Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase. In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

Dasatinib is indicated for the treatment of adults with:

• Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
• Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.
• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

The recommended starting dosage of Dasatinib for:

• Chronic phase CML is 100 mg administered orally once daily.
• Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily.

Tablets should not be crushed or cut; they should be swallowed whole. Dasatinib can be taken with or without a meal, either in the morning or in the evening.

In clinical studies, treatment with Dasatinib was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response (including complete cytogenetic response [CCyR]) or major molecular response (MMR) is not known.

Concomitant use with CYP3A4 inhibitors (e.g. atazanavir, clarithromycin, erythromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole or grapefruit juice); CYP3A4 inducers (e.g. carbamazepine, dexamethasone, phenytoin, phenobarbital, rifampicin or St John's wort); antacid. Pregnancy.

Reversible myelosuppression, neutropenia, anaemia, thrombocytopenia, fluid retention, pulmonary arterial HTN, QT prolongation, cardiac failure, arrhythmias, HTN, musculoskeletal pain, GI disturbances, headache, chills, fatigue, asthenia, myalgia, chest pain, arthralgia, pyrexia, mucositis, flushing, colitis, electrolyte disturbances, appetite and wt disturbances, rash, dermatitis, hyperhidrosis, pruritus, acne.

Overdose Effects

Symptoms: Significant platelet count reduction. Management: Closely monitor for myelosuppression. Supportive and symptomatic treatment.

Patients with predisposing factors for QT prolongation (e.g. congenital long QT syndrome, hypokalaemia, hypomagnesaemia, on antiarrhythmic therapy, or receiving cumulative high doses of anthracyclines). Hepatic impairment. Lactation.

Use in Special Populations

Pediatric Use: The safety and efficacy of Dasatinib in patients less than 18 years of age have not been established.

Geriatric Use: No differences in confirmed Complete Cytogenetic Response (cCCyR) and MMR were observed between older and younger patients. Of the 2712 patients in clinical studies of Dasatinib, 617 (23%) were 65 years of age and older, and 123 (5%) were 75 years of age and older. While the safety profile of Dasatinib in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease, and should be monitored closely.

Hepatic Impairment: No dosage adjustment is necessary in patients with hepatic impairment. Caution is recommended when administering Dasatinib to patients with hepatic impairment.

Renal Impairment: There are currently no clinical studies with Dasatinib in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney.

Pregnancy & Lactation

Pregnancy category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).