SPRYCEL (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C 22 H 26 ClN 7 O 2 S • H 2 O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure: Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol. dasatinib-struct.jpg

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. (1 , 14) • adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. (1 , 14) • adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. (1 , 14) • pediatric patients 1 year of age and older with Ph+ CML in chronic phase. (1 , 14) • pediatric patients 1 year of age and older with newly diagnosed Ph+ ALL in combination with chemotherapy. (1 , 14)

SPRYCEL (dasatinib) Tablets are available as 20-mg, 50-mg, 70-mg, 80-mg, 100-mg, and 140-mg white to off-white, biconvex, film-coated tablets. Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg.

• 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

Dosage of SPRYCEL in Adult Patients The recommended starting dosage of SPRYCEL for chronic phase CML in adults is 100 mg administered orally once daily. The recommended starting dosage of SPRYCEL for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults is 140 mg administered orally once daily. Tablets should not be crushed, cut, or chewed; they should be swallowed whole. SPRYCEL can be taken with or without a meal, either in the morning or in the evening

Dosage of SPRYCEL in Pediatric Patients with CML or Ph+ ALL The recommended starting dosage for pediatrics is based on body weight as shown in Table 1. The recommended dose should be administered orally once daily with or without food. Recalculate the dose every 3 months based on changes in body weight, or more often if necessary. Do not crush, cut or chew tablets. Swallow tablets whole. There are additional administration considerations for pediatric patients who have difficulty swallowing tablets whole . Table 1: Dosage of SPRYCEL for Pediatric Patients a Body Weight (kg) b Daily Dose (mg) a For pediatric patients with Ph+ ALL, begin SPRYCEL therapy on or before day 15 of induction chemotherapy, when diagnosis is confirmed and continue for 2 years. b Tablet dosing is not recommended for patients weighing less than 10 kg. 10 to less than 20 40 mg 20 to less than 30 60 mg 30 to less than 45 70 mg at least 45 100 mg Refer to Section 2.4 for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML

Dose Modification Strong CYP3A4 Inducers Avoid the use of concomitant strong CYP3A4 inducers and St. John’s wort. If patients must be coadministered a strong CYP3A4 inducer, consider a SPRYCEL dose increase. If the dose of SPRYCEL is increased, monitor the patient carefully for toxicity . Strong CYP3A4 Inhibitors Avoid the use of concomitant strong CYP3A4 inhibitors and grapefruit juice. Recommend selecting an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible. If SPRYCEL must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to: • 40 mg daily for patients taking SPRYCEL 140 mg daily. • 20 mg daily for patients taking SPRYCEL 100 mg daily. • 20 mg daily for patients taking SPRYCEL 70 mg daily. For patients taking SPRYCEL 60 mg or 40 mg daily, consider interrupting SPRYCEL until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating SPRYCEL. These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors; however, clinical data are not available with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt SPRYCEL until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the SPRYCEL dose is increased

