Dasatinib

1 INDICATIONS AND USAGE Dasatinib tablets are 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 tablets are 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. Dasatinib tablets are 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 )

2 DOSAGE AND ADMINISTRATION 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 and ALL 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. 2.2 Dosage of Dasatinib Tablets 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 [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. Table 1: Dosage of Dasatinib Tablets for Pediatric Patients a 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 a For pediatric patients with Ph+ ALL, begin dasatinib tablets 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. Refer to Section 2.4 for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML. 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 tablets dose increase. If the dose of dasatinib tablets 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 tablets 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 tablets are 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 tablets 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 tablets is administered in combination with chemotherapy. Escalate the dasatinib tablets 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 Stop dasatinib tablets until ANC ≥1.0 × 10 9 /L and platelets ≥50 × 10 9 /L. Resume treatment with dasatinib tablets at the original starting dose if recovery occurs in ≤7 days. 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 Check if cytopenia is related to leukemia (marrow aspirate or biopsy). If cytopenia is unrelated to leukemia, stop dasatinib tablets until ANC ≥1.0 × 10 9 /L and platelets ≥20 × 10 9 /L and resume at the original starting dose. 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). 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 Dose (maximum dose per day) If cytopenia persists for more than 3 weeks, check if cytopenia is related to leukemia (marrow aspirate or biopsy). If cytopenia is unrelated to leukemia, stop dasatinib tablets until ANC* ≥1.0 x 10 9 /L and platelets ≥75 x 10 9 /L and resume at the original starting dose or at a reduced dose. If cytopenia recurs, repeat marrow aspirate/biopsy and resume dasatinib tablets 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 *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. 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 dasatinib tablets 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 dasatinib tablets 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 dasatinib tablets 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 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) ] . 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 dasatinib tablets. Dose reduction recommendations are described in Table 5. Table 5: Dose Adjustments for Non-Hematologic Toxicities in Pediatric Patients Dose (maximum dose per day) If a non-hematologic toxicity grade 2 occurs, consider interrupting dasatinib tablets if no recovery despite symptomatic therapy; once recovered to grade ≤1, resume at the original starting dose. Resume dasatinib tablets at a reduced dose for recurrent events. If a non-hematologic toxicity grade 3 occurs, stop dasatinib tablets until recovery to grade ≤1 and then resume at a reduced dose. If direct bilirubin is >5 ULN or AST/ALT >15 ULN, interrupt dasatinib tablets until recovery to grade ≤1 and then resume dasatinib tablets at the original starting dose. Resume dasatinib tablets 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 ** lower tablet dose not available 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. In clinical studies, treatment with dasatinib tablets in pediatric patients with Ph+ ALL was administered for a maximum duration of 2 years [see Dosage and Administration (2.2) and Clinical Studies (14.4)] . Dasatinib tablets are hazardous products. Follow applicable special handling and disposal procedures. 1

6 ADVERSE REACTIONS 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 tablets as single-agent therapy included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. ( 6 ) Most common adverse reactions (≥30%) in pediatric patients receiving dasatinib tablets in combination with chemotherapy included mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, edema, infections (bacterial, viral and fungal), hypotension, decreased appetite, hypersensitivity, dyspnea, epistaxis, peripheral neuropathy, and altered state of consciousness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc., at 1-866-924-6266 or 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, 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 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. 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 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 2 <1 2 <1 dysfunction a 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) 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. 100 mg Once Daily Chronic (n=165) Adverse Reaction 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 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 Adverse Reaction All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Percent (%) of Patients a Randomized dose-optimization trial results reported in the recommended starting dose of 100 mg once daily (n=165) population. 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 Table 10: Adverse Reactions Reported in ≥10% of Adult Patients with Advanced Phase CML Resistant or Intolerant to Prior Imatinib Therapy 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. 140 mg Once Daily Accelerated (n=157) Myeloid Blast (n=74) Lymphoid Blast (n=33) Adverse Reaction 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 Table 11: Adverse Reactions Reported in ≥10% of Dasatinib-Treated Pediatric Patients with Chronic Phase CML (n=97) Adverse Reaction All Grades Grade 3/4 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 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 9 /L, Grade 4 <0.5 × 10 9 /L); thrombocytopenia (Grade 3 ≥25–<50 × 10 9 /L, Grade 4 <25 × 10 9 /L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). 