Dasatinib

When ATH:
L01XE06

Pharmacological action

The antitumor agent, an inhibitor of protein tyrosine kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2 и PDGFR бета. Associated with many формами ABL киназы, active in the leukemia cell lines, how sensitive, or resistant to imatinib. It inhibits the growth of cell lines and chronic myelogenous leukemia acute lymphoblastic leukemia overexpressing BCR-ABL. Overcome imatinib resistance, 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

TCmax - 0,5-6, AUC and elimination is proportional to dose 15-240 mg / day. At a dose of 100 mg after 30 minutes after a fatty meal AUC increases by 14% (the impact of food has no clinical significance). The volume of distribution - 2505 l (considerably distributed in the extravascular space). Contact proteins dasatinib - 96%, ego aktivnogo metabolites - 93%, and is independent of concentration in the range of 100-500 ng / ml. Metabolized by the cytochrome P450 enzymes ZA4, flavin-containing monooxygenase 3 and uridine diphosphate-glucuronosyltransferase. CYP3A4 is the major enzyme, participating in the formation of the active metabolite. AUC aktivnogo metabolites - 5% от AUC дазатиниба, point O. active metabolite has no significant pharmacological action. In liver microsomes, dasatinib is weak, Regardless of the time inhibitory effect against CYP3A4. T1/2 — 3–5 ч. Displayed (during 10 days) mainly the intestines - 85% (19% in unchanged form), buds - 4% (0,1% in unchanged form).

Testimony

Chronic myelogenous leukemia in chronic phase, accelerated phase, limfoidnogo or mieloidnogo blastnogo crisis (the ineffectiveness of previous therapy, including as imatinib). Acute lymphoblastic leukemia with Philadelphia chromosome positive (the ineffectiveness of previous therapy).

Contraindications

Hypersensitivity, pregnancy, lactation, childhood and adolescence (to 18 years).

Carefully. Hepatic failure.

Dosage regimen

Inside, swallowing whole, regardless of the meal.

In the chronic phase chronic myeloid leukemia 100-140 mg 1 time (in the morning or evening) or 100 mg 2 times a day in advanced chronic myeloid leukemia and acute lymphoblastic leukemia with Philadelphia chromosome positive.

In other cases, 70 mg 2 once a day (while eating) or 140 mg 1 once a day (fasting).

By reducing the absolute neutrophil count below 500 / l and / or platelet count less than 50,000 / microliter (chronic myeloid leukemia in chronic phase) should take a break in treatment until the absolute neutrophil count of more than 1000 / l and platelet count greater than 50,000 / microliter. Then resume therapy at the same dose.

If the platelet count is less than 25000 / l and / or absolute neutrophil count becomes less than 500 / mm (over a 7 days) - Make a break in treatment and, after reaching the benchmarks, therapy resumed at a reduced dose 80 mg 1 once a day (the second episode) or stop treatment (third episode).

In case the absolute neutrophil count less than 500 / l and / or platelet count less than 10,000 / microliter in accelerated phase or blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with a positive Philadelphia chromosome should first make 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 the absolute neutrophil count of more than 1000 / l and platelet count of more than 20,000 / microliter and resume therapy at the same dose.

In the case of recurrence should again confirm the nature of cytopenia and resume therapy at a reduced dose 50 mg 2 once a day (the second episode) or 40 mg 2 once a day (third episode). If originated cytopenia associated with leukemia, should consider increasing the dose to 100 mg 2 once a day.

Side effect

Frequency: often (more 1/100 less 10/100), infrequently (more 1/1000 less 1/100).

From the digestive system: often - diarrhea, nausea, vomiting, constipation, abdominal pain, inflammation of the oral mucosa (including mucositis / stomatitis), gastritis, colitis, enterocolitis, anal fissures, dysphagia, eating disorders; rarely - esophagitis, upper gastrointestinal ulcers, bowel obstruction, pancreatitis, cholecystitis, hepatitis, cholestasis, increase in transaminases, giperʙiliruʙinemija, ascites.

For the skin and skin appendages: Parts - alopecia, xerosis, acne, hives, dermatitis (including eczema), photosensitivity, nail changes, pigmentation disorders; rarely - skin ulcers, acute febrile neutrophilic dermatosis, bullous dermatitis, hand-foot syndrome eritrodizestezii.