Dose Escalation in Adults with CML and Ph+ ALL, and Pediatric Patients with CML For adult patients with CML and Ph+ ALL, consider dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) in patients who do not achieve a hematologic or cytogenetic response at the recommended starting dosage. For pediatric patients with CML, consider dose escalation to 120 mg once daily . Dose escalation is not recommended for pediatric patients with Ph+ ALL, where SPRYCEL is administered in combination with chemotherapy. Escalate the SPRYCEL dose as shown in Table 2 in pediatric patients with chronic phase CML who do not achieve a hematologic or cytogenetic response at the recommended starting dosage. Table 2: Dose Escalation for Pediatric CML Formulation Dose (maximum dose per day) Starting Dose Escalation Tablets 40 mg 50 mg 60 mg 70 mg 70 mg 90 mg 100 mg 120 mg 2.5 Dose Adjustment for Adverse Reactions Myelosuppression In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications for adult and pediatric patients are summarized in Tables 3 and 4, respectively. Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adults * ANC: absolute neutrophil count Chronic Phase CML (starting dose 100 mg once daily) ANC* <0.5 × 10 9 /L or Platelets <50 × 10 9 /L 1. Stop SPRYCEL until ANC ≥1.0 × 10 9 /L and platelets ≥50 × 10 9 /L. 2. Resume treatment with SPRYCEL at the original starting dose if recovery occurs in ≤7 days. 3. If platelets <25 × 10 9 /L or recurrence of ANC <0.5 × 10 9 /L for >7 days, repeat Step 1 and resume SPRYCEL at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue SPRYCEL (for patients resistant or intolerant to prior therapy including imatinib). Accelerated Phase CML, Blast Phase CML and Ph+ ALL (starting dose 140 mg once daily) ANC* <0.5 × 10 9 /L or Platelets <10 × 10 9 /L 1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukemia, stop SPRYCEL until ANC ≥1.0 × 10 9 /L and platelets ≥20 × 10 9 /L and resume at the original starting dose. 3. If recurrence of cytopenia, repeat Step 1 and resume SPRYCEL at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode). 4. If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily. Table 4: Dose Adjustments for Neutropenia and Thrombocytopenia in Pediatric Patients with Ph+ CML *ANC: absolute neutrophil count ** lower tablet dose not available Dose (maximum dose per day) 1. If cytopenia persists for more than 3 weeks, check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukemia, stop SPRYCEL until ANC* ≥1.0 × 10 9 /L and platelets ≥75 × 10 9 /L and resume at the original starting dose or at a reduced dose. 3. If cytopenia recurs, repeat marrow aspirate/biopsy and resume SPRYCEL at a reduced dose. Original Starting Dose One-Level Dose Reduction Two-Level Dose Reduction Tablets 40 mg 20 mg ** 60 mg 40 mg 20 mg 70 mg 60 mg 50 mg 100 mg 80 mg 70 mg For pediatric patients with chronic phase CML, if Grade ≥ 3 neutropenia or thrombocytopenia recurs during complete hematologic response (CHR), interrupt SPRYCEL and resume at a reduced dose. Implement temporary dose reductions for intermediate degrees of cytopenia and disease response as needed. For pediatric patients with Ph+ ALL, if neutropenia and/or thrombocytopenia result in a delay of the next block of treatment by more than 14 days, interrupt SPRYCEL and resume at the same dose level once the next block of treatment is started. If neutropenia and/or thrombocytopenia persist and the next block of treatment is delayed another 7 days, perform a bone marrow assessment to assess cellularity and percentage of blasts. If marrow cellularity is <10%, interrupt treatment with SPRYCEL until ANC >500/μL (0.5 x 10 9 /L), at which time treatment may be resumed at full dose. If marrow cellularity is >10%, resumption of treatment with SPRYCEL may be considered. Non-Hematologic Adverse Reactions For adults with Ph+ CML and ALL, and pediatric patients with Ph+ CML, if a severe non-hematologic adverse reaction develops with SPRYCEL use, treatment must be withheld until the adverse reaction has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence . For pediatric patients with Ph+ ALL, interrupt treatment for cases of grade ≥ 3 non-hematologic adverse reactions with the exception of liver function test abnormalities, and resume at a reduced dose when resolved to grade ≤1. For elevated direct bilirubin over 5 times the institutional upper limit of normal (ULN), interrupt treatment until improvement to baseline or grade ≤1. For elevated AST/ALT over 15 times the institutional ULN, interrupt treatment until improvement to baseline or grade <1. For recurrent liver function test abnormalities as above, reduce the dose if this adverse reaction recurs after reinitiation of SPRYCEL. Dose reduction recommendations are described in Table 5. Table 5: Dose Adjustments for Non-Hematologic Toxicities in Pediatric Patients ** lower tablet dose not available Dose (maximum dose per day) 1. If a non-hematologic toxicity grade 2 occurs, consider interrupting SPRYCEL if no recovery despite symptomatic therapy; once recovered to grade ≤1, resume at the original starting dose. Resume SPRYCEL at a reduced dose for recurrent events. 2. If a non-hematologic toxicity grade 3 occurs, stop SPRYCEL until recovery to grade ≤1 and then resume at a reduced dose. 3. If direct bilirubin is >5 ULN or AST/ALT >15 ULN, interrupt SPRYCEL until recovery to grade ≤1 and then resume SPRYCEL at the original starting dose. Resume SPRYCEL at a reduced dose for recurrent hepatotoxicity. Original Starting Dose One-Level Dose Reduction Two-Level Dose Reduction Tablets 40 mg 20 mg ** 60 mg 40 mg 20 mg 70 mg 60 mg 50 mg 100 mg 80 mg 70 mg 2.6 Duration of Treatment In clinical studies, treatment with SPRYCEL in adults and in pediatric patients with chronic phase CML 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 and MR4.5) has not been established. In clinical studies, treatment with SPRYCEL in pediatric patients with Ph+ ALL was administered for a maximum duration of 2 years . SPRYCEL is a hazardous product. Follow applicable special handling and disposal procedures. 1

