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Dasatinib

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

DasatinibSynonyms: BMS-354825
USAN: Dasatinib
INN: Dasatinib [pINN (en)]
INN: Dasatinib [pINN (es)]
INN: Dasatinib [pINN (fr)]
INN: Dasatinibum [pINN (la)]
INN: Дазатиниб [pINN (ru)]
Chemical name: N-(2-Chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl}amino)-5-thiazolecarboxamide
Molecular formula: C22H26ClN7O2S =488.0
CAS: 302962-49-8

Adverse Effects, Treatment, and Precautions

The most common adverse effects of dasatinib include fluid retention, gastrointestinal disturbances, and bleeding. Fluid retention may be severe, and can result in pleural and pericardial effusion, pulmonary oedema, and ascites. Severe CNS haemorrhages, sometimes fatal, have been reported. Gastrointestinal haemorrhage may require interruption of therapy, and transfusions. Myelosuppression, manifest as neutropenia, thrombocytopenia, or anaemia, occurs more frequently in patients with advanced chronic myeloid leukaemia (CML) or acute lymphoblastic leukaemia than in patients in chronic phase. Recovery generally occurs after dose interruption and/or reduction, although treatment may need to be stopped.

Febrile neutropenia has been reported. In patients with chronic phase CML, myelosuppression and fluid retention occur more often with twice daily dosing than once daily dosage. Other adverse effects include headache, pyrexia, musculoskeletal pain, fatigue, skin rashes, dyspnoea, cough, dizziness, chest pain, neuropathy, chills, and pruritus. Infections, including pneumonia, have been reported. Cardiac failure and arrhythmias can occur. Dasatinib has the potential to prolong the QT interval, and should be given with caution to patients at risk of this, such as those with hypokalaemia, hypomagnesaemia, or those on antiarrhythmic therapy, or receiving cumulative high doses of anthracyclines.

Effects on the skin

Parmiculitis has been reported with the use of dasatinib, which resolved upon stopping therapy. In one case, dasatinib was restarted with prednisone, and no recurrence of parmiculitis was noted. In another patient, however, a rash recurred on restarting therapy that was not sensitive to corticosteroid treatment.

Interactions

Dasatinib is metabolised by the cytochrome P450 isoenzyme CYP3A4, and drugs that inhibit this enzyme, such as azole antifungals, macrolide antibacterials, HIV-protease inhibitors, and nefazodone may increase blood concentrations of dasatinib. Equally, inducers of CYP3A4 (such as carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampicin) may reduce blood concentrations of dasatinib. When use with such drugs cannot be avoided, dose adjustment of dasatinib may be necessary (see Uses and Administration, below). Since St John’s wort may decrease dasatinib concentrations unpredictably, these drugs should not be given together.

Dasatinib is a substrate of the cytochrome P450 isoenzyme CYP3 A4, and may alter blood concentrations of other drugs that are substrates of this enzyme. Since the solubility of dasatinib is dependent on pH, use with antacids should be avoided. If antacid therapy is needed, it should be given at least 2 hours before or 2 hours after the dose of dasatinib. Similarly, histamine H2-receptor antagonists or proton pump inhibitors such as famotidine or omeprazole should not be given with dasatinib as long-term suppression of gastric acid secretion is likely to reduce dasatinib exposure.

Pharmacokinetics

Maximum plasma concentrations of dasatinib are achieved between 0.5 and 6 hours after an oral dose. The mean terminal half-life is about 5 hours. Consumption of a high-fat meal may increase exposure to dasatinib, but this effect is not considered to be of clinical significance. Dasatinib is extensively distributed and metabolised. Metabolism occurs primarily by the cytochrome P450 isoenzyme CYP3A4, forming an active metabolite. Plasma protein binding of dasatinib and its active metabolite is about 96% and 93%, respectively Elimination is mainly via the faeces; about 4% is recovered in the urine.

Uses and Administration

Dasatinib is a tyrosine kinase inhibitor that is used for the treatment of adults with all phases of chronic myeloid leukaemia (CML) who have resistance or intolerance to previous therapy, including imatinib. It is also used for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL) who are resistant to or intolerant of prior therapy.

A recommended oral starting dose of dasatinib in chronic phase CML is 100 mg once daily: tablets, which should be swallowed whole, not crushed or chewed, should be taken consistently either in the morning or the evening. The recommended starting dose for accelerated, myeloid, or lymphoid blast phase CML or Philadelphia chromosome-positive ALL is 70 mg twice daily. Dosage may be adjusted according to response and tolerability; doses of up to 140 mg once daily have been used in patients with chronic phase CML, anduptolOOmg twice daily in those with advanced phase, or with ALL. Treatment is continued until disease progression or unacceptable toxicity occurs.

If concurrent use of potent inhibitors or inducers of cytochrome P450 isoenzyme CYP3A4 cannot be avoided, dose adjustments are considered necessary. A dose increase should be considered in those patients given strong CYP3A4 inducers, and the patient should be monitored for toxicity. For those given a strong CYP3A4 inhibitor, the dose of dasatinib should be reduced to 20 mg daily. If this is not tolerated, then either drug should be stopped; if the inhibitor is stopped, a washout period of about 1 week should be allowed before the dose of dasatinib is increased.

Proprietary Preparations

Argentina: Sprycel;

Australia: Sprycel;

Czech Republic: Sprycel;

France: Sprycel;

Greece: Sprycel;

Hungary: Sprycel;

Indonesia: Sprycel;

Malaysia: Sprycel;

New Zealand: Sprycel;

United Kingdom (UK): Sprycel;

United States of America (US and USA): Sprycel.

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