DASATINIB

Dasatinib tablet 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 off-white to yellowish powder. The drug substance is practically insoluble in water and slightly to very slightly soluble in methanol and freely soluble in dimethyl sulfoxide, soluble in N,N-dimethyl formamide. Dasatinib tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate and microcrystalline cellulose. The tablet coating consists of hypromellose, polyethylene glycol and titanium dioxide. structure

Dasatinib tablet 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. Dasatinib tablet is indicated for the treatment of pediatric patients 1 year of age and older with • Ph+ CML in chronic phase. Additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Dasatinib tablet 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)

• Chronic phase CML in adults: 100 mg once daily. (2) • Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults: 140 mg once daily. (2) • Chronic phase CML in pediatrics: starting dose based on body weight. (2) • Administer orally, with or without a meal. Do not crush, cut, or chew tablets. (2) 2.1 Dosage of Dasatinib Tablets in Adult Patients The recommended starting dosage of dasatinib tablets for chronic phase CML in adults is 100 mg administered orally once daily. The recommended starting dosage of dasatinib tablets 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. Dasatinib tablets can be taken with or without a meal, either in the morning or in the evening. Refer to Section 2.4 for recommendations on dose escalation in adults with CML and Ph+ ALL. Pediatric use information is approved for Bristol-Myers Squibb Company’s Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.2 Dosage of Dasatinib Tablets in Pediatric Patients with CML 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. Table 1: Dosage of Dasatinib Tablets for Pediatric Patients Body Weight (kg) b Daily Dose (mg) 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 b Tablet dosing is not recommended for patients weighing less than 10 kg. Refer to Section 2.4 for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML. Additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.3 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 dasatinib tablet dose increase. If the dose of dasatinib tablet is increased, monitor the patient carefully for toxicity [see Drug Interactions (7.1)]. 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 dasatinib tablet must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to: • 40 mg daily for patients taking dasatinib tablets 140 mg daily. • 20 mg daily for patients taking dasatinib tablets 100 mg daily. • 20 mg daily for patients taking dasatinib tablets 70 mg daily. For patients taking dasatinib tablets 60 mg or 40 mg daily, consider interrupting dasatinib tablets until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating dasatinib tablets. These reduced doses of dasatinib tablets 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 dasatinib tablet is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib tablets until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the dasatinib tablet dose is increased [see Drug Interactions (7.1)]. 2.4 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 (see Table 2 below). Dose escalation is not recommended for pediatric patients with Ph+ ALL, where dasatinib tablet is administered in combination with chemotherapy. Escalate the dasatinib tablet 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 Table 3 and 4, respectively. Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adults Chronic Phase CML (starting dose 100 mg once daily) ANC* <0.5 × 10 9 /L or Platelets <50 × 10 9 /L 1. Stop dasatinib tablets until ANC ≥1×10 9 /L and platelets ≥50×10 9 /L. 2. Resume treatment with dasatinib tablets 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 dasatinib tablets 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 dasatinib tablets (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 dasatinib tablets until ANC ≥1 × 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 dasatinib tablets 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. *ANC: absolute neutrophil count Table 4: Dose Adjustments for Neutropenia and Thrombocytopenia in Pediatric Patients with Ph+ CML Dose (maximum dose per day) Original Starting Dose One-Level Dose Reduction Two-Level Dose Reduction 1. If cytopenia persists for more than 3 weeks, check if cytopenia is related to leukemia (marrow aspirate or biopsy). Tablets 40 mg 60 mg 70 mg 100 mg 20 mg 40 mg 60 mg 80 mg ** 20 mg 50 mg 70 mg 2. If cytopenia is unrelated to leukemia, stop dasatinib tablets until ANC* ≥1 × 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 dasatinib tablets at a reduced dose. *ANC: absolute neutrophil count ** lower tablet dose not available For pediatric patients with chronic phase CML, if Grade ≥3 neutropenia or thrombocytopenia recurs during complete hematologic response (CHR), interrupt dasatinib tablets and resume at a reduced dose. Implement temporary dose reductions for intermediate degrees of cytopenia and disease response as needed. 