Dasatinib

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Dasatinib Prescribing Information

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.

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

Ph+ CML in Chronic Phase

The safety and effectiveness of dasatinib monotherapy have been demonstrated in pediatric patients with newly diagnosed chronic phase CML

[see

14.3 CML in Pediatric Patients

The efficacy of dasatinib in pediatric patients was evaluated in two pediatric studies of 97 patients with chronic phase CML. Among 97 patients with chronic phase CML treated in two pediatric studies, an open-label, non-randomized dose-ranging trial (NCT00306202) and an open-label, non-randomized, single-arm trial (NCT00777036), 51 patients (exclusively from the single-arm trial) had newly diagnosed chronic phase CML and 46 patients (17 from the dose-ranging trial and 29 from the single-arm trial) were resistant or intolerant to previous treatment with imatinib. Ninety-one of the 97 pediatric patients were treated with dasatinib tablets 60 mg/m²once daily (maximum dose of 100 mg once daily for patients with high BSA). Patients were treated until disease progression or unacceptable toxicity.

Baseline demographic characteristics of the 46 imatinib resistant or intolerant patients were: median age 13.5 years (range 2 to 20 years), 78.3% White, 15.2% Asian, 4.4% Black, 2.2% other, and 52% female. Baseline characteristics of the 51 newly diagnosed patients were: median age 12.8 years (range 1.9 to 17.8 years), 60.8% White, 31.4% Asian, 5.9% Black, 2% Other, and 49% female.

Median duration of follow-up was 5.2 years (range 0.5 to 9.3 years) for the imatinib resistant or intolerant patients and 4.5 years (range 1.3 to 6.4 years) for the newly diagnosed patients, respectively. Efficacy results for the two pediatric studies are summarized in Table 20.

Table 20 shows increasing trend for response for CCyR, MCyR, and MMR across time (3 months to 24 months). The increasing trend in response for all three endpoints is seen in both the newly diagnosed and imatinib resistant or intolerant patients.

Table 20: Efficacy of Dasatinib in Pediatric Patients with CP-CML Cumulative Response Over Time by Minimum Follow-Up Period

	3 months	6 months	12 months	24 months
CCyR (95% CI)
Newly diagnosed	43.1%	66.7%	96.1%	96.1%
(N = 51)^a	(29.3, 57.8)	(52.1, 79.2)	(86.5, 99.5)	(86.5, 99.5)
Prior imatinib	45.7%	71.7%	78.3%	82.6%
(N = 46)^b	(30.9, 61.0)	(56.5, 84.0)	(63.6, 89.1)	(68.6, 92.2)
MCyR (95% CI)
Newly diagnosed	60.8%	90.2%	98.0%	98.0%
(N = 51)^a	(46.1, 74.2)	(78.6, 96.7)	(89.6, 100)	(89.6, 100)
Prior imatinib	60.9%	82.6%	89.1%	89.1%
(N = 46)^b	(45.4, 74.9)	(68.6, 92.2)	(76.4, 96.4)	(76.4, 96.4)
MMR (95% CI)
Newly diagnosed	7.8%	31.4%	56.9%	74.5%
(N = 51)^a	(2.2, 18.9)	(19.1, 45.9)	(42.2, 70.7)	(60.4, 85.7)
Prior imatinib	15.2%	26.1%	39.1%	52.2%
(N = 46)^b	(6.3, 28.9)	(14.3, 41.1)	(25.1, 54.6)	(36.9, 67.1)

^aPatients from pediatric study of newly diagnosed CP-CML receiving oral tablet formulation

^bPatients from pediatric studies of imatinib-resistant or -intolerant CP-CML receiving oral tablet formulation

With a median follow-up of 4.5 years in newly diagnosed patients, the median durations of CCyR,

MCyR, MMR could not be estimated as more than half of the responding patients had not progressed at the time of data cut-off. Range of duration of response was (2.5+ to 66.5+ months for CCyR), (1.4 to 66.5+ months for MCyR), and (5.4+ to 72.5+ months for subjects who achieved

MMR by month 24 and 0.03+ to 72.5+ months for subjects who achieved MMR at any time), where ‘+’ indicates a censored observation.

With a median follow-up of 5.2 years in imatinib-resistant or -intolerant patients, the median durations of CCyR, MCyR, and MMR could not be estimated as more than half the responding patients had not progressed at the time of data cut-off. Range of duration of response was (2.4 to 86.9+ months for CCyR), (2.4 to 86.9+ months for MCyR), and (2.6+ to 73.6+ months for MMR), where ‘+’ indicates a censored observation.

The median time to response for MCyR was 2.9 months (95% CI: 2.8 months, 3.5 months) in the pooled imatinib-resistant/intolerant CP-CML patients. The median time to response for CCyR was 3.3 months (95% CI: 2.8 months, 4.7 months) in the pooled imatinib-resistant/intolerant CP-CML patients. The median time to response for MMR was 8.3 months (95% CI: 5.0 months, 11.8 months) in the pooled imatinib- resistant/intolerant CP-CML patients.

The median time to response for MCyR was 3.0 months (95% CI: 2.8 months, 4.3 months) in the newly diagnosed treatment-naïve CP-CML patients. The median time to response for CCyR was 5.5 months (95% CI: 3.0 months, 5.7 months) in the newly diagnosed treatment-naïve CP-CML patients. The median time to response for MMR was 8.9 months (95% CI: 6.2 months, 11.7 months) in the newly diagnosed treatment-naïve CP-CML patients.

In the Phase II pediatric study, 1 newly diagnosed patient and 2 imatinib-resistant or -intolerant patients progressed to blast phase CML.

]

. There are no data in children under 1 year of age. Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of patients

[see

5.10 Effects on Growth and Development in Pediatric Patients

In pediatric trials of dasatinib in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia

[ see Adverse Reactions (6.1)and Use in Specific Populations (8.4)]

. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.

Monitor bone growth and development in pediatric patients.

]

Ph+ ