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 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 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in othersections 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 ) 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 Dr. Reddy’s Laboratories, Inc.

at 1-888-375-3784 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, 2,388 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 2,712 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 1,618 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months).

The median duration of therapy in 1,094 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 2,712 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 1,618 patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients; among the 1,094 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) 100 mg Once Daily Chronic (n=165) All Grades Grade 3/4 Adverse Reaction 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 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 Adverse Reaction 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 <1.0 × 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 grams/L, Grade 4 <65 grams/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 <7.0 to 6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0 to 1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0 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 <1.0 × 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 grams/L, Grade 4 <65 grams/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 <7.0 to 6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0 to 1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0 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%).

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% 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, VII th 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-glutamyltransferase 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.

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