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 dasatinib tablets 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 [see Warnings and Precautions (5)]. Additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.6 Duration of Treatment In clinical studies, treatment with dasatinib tablets 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. Dasatinib tablet is a hazardous product. Follow applicable special handling and disposal procedures. 1 Additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

None. None. (4)

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)]. • Bleeding-related events [see Warnings and Precautions (5.2)]. • Fluid retention [see Warnings and Precautions (5.3)]. • Cardiovascular toxicity [see Warnings and Precautions (5.4)]. • Pulmonary arterial hypertension [see Warnings and Precautions (5.5)]. • QT prolongation [see Warnings and Precautions (5.6)]. • Severe dermatologic reactions [see Warnings and Precautions (5.7)]. • Tumor lysis syndrome [see Warnings and Precautions (5.8)]. • Effects on growth and development in pediatric patients [see Warnings and Precautions (5.10)]. • Hepatotoxicity [see Warnings and Precautions (5.11)]. Most common adverse reactions (≥15%) in patients receiving dasatinib as single-agent therapy included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. (6) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to dasatinib administered as single-agent therapy at all doses tested in clinical studies (n=2809), including 324 adult patients with newly diagnosed chronic phase CML, and 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic phase CML. The median duration of therapy in a total of 2712 adult patients was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. The median duration of therapy in 1618 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months). The median duration of therapy in 1094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). In two non-randomized trials in 97 pediatric patients with chronic phase CML (51 patients newly diagnosed and 46 patients resistant or intolerant to previous treatment with imatinib), the median duration of therapy was 51.1 months (range 1.9 to 99.6 months). In the overall population of 2712 adult patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation. In the randomized trial in adult patients with newly diagnosed chronic phase CML, drug was discontinued for adverse reactions in 16% of patients with a minimum of 60 months of follow-up. After a minimum of 60 months of follow-up, the cumulative discontinuation rate was 39%. Among the 1618 patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients; among the 1094 patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients. Among the 97 pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient (1%). Adverse reactions reported in ≥10% of adult patients, and other adverse reactions of interest, in a randomized trial in patients with newly diagnosed chronic phase CML at a median follow-up of approximately 60 months are presented in Table 6. Adverse reactions reported in ≥10% of adult patients treated at the recommended dose of 100 mg once daily (n=165), and other adverse reactions of interest, in a randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy at a median follow-up of approximately 84 months are presented in Table 8. Adverse reactions reported in ≥10% of pediatric patients at a median follow-up of approximately 51.1 months are presented in Table 11. Drug-related serious adverse reactions (SARs) were reported for 16.7% of adult patients in the randomized trial of patients with newly diagnosed chronic phase CML. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%). Drug-related SARs were reported for 26.1% of patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of adult patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%). Drug-related SARs were reported for 14.4% of pediatric patients. Chronic Myeloid Leukemia (CML) Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of adult patients are shown in Table 6 for newly diagnosed patients with chronic phase CML and Tables 8 and 10 for CML patients with resistance or intolerance to prior imatinib therapy. Table 6: Adverse Reactions Reported in ≥10% of Adult Patients with Newly Diagnosed Chronic Phase CML (minimum of 60 months follow-up) All Grades Grade 3/4 Dasatinib (n=258) Imatinib (n=258) Dasatinib (n=258) Imatinib (n=258) Adverse Reaction Percent (%) of Patients Fluid retention 38 45 5 1 Pleural effusion 28 1 3 0 Superficial localized edema 14 38 0 <1 Pulmonary hypertension 5 <1 1 0 Generalized edema 4 7 0 0 Pericardial effusion 4 1 1 0 Congestive heart failure / cardiac dysfunction a 2 1 <1 <1 Pulmonary edema 1 0 0 0 Diarrhea 22 23 1 1 Musculoskeletal pain 14 17 0 <1 Rash b 14 18 0 2 Headache 14 11 0 0 Abdominal pain 11 8 0 1 Fatigue 11 12 <1 0 Nausea 10 25 0 0 Myalgia 7 12 0 0 Arthralgia 7 10 0 <1 Hemorrhage c 8 8 1 1 Gastrointestinal bleeding 2 2 1 0 Other bleeding d 6 6 0 <1 CNS bleeding <1 <1 0 <1 Vomiting 5 12 0 0 Muscle spasms 5 21 0 <1 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage. A comparison of cumulative rates of adverse reactions reported in ≥10% of patients with minimum follow-up of 1 and 5 years in a randomized trial of newly diagnosed patients with chronic phase CML treated with dasatinib are shown in Table 7. Table 7: Adverse Reactions Reported in ≥10% of Adult Patients with Newly Diagnosed Chronic Phase CML in the Dasatinib-Treated Arm (n=258) Minimum of 1 Year Follow-up Minimum of 5 Years Follow-up All Grades Grade 3/4 All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Fluid retention 19 1 38 5 Pleural effusion 10 0 28 3 Superficial localized edema 9 0 14 0 Pulmonary hypertension 1 0 5 1 Generalized edema 2 0 4 0 Pericardial effusion 1 <1 4 1 Congestive heart failure / cardiac dysfunction a 2 <1 2 <1 Pulmonary edema <1 0 1 0 Diarrhea 17 <1 22 1 Musculoskeletal pain 11 0 14 0 Rash b 11 0 14 0 Headache 12 0 14 0 Abdominal pain 7 0 11 0 Fatigue 8 <1 11 <1 Nausea 8 0 10 0 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. At 60 months, there were 26 deaths in dasatinib-treated patients (10.1%) and 26 deaths in imatinib-treated patients (10.1%); 1 death in each group was assessed by the investigator as related to study therapy. Table 8: Adverse Reactions Reported in ≥10% of Adult Patients with Chronic Phase CML Resistant or Intolerant to Prior Imatinib Therapy (minimum of 84 months follow- up) Adverse Reaction 100 mg Once Daily Chronic (n=165) All Grades Grade 3/4 Percent (%) of Patients Fluid retention 48 7 Superficial localized edema 22 0 Pleural effusion 28 5 Generalized edema 4 0 Pericardial effusion 3 1 Pulmonary hypertension 2 1 Headache 33 1 Diarrhea 28 2 Fatigue 26 4 Dyspnea 24 2 Musculoskeletal pain 22 2 Nausea 18 1 Skin rash a 18 2 Myalgia 13 0 Arthralgia 13 1 Infection (including bacterial, viral, fungal, and non-specified) 13 1 Abdominal pain 12 1 Hemorrhage 12 1 Gastrointestinal bleeding 2 1 Pruritus 12 1 Pain 11 1 Constipation 10 1 a Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. Cumulative rates of selected adverse reactions that were reported over time in patients treated with the 100 mg once daily recommended starting dose in a randomized dose-optimization trial of imatinib-resistant or -intolerant patients with chronic phase CML are shown in Table 9. Table 9: Selected Adverse Reactions Reported in Adult Dose Optimization Trial (Imatinib-Intolerant or -Resistant Chronic Phase CML) a Minimum of 2 Years Follow-up Minimum of 5 Years Follow-up Minimum of 7 Years Follow-up All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Diarrhea 27 2 28 2 28 2 Fluid retention 34 4 42 6 48 7 Superficial edema 18 0 21 0 22 0 Pleural effusion 18 2 24 4 28 5 Generalized edema 3 0 4 0 4 0 Pericardial effusion 2 1 2 1 3 1 Pulmonary hypertension 0 0 0 0 2 1 Hemorrhage 11 1 11 1 12 1 Gastrointestinal bleeding 2 1 2 1 2 1 a Randomized dose-optimization trial results reported in the recommended starting dose of 100 mg once daily (n=165) population. Table 10: Adverse Reactions Reported in ≥10% of Adult Patients with Advanced Phase CML Resistant or Intolerant to Prior Imatinib Therapy Adverse Reaction 140 mg Once Daily Accelerated (n=157) Myeloid Blast (n=74) Lymphoid Blast (n=33) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Percent (%) of Patients Fluid retention 35 8 34 7 21 6 Superficial localized edema 18 1 14 0 3 0 Pleural effusion 21 7 20 7 21 6 Generalized edema 1 0 3 0 0 0 Pericardial effusion 3 1 0 0 0 0 Congestive heart failure / cardiac dysfunction a 0 0 4 0 0 0 Pulmonary edema 1 0 4 3 0 0 Headache 27 1 18 1 15 3 Diarrhea 31 3 20 5 18 0 Fatigue 19 2 20 1 9 3 Dyspnea 20 3 15 3 3 3 Musculoskeletal pain 11 0 8 1 0 0 Nausea 19 1 23 1 21 3 Skin rash b 15 0 16 1 21 0 Arthralgia 10 0 5 1 0 0 Infection (including bacterial, viral, fungal, and non-specified) 10 6 14 7 9 0 Hemorrhage 26 8 19 9 24 9 Gastrointestinal bleeding 8 6 9 7 9 3 CNS bleeding 1 1 0 0 3 3 Vomiting 11 1 12 0 15 0 Pyrexia 11 2 18 3 6 0 Febrile neutropenia 4 4 12 12 12 12 a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. Table 11: Adverse Reactions Reported in ≥10% of Dasatinib-Treated Pediatric Patients with Chronic Phase CML (n=97) All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Headache 28 3 Nausea 20 0 Diarrhea 21 0 Skin rash 19 0 Vomiting 13 0 Pain in extremity 19 1 Abdominal pain 16 0 Fatigue 10 0 Arthralgia 10 1 Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of pediatric patients with chronic phase CML [see Warnings and Precautions (5.10)]. Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 12 and 13). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of adult patients with newly diagnosed chronic phase CML and 5% of adult patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions (5.1)]. Grade 3 or 4 elevations of transaminases or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during dasatinib therapy often had recovery with oral calcium supplementation. Laboratory abnormalities reported in adult patients with newly diagnosed chronic phase CML are shown in Table 12. There were no discontinuations of dasatinib therapy in this patient population due to biochemical laboratory parameters. Table 12: CTC Grade 3/4 Laboratory Abnormalities in Adult Patients with Newly Diagnosed Chronic Phase CML (minimum of 60 months follow-up) Dasatinib (n=258) Imatinib (n=258) Percent (%) of Patients Hematology Parameters Neutropenia 29 24 Thrombocytopenia 22 14 Anemia 13 9 Biochemistry Parameters Hypophosphatemia 7 31 Hypokalemia 0 3 Hypocalcemia 4 3 Elevated SGPT (ALT) <1 2 Elevated SGOT (AST) <1 1 Elevated Bilirubin 1 0 Elevated Creatinine 1 1 CTC grades: neutropenia (Grade 3 ≥0.5 to <1 × 10 9 /L, Grade 4 <0.5 × 10 9 /L); thrombocytopenia (Grade 3 ≥25 to <50 × 10 9 /L, Grade 4 <25 × 10 9 /L); anemia (hemoglobin Grade 3 ≥65 to <80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3 to 6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3 to 10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5 to 20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7 to 6 mg/dL, Grade 4 <6 mg/dL); hypophosphatemia (Grade 3 <2 to 1 mg/dL, Grade 4 <1 mg/dL); hypokalemia (Grade 3 <3 to 2.5 mmol/L, Grade 4 <2.5 mmol/L). Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of dasatinib are shown by disease phase in Table 13. Table 13: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML in Adults: Resistance or Intolerance to Prior Imatinib Therapy Chronic Phase CML 100 mg Once Daily Advanced Phase CML 140 mg Once Daily (n=165) Accelerated Phase (n=157) Myeloid Blast Phase (n=74) Lymphoid Blast Phase (n=33) Percent (%) of Patients Hematology Parameters* Neutropenia 36 58 77 79 Thrombocytopenia 24 63 78 85 Anemia 13 47 74 52 Biochemistry Parameters Hypophosphatemia 10 13 12 18 Hypokalemia 2 7 11 15 Hypocalcemia <1 4 9 12 Elevated SGPT (ALT) 0 2 5 3 Elevated SGOT (AST) <1 0 4 3 Elevated Bilirubin <1 1 3 6 Elevated Creatinine 0 2 8 0 CTC grades: neutropenia (Grade 3 ≥0.5 to <1 × 10 9 /L, Grade 4 <0.5 × 10 9 /L); thrombocytopenia (Grade 3 ≥25 to <50 × 10 9 /L, Grade 4 <25 × 10 9 /L); anemia (hemoglobin Grade 3 ≥65 to <80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3 to 6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3 to 10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5 to 20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7 to 6 mg/dL, Grade 4 <6 mg/dL); hypophosphatemia (Grade 3 <2 to 1 mg/dL, Grade 4 <1 mg/dL); hypokalemia (Grade 3 <3 to 2.5 mmol/L, Grade 4 <2.5 mmol/L). * Hematology parameters for 100 mg once-daily dosing in chronic phase CML reflects 60-month minimum follow-up. Among adult patients with chronic phase CML with resistance or intolerance to prior imatinib therapy, cumulative Grade 3 or 4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%). In the pediatric studies in CML, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults. Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Adults A total of 135 adult patients with Ph+ ALL were treated with dasatinib in clinical studies. The median duration of treatment was 3 months (range 0.03 to 31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events, such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders, such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. Serious adverse reactions reported in ≥5% of patients included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), and infection (5%). Additional Pooled Data from Clinical Trials The following additional adverse reactions were reported in adult and pediatric patients (n= 2809) in dasatinib CML clinical studies and adult patients in Ph+ ALL clinical studies at a frequency of ≥10%, 1% to <10%, 0.1% to <1%, or <0.1%. These adverse reactions are included based on clinical relevance. Gastrointestinal Disorders: 1% to <10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1% to <1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis, gastroesophageal reflux disease; <0.1% – protein