Dasatinib

SPRYCEL (dasatinib) is indicated for the treatment of adult patients 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. SPRYCEL (dasatinib) is indicated for the treatment of pediatric patients 1 year of age and older with • Ph+ CML in chronic phase. • newly diagnosed Ph+ ALL in combination with chemotherapy. SPRYCEL is a kinase inhibitor indicated for the treatment of • newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.

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 could 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.

• Chronic phase CML in adults: 100 mg once daily. • Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults: 140 mg once daily. • Chronic phase CML and ALL in pediatrics: starting dose based on body weight. • Administer orally, with or without a meal. Do not crush, cut, or chew tablets.

None. None.

• Myelosuppression and Bleeding Events: Severe thrombocytopenia, neutropenia, and anemia may occur. Use caution if used concomitantly with medications that inhibit platelet function or anticoagulants. Monitor complete blood counts regularly. Transfuse and interrupt SPRYCEL when indicated. • Fluid Retention: Fluid retention, sometimes severe, including pleural effusions. Manage with supportive care measures and/or dose modification. • Cardiovascular Toxicity: Monitor patients for signs or symptoms and treat appropriately. • Pulmonary Arterial Hypertension (PAH): SPRYCEL may increase the risk of developing PAH which may be reversible on discontinuation. Consider baseline risk and evaluate patients for signs and symptoms of PAH during treatment. Stop SPRYCEL if PAH is confirmed. • QT Prolongation: Use SPRYCEL with caution in patients who have or may develop prolongation of the QT interval.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression. • Bleeding-related events. • Fluid retention. • Cardiovascular toxicity. • Pulmonary arterial hypertension. • QT prolongation. • Severe dermatologic reactions. • Tumor lysis syndrome. • Effects on growth and development in pediatric patients. • Hepatotoxicity. Most common adverse reactions (≥15%) in patients receiving SPRYCEL as single-agent therapy included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain.

• Strong CYP3A4 Inhibitors: Dose reduction may be necessary. • Strong CYP3A4 Inducers: Dose increase may be necessary. • Antacids: Avoid simultaneous administration. • Methotrexate: SPRYCEL may delay the clearance of methotrexate when methotrexate is used at high doses (≥500 mg/m 2 ). • H 2 Antagonists and Proton Pump Inhibitors: Avoid coadministration.

Storage SPRYCEL tablets should be stored at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F).