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

CNS: often - drowsiness, fainting, tremor, convulsions; Necas - Amnesia, cerebrovascular accident, transient ischemic, reversible posterior leukoencephalopathy syndrome.

From the side of hematopoiesis: Parts - thrombocytopenia, anemia, neutropenia; infrequently - hypocoagulation, erythroblastopenia.

On the part of the musculoskeletal system: often - myositis, muscular weakness, muscle stiffness; infrequently - tendonitis, raʙdomioliz.

From the CCC: often - tachycardia, angina, kardiomegalija, myocardial infarction, "Tides" heat, increase / decrease in blood pressure; infrequently - pericarditis, ventricular tachycardia, acute coronary syndrome, miokardit, QTc prolongation on the ECG.

From the urinary system: often - frequent urination, renal failure; Necas - proteinuria.

Reproductive system: often - gynecomastia; infrequently - menstrual disorders, decreased libido.

From the senses: often - conjunctivitis, dry eyes, noise in ears, vertigo; dysgeusia.

Laboratory findings: often - increased activity of CPK, increased concentration of troponin, hyperuricemia (Tumor lysis syndrome); infrequently - hypoalbuminemia, violation of platelet aggregation, hypocalcemia, gipofosfatemiя.

Other: often - weakness, herpes infection, sepsis (including fatal), enterocolitis, fluid retention (peripheral edema); rarely - hypersensitivity.

Overdose

Treatment: simptomaticheskaya therapy.

Drug Interactions

Avoid joint use with the CYP3A4 ingibitoramimi (ketoconazole, itraconazole, Erythromycin, clarithromycin, atazanavir, indinavir, nefazodon, Nelfinavir, ritonavir, saquinavir, telithromycin) - Increase in the concentration of dasatinib plasma. If necessary, the joint use of dasatinib reduced dose of 20-40 mg / day.

When combined with inducers of CYP3A4 (Dexamethasone, phenytoin, Carbamazepine, rifampicin, phenobarbital) dasatinib plasma concentration decreases. Should be prescribed a lower ability to induce the enzyme.

Hypericum perforatum preparations dasatinib reduces the concentration in the blood plasma, so their combined use is not recommended.

The simultaneous use of antacids is undesirable; if necessary, they are taken for 2 hours before or after 2 h after administration of dasatinib.

The suppression of secretion of HCl blockers H2 histamine receptors and proton pump inhibitors (famotidine and omeprazole) reduces the concentration of dasatinib. Their joint use is not recommended.

CYP3A4 substrates with a narrow therapeutic range (alfentanil, astemizol, terfenadine, cisapride, cyclosporine, Fentanyl, pimozid, quinidine, sirolimus, tacrolimus, ergotamin, digidroergotamin) should be used with caution when combined with dasatinib.

Cautions

In the treatment of severe thrombocytopenia can occur, anemia and neutropenia, more frequently in patients with advanced phase CML or acute lymphoblastic leukemia with Philadelphia chromosome positive. Bone marrow suppression is reversible and takes place at the time the cancellation or reduction of dose.

Complete blood counts should be performed 1 once a week in the first 2 months of treatment, then 1 once a month, or more often (as clinically indicated).

In severe thrombocytopenia may be observed bleeding, bleeding in the brain, including fatal.

You may experience fluid retention (pleural, pericardial effusion, vyrajyennyi ascites, generalized edema, pulmonary edema).

Fluid retention adjusted diuretics or short courses of corticosteroids, in severe pleural effusion may require thoracentesis and oxygen therapy.

Dasatinib is used with caution in patients with prolonged QTc interval or at risk of its elongation (kaliopenia, gipomagniemiya, congenital long QT syndrome, with antiarrhythmic therapy, etc.. PM, able to prolong the QT interval, previous therapy with high doses of anthracyclines). Before treatment dasatinib should carry out the correction of hypokalemia and hypomagnesemia.

Increase in transaminases, giperʙiliruʙinemija 3 or 4 Art., hypocalcemia and hypophosphatemia 3 or 4 Article. were observed more frequently in patients with myeloid or lymphoid phase blast crisis of chronic myeloid leukemia, with acute lymphoblastic leukemia with Philadelphia chromosome positive.

The normalization of transaminases and / or bilirubin concentration occurs after dose reduction or treatment interruption. Relief of hypocalcemia 3 or 4 Article. carried drugs Ca2 (inside).