losing gastroenteropathy, ileus, acute pancreatitis, anal fistula. General Disorders and Administration-Site Conditions: ≥ 10% – peripheral edema, face edema; 1% to <10% – asthenia, chest pain, chills; 0.1% to <1% – malaise, other superficial edema, peripheral swelling; <0.1% – gait disturbance. Skin and Subcutaneous Tissue Disorders: 1% to <10% – alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1% to <1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome, hair disorder; <0.1% – leukocytoclastic vasculitis, skin fibrosis. Respiratory, Thoracic, and Mediastinal Disorders: 1% to <10% – lung infiltration, pneumonitis, cough; 0.1% to <1% – asthma, bronchospasm, dysphonia, pulmonary arterial hypertension; <0.1% – acute respiratory distress syndrome, pulmonary embolism. Nervous System Disorders: 1% to <10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1% to <1% – amnesia, tremor, syncope, balance disorder; <0.1% –convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis, VIIth nerve paralysis, dementia, ataxia. Blood and Lymphatic System Disorders: 0.1% to <1% – lymphadenopathy, lymphopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1% to <10% – muscular weakness, musculoskeletal stiffness; 0.1% to <1% – rhabdomyolysis, tendonitis, muscle inflammation, osteonecrosis, arthritis; <0.1% – epiphyses delayed fusion (reported at 1% to <10% in the pediatric studies), growth retardation (reported at 1% to <10% in the pediatric studies). Investigations: 1% to <10% – weight increased, weight decreased; 0.1% to <1% – blood creatine phosphokinase increased, gamma-glutamyl transferase increased. Infections and Infestations: 1% to <10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including fatal outcomes [0.2%]). Metabolism and Nutrition Disorders: 1% to <10% – appetite disturbances, hyperuricemia; 0.1% to <1% – hypoalbuminemia, tumor lysis syndrome, dehydration, hypercholesterolemia; <0.1% – diabetes mellitus. Cardiac Disorders: 1% to <10% – arrhythmia (including tachycardia), palpitations; 0.1% to <1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia), electrocardiogram T-wave abnormal, troponin increased; <0.1% – cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis. Eye Disorders: 1% to <10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1% to <1% – conjunctivitis, visual impairment, lacrimation increased, <0.1% – photophobia. Vascular Disorders: 1% to <10% – flushing, hypertension; 0.1% to <1% – hypotension, thrombophlebitis, thrombosis; <0.1% – livedo reticularis, deep vein thrombosis, embolism. Psychiatric Disorders: 1% to <10% – insomnia, depression; 0.1% to <1% – anxiety, affect lability, confusional state, libido decreased. Pregnancy, Puerperium, and Perinatal Conditions: <0.1% – abortion. Reproductive System and Breast Disorders: 0.1% to <1% – gynecomastia, menstrual disorder. Injury, Poisoning, and Procedural Complications: 1% to <10% – contusion. Ear and Labyrinth Disorders: 1% to <10% – tinnitus; 0.1% to <1% – vertigo, hearing loss. Hepatobiliary Disorders: 0.1% to <1% – cholestasis, cholecystitis, hepatitis. Renal and Urinary Disorders: 0.1% to <1% – urinary frequency, renal failure, proteinuria; <0.1% – renal impairment. Immune System Disorders: 0.1% to <1% – hypersensitivity (including erythema nodosum). Endocrine Disorders: 0.1% to <1% – hypothyroidism; <0.1% – hyperthyroidism, thyroiditis. Additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of dasatinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: hepatitis B virus reactivation Cardiac disorders: atrial fibrillation/atrial flutter Respiratory, thoracic, and mediastinal disorders: interstitial lung disease, chylothorax Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome Renal and urinary disorders: nephrotic syndrome Blood and lymphatic system disorders: thrombotic microangiopathy Hepatobiliary disorders: hepatotoxicity

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. (7.1) H 2 Antagonists and Proton Pump Inhibitors: Avoid coadministration. (7.1) 7.1 Effect of Other Drugs on Dasatinib Strong CYP3A4 Inhibitors The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations [see Clinical Pharmacology (12.3)]. 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 dasatinib dose reduction [see Dosage and Administration (2.5)]. Strong CYP3A4 Inducers The coadministration of dasatinib with strong CYP3A inducers may decrease dasatinib concentrations [see Clinical Pharmacology (12.3)] . 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 dasatinib dose increase. Gastric Acid Reducing Agents The coadministration of dasatinib 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 dasatinib. 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 dasatinib. Avoid simultaneous administration of dasatinib with antacids.