.

From the urinary system: often – frequent urination, renal failure; sometimes – proteinuria.

On the part of the reproductive system: often – gynecomastia; sometimes – menstrual irregularities, decreased libido.

From the senses: often – conjunctivitis, dry eyes, noise in ears, vertigo.

Dermatological reactions: often – fluid retention (superficial edema), alopecia, xerosis, acne, hives, dermatitis (including eczema), photosensitivity, nail changes, pigmentation disorders; occasionally ulcerative skin lesions, acute febrile neutrophilic dermatosis, Bullous Dermatosis, hand-foot syndrome eritrodizestezii.

From the laboratory parameters: often increased activity of KFK , increasing the level of Troponin, hyperuricemia (Tumor lysis syndrome); sometimes – hypoalbuminemia, violation of platelet aggregation, hypocalcemia, gipofosfatemiя.

Other: often – weakness, herpes infection, sepsis (including fatal); sometimes – hypersensitivity.

Contraindications

- Pregnancy;

- Lactation (breast-feeding);

- Childhood and adolescence up 18 years (efficacy and safety have not been established);

-hypersensitivity to dazatinibu or other components of the drug.

FROM caution the drug should be used in patients with hepatic insufficiency.

Pregnancy and lactation

The drug is contraindicated during pregnancy and lactation (breast-feeding).

Cautions

Attention! The packaging of the drug placed a container of desiccant, which marked the picture and a warning inscription – Do not eat. Contents: Silica Gel – There are not. Contents: Silica gel. The dehumidifier is designed to protect the drug from moisture. Container with a desiccant is not open; the contents of the container are not taken orally.

Bone marrow suppression

When treating drug Sprajsel there may be heavy (3 and 4 degree classification NCI CTC) thrombocytopenia, anemia and neutropenia. Often these reactions are recorded in patients with far advanced phase chronic myeloid leukemia or acute lymphoblastic leukemia with positive Philadelphia chromosome, than in patients with chronic phase chronic myeloid leukemia. Full blood test should be carried out first on a weekly basis 2 month of treatment, and then every month or more often, as clinically indicated. Oppression bone marrow is usually reversible and is a temporary repealing or reducing the dose Sprajsela.

Bleeding

Most cases of bleeding against the backdrop of the drug were associated with severe thrombocytopenia. Heavy bleeding in the brain, including fatal, registered with less 1% patients, receiving Sprajsel. Severe gastrointestinal bleeding are noted in 4% patients; usually require suspension of the drug and blood. Other heavy bleeding registered 2% patients.

Fluid retention

When receiving Sprajsela may experience fluid retention. Severe fluid retention was registered 7% patients, including pronounced pleural and pericardialny effusion at 4% and 1% patients, respectively. Pronounced liver and generalized edema developed less 1% patients. In 1% patients registered heavy pulmonary edema. With the emergence of breathlessness or dry cough requires x-ray chest control. Fluid retention usually docked when applying maintenance therapy from inclusion of diuretics or a short course of CORTICOSTEROIDS. The expression of determination vypote required oxygen therapy and thoracentesis.

QT prolongation

Dasatinib should be used with caution in patients with long QT interval_from or risk an elongation (if hypokalemia, gipomagniemii, congenital long QT syndrome, If antiarrhythmic therapy and other medications, able to prolong the QT interval, When prior therapy with high doses of antratziklinov). Prior to his appointment Sprycel should carry out the correction of hypokalemia and hypomagnesemia.

Laboratory abnormalities

Increased transaminases and bilirubin levels 3 or 4 degree and hypocalcemia and hypophosphatemia 3 or 4 degrees were observed more frequently in patients with lymphoid or myeloid blastic phase kriza chronic myeloid leukemia and acute lymphoblastic leukemia with positive Philadelphia chromosome. Normalizing the activity of transaminase and / or bilirubin usually occurred after dose reduction or interruption of treatment. Relief of hypocalcemia 3 or 4 degrees was observed at the time of appointment drugs calcium intake.

Overdose

Described 1 event admission 280 mg drug Sprajsel the patient with chronic myelogenous leukemia, not accompanied by clinical symptoms and laboratory abnormalities.

Treatment: monitoring, if necessary – simptomaticheskaya therapy.

Drug Interactions

CYP3A4 inhibitors (eg, ketoconazole, itraconazole, Erythromycin, clarithromycin, atazanavir, indinavir, nefazodon, nelfinavir, ritonavir, saquinavir, telithromycin) can increase the concentration of dazatiniba in plasma. These combinations should be avoided, in the case of joint use of the dose should be reduced by Sprycel 20-40 mg / day.

CYP3A4 inducers may decrease concentrations of dasatinib plasma. Patients, receiving inducers of CYP3A4 (eg, Dexamethasone, phenytoin, Carbamazepine, rifampicin, phenobarbital), drugs should be administered with less ability to induce this enzyme.

The herb St. John's wort (Hypericum perforatum) may decrease dasatinib plasma concentrations, so the treatment Sprycel should not be given drugs, this plant comprising.

Concomitant use of Sprycel and antacids is not recommended. In the case of the need to declare them should take antacids at least 2 hours before or after 2 h after administration Sprajsela.

Due to long-term suppression of acid secretion in patients receiving histamine H₂-receptors and proton pump inhibitors (eg, famotidine and omeprazole) may decrease concentrations of dasatinib. The simultaneous use of these drugs are not recommended and Sprycel.

CYP3A4 substrates with a narrow therapeutic range, such as alfentanil, astemizol, terfenadine, cisapride, cyclosporine, Fentanyl, pimozid, quinidine, sirolimus, Ergot derivatives of tacrolimus and (ergotamin, digidroergotamin), should be used with caution in patients, receiving Sprajsel.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at temperature from 15 ° to 30 ° C. Shelf life – 2 year.