• 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. (2.5 , 5.1 , 5.2) • Fluid Retention: Fluid retention, sometimes severe, including pleural effusions. Manage with supportive care measures and/or dose modification. (2.5 , 5.3) • 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. • Severe Dermatologic Reactions: Individual cases of severe mucocutaneous dermatologic reactions have been reported. • Tumor Lysis Syndrome: Tumor lysis syndrome has been reported. Maintain adequate hydration and correct uric acid levels prior to initiating therapy with SPRYCEL. • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of potential risk to fetus and to use effective contraception. (5.9 , 8.1 , 8.3) • Effects on Growth and Development in Pediatric Patients: epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia have been reported. Monitor bone growth and development in pediatric patients. (5.10) • Hepatotoxicity: Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. (5.11) 5.1 Myelosuppression Treatment with SPRYCEL is associated with severe (NCI CTCAE Grade 3 or 4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML . In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated. In pediatric patients with Ph+ ALL treated with SPRYCEL in combination with chemotherapy, perform CBCs prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery. Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily and/or dose reduction

Bleeding-Related Events SPRYCEL can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. The incidence of Grade 3/4 hemorrhage occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal . Most bleeding events in clinical studies were associated with severe thrombocytopenia. In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro . Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage

Fluid Retention SPRYCEL may cause fluid retention . After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), Grade 3 or 4 fluid retention was reported in 5% of patients, including 3% of patients with Grade 3 or 4 pleural effusion. In adult patients with newly diagnosed or imatinib-resistant or -intolerant chronic phase CML, Grade 3 or 4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In adult patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), Grade 3 or 4 fluid retention was reported in 8% of patients, including Grade 3 or 4 pleural effusion reported in 7% of patients. In pediatric patients with chronic phase CML, cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients. Evaluate patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough, promptly with a chest x-ray or additional diagnostic imaging as appropriate. Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids. Severe pleural effusion may require thoracentesis and oxygen therapy. Consider dose reduction or treatment interruption

Cardiovascular Toxicity SPRYCEL can cause cardiac dysfunction . After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial in adults (n=258), the following cardiac adverse reactions occurred: cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac-related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately

Pulmonary Arterial Hypertension SPRYCEL may increase the risk of developing pulmonary arterial hypertension (PAH) in adult and pediatric patients which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention . PAH may be reversible on discontinuation of SPRYCEL. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued

QT Prolongation SPRYCEL may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy . Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL administration

Severe Dermatologic Reactions Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL. Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified

Tumor Lysis Syndrome Tumor lysis syndrome has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease. Due to potential for tumor lysis syndrome, maintain adequate hydration, correct uric acid levels prior to initiating therapy with SPRYCEL, and monitor electrolyte levels. Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently

Embryo-Fetal Toxicity Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects of SPRYCEL including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with SPRYCEL and for 30 days after the last dose

Effects on Growth and Development in Pediatric Patients In pediatric trials of SPRYCEL in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia . Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment. Monitor bone growth and development in pediatric patients

Hepatotoxicity SPRYCEL may cause hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase . Monitor transaminases at baseline and monthly or as clinically indicated during treatment. Reduce dose, withhold, or permanently discontinue SPRYCEL based on severity . When SPRYCEL is administered in combination with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Monitor hepatic function when SPRYCEL is used in combination with chemotherapy.

• Strong CYP3A4 Inhibitors: Dose reduction may be necessary. (2.3 , 7.1) • Strong CYP3A4 Inducers: Dose increase may be necessary. (2.3 , 7.1) • Antacids: Avoid simultaneous administration. • H 2 Antagonists and Proton Pump Inhibitors: Avoid coadministration

Effect of Other Drugs on Dasatinib Strong CYP3A4 Inhibitors The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations . Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a SPRYCEL dose reduction . Strong CYP3A4 Inducers The coadministration of SPRYCEL with strong CYP3A inducers may decrease dasatinib concentrations . Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a SPRYCEL dose increase. Gastric Acid Reducing Agents The coadministration of SPRYCEL with a gastric acid reducing agent may decrease the concentrations of dasatinib. Decreased dasatinib concentrations may reduce efficacy. Do not administer H 2 antagonists or proton pump inhibitors with SPRYCEL. Consider the use of antacids in place of H 2 antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of SPRYCEL. Avoid simultaneous administration of SPRYCEL with antacids.