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 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 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 9 /L, Grade 4 <0.5 × 10 9 /L); thrombocytopenia (Grade 3 ≥25–<50 × 10 9 /L, Grade 4 <25 × 10 9 /L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 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. Chronic Phase CML 100 mg Once Daily Advanced Phase CML 140 mg Once Daily Accelerated Phase Myeloid Blast Phase Lymphoid Blast Phase (n=165) (n=157) (n=74) (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 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 0.03–31 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%). Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Pediatric Patients The safety of dasatinib administered continuously in combination with multiagent chemotherapy was determined in a multicohort study of 81 pediatric patients with newly diagnosed Ph+ ALL. [see Clinical Studies (14.4)] . The median duration of therapy was 24 months (range 2 to 27 months). Fatal adverse reactions occurred in 3 patients (4%), all of which were due to infections. Eight (10%) patients experienced adverse reactions leading to treatment discontinuation, including fungal sepsis, hepatotoxicity in the setting of graft versus host disease, thrombocytopenia, CMV infection, pneumonia, nausea, enteritis and drug hypersensitivity. The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain, and musculoskeletal pain. The incidence of common adverse reactions (incidence ≥20%) on study are shown in Table 14: Table 14: Adverse Reactions Reported in ≥20% of Pediatric Patients with Ph+ ALL Treated with Dasatinib in Combination with Chemotherapy CA180372 (N=81) Percent (%) of Patients Adverse Reaction All Grades Grade 3/4 Mucositis 93 60 Febrile neutropenia 86 86 Pyrexia 85 17 Diarrhea 84 31 Nausea 84 11 Vomiting 83 17 Musculoskeletal pain 83 25 Abdominal pain 78 17 Cough 78 1 Headache 77 15 Rash 68 7 Fatigue 59 3 Constipation 57 1 Arrhythmia 47 12 Hypertension 47 10 Edema 47 6 Viral infection 40 12 Hypotension 40 26 Decreased appetite 38 22 Hypersensitivity 36 20 Upper respiratory tract infection 36 10 Dyspnea 35 10 Epistaxis 31 6 Peripheral neuropathy 31 7 Sepsis (excluding fungal) n/a 31 Altered state of consciousness 30 4 Fungal infection 30 11 Pneumonia (excluding fungal) 28 25 Pruritus 28 - Clostridial infection (excluding sepsis) 25 14 Urinary Tract Infection 24 14 Bacteremia (excluding fungal) 22 20 Erythema 22 6 Chills 21 - Pleural effusion 21 9 Sinusitis 21 10 Dehydration 20 9 Renal insufficiency 20 9 Visual impairment 20 - The incidence of common adverse reactions attributed by the investigator to dasatinib (reported at a frequency of ≥10%, all grades and grade 3/4, respectively) on study (N=81), included febrile neutropenia (23%, 23%), nausea (21%, 4%), vomiting (19%, 4%), mucositis (17%, 6%), musculoskeletal pain (17%, 2%), abdominal pain (16%, 5%), diarrhea (16%, 7%), rash (15%, 0%), fatigue (12%, 0%), pyrexia (12%, 6%), and headache (12%, 5%). CTCAE grade 3/4 laboratory abnormalities in pediatric patients with Ph+ ALL treated with dasatinib in combination with chemotherapy are shown in Table 15. Table 15: CTCAE Grade 3/4 Laboratory Abnormalities in ≥10% of Pediatric Patients with Ph+ ALL Treated with Dasatinib in Combination with Chemotherapy CA180372 (N=81) Percent (%) of Patients Hematology Parameters Neutropenia 96 Thrombocytopenia 88 Anemia 82 Biochemistry Parameters Elevated SGPT (ALT) 47 Hypokalemia 40 Elevated SGOT (AST) 26 Hypocalcemia 19 Hyponatremia 19 Elevated Bilirubin 11 Hypophosphatemia 11 Toxicity grading is per CTCAE version 4. 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%–<10%, 0.1%–<1%, or <0.1%. These adverse reactions are included based on clinical relevance. Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<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%– <10% – asthenia, chest pain, chills; 0.1%–<1% – malaise, other superficial edema, peripheral swelling; <0.1% – gait disturbance. Skin and Subcutaneous Tissue Disorders: 1%–<10% – alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<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%–<10% – lung infiltration, pneumonitis, cough; 0.1%–<1% – asthma, bronchospasm, dysphonia, pulmonary arterial hypertension; <0.1% – acute respiratory distress syndrome, pulmonary embolism. Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy) , dizziness, dysgeusia, somnolence; 0.1%–<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%–<1% – lymphadenopathy, lymphopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness, musculoskeletal stiffness; 0.1%–<1% – rhabdomyolysis, tendonitis, muscle inflammation, osteonecrosis, arthritis; <0.1% – epiphyses delayed fusion (reported at 1%–<10% in the pediatric studies), growth retardation (reported at 1%–<10% in the pediatric studies). Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased, gamma-glutamyltransferase increased. Infections and Infestations: 1%–<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%–<10% – appetite disturbances, hyperuricemia; 0.1%–<1% – hypoalbuminemia, tumor lysis syndrome, dehydration, hypercholesterolemia; <0.1% – diabetes mellitus. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<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%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis, visual impairment, lacrimation increased, <0.1% – photophobia. Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis, thrombosis; <0.1% – livedo reticularis, deep vein thrombosis, embolism. Psychiatric Disorders: 1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased. Pregnancy, Puerperium, and Perinatal Conditions: <0.1% – abortion. Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstrual disorder. Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo, hearing loss. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria; <0.1% – renal impairment. Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum). Endocrine Disorders: 0.1%–<1% – hypothyroidism; <0.1% – hyperthyroidism, thyroiditis. 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

12.3 Pharmacokinetics The pharmacokinetics of dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg/day (0.15 times the lowest approved recommended dose) to 240 mg/day (1.7 times the highest approved recommended dose). At 100 mg QD, the maximum concentration at steady state (C max ) is 82.2 ng/mL (CV% 69%), area under the plasma drug concentration time curve (AUC) is 397 ng/mL*hr (CV% 55%). The clearance of dasatinib is found to be time-invariant. When administered to adult healthy subjects as dispersed tablets in juice, the adjusted geometric mean ratio was 0.97 (90% CI: 0.85, 1.10) for Cmax and 0.84 (90% CI: 0.78, 0.91) for AUC as compared to intact tablets. Absorption The maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 hours and 6 hours (Tmax) following oral administration. Food Effect A high-fat meal increased the mean AUC of dasatinib following a single dose of 100 mg by 14%. The total calorie content of the high-fat meal was 985 kcal. The calories derived from fat, carbohydrates, and protein were 52%, 34%, and 14% for the high-fat meal. Distribution The apparent volume of distribution is 2505 L (CV% 93%). Binding of dasatinib to human plasma proteins in vitro was approximately 96% and of its active metabolite was 93%, with no concentration dependence over the range of 100 ng/mL to 500 ng/mL. Dasatinib is a P-gp substrate in vitro . Elimination The mean terminal half-life of dasatinib is 3 hours to 5 hours. The mean apparent oral clearance is 363.8 L/hr (CV% 81.3%). Metabolism Dasatinib is metabolized in humans, primarily by CYP3A4. CYP3A4 is the primary enzyme responsible for the formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO‑- 3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites. The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% of the AUC of dasatinib. The active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also has several other inactive oxidative metabolites. Excretion Elimination is primarily via the feces. Following a single radiolabeled dose of oral dasatinib, 4% of the administered radioactivity was recovered in the urine and 85% in the feces within 10 days. Unchanged dasatinib accounted for 0.1% of the administered dose in the urine and 19% of the administered dose in the feces with the remainder of the dose being metabolites. Specific Populations Age (15 to 86 years old), sex, and renal impairment (creatinine clearance 21.6 mL/min to 342.3 mL/min as estimated by Cockcroft Gault) have no clinically relevant effect on the pharmacokinetics of dasatinib. Pediatric Patients The pharmacokinetics of dasatinib were evaluated in 43 pediatric patients with leukemia or solid tumors at oral doses ranging from 60 mg/m 2 to 120 mg/m 2 once daily, taken with or without food. The pharmacokinetics showed dose proportionality with a dose-related increase in exposure. The mean T max was observed between 0.5 hours and 6 hours and the mean half-life was 2 hours to 5 hours. The geometric mean (CV%) of body weight normalized clearance in these 43 pediatric patients is 5.98 (41.5%) L/h/kg. In pediatric patients with a dosing regimen of 60 mg/m 2 , the model simulated geometric mean (CV%) steady-state plasma average concentrations of dasatinib were 14.7 (64.6%) ng/mL (for 2 to <6 years old), 16.3 (97.5%) ng/mL (for 6 to <12 years old), and 18.2 (67.7%) ng/mL (for 12 years and older) [see Dosage and Administration (2.2)] . Dasatinib clearance and volume of distribution change with body weight in pediatric patients. Dasatinib has not been studied in patients < 1 year old. The bioavailability of dispersed tablets in pediatric patients was estimated to be 36% lower than that of intact tablets. Patients with Hepatic Impairment Compared to subjects with normal liver function, patients with moderate hepatic impairment (Child Pugh B) had decreases in mean Cmax by 47% and mean AUC by 8%. Patients with severe hepatic impairment (Child Pugh C) had decreases in mean Cmax by 43% and in mean AUC by 28% compared to the subjects with normal liver function. Drug Interaction Studies Cytochrome P450 Enzymes The coadministration of ketoconazole (strong CYP3A4 inhibitor) twice daily increased the mean Cmax of dasatinib by 4-fold and the mean AUC of dasatinib by 5-fold following a single oral dose of 20 mg. The coadministration of rifampin (strong CYP3A4 inducer) once daily decreased the mean Cmax of dasatinib by 81% and the mean AUC of dasatinib by 82%. Dasatinib is a time-dependent inhibitor of CYP3A4. Dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib does not induce CYP enzymes. Gastric Acid Reducing Agents The administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single dose of dasatinib was associated with no relevant change in the mean AUC of dasatinib; however, the mean Cmax of dasatinib was increased by 26%. The simultaneous administration of 30 mL of aluminum hydroxide/magnesium hydroxide with a single dose of dasatinib was associated with a 55% reduction in the mean AUC of dasatinib and a 58% reduction in the mean C max of dasatinib. The administration of a single dose of dasatinib 10 hours following famotidine (H2 antagonist) reduced the mean AUC of dasatinib by 61% and the mean Cmax of dasatinib by 63%. The administration of a single 100 mg dose of dasatinib 22 hours following a 40 mg dose of omeprazole (proton pump inhibitor) at steady state reduced the mean AUC of dasatinib by 43% and the mean C max of dasatinib by 42%. Transporters Dasatinib is not an inhibitor of P-gp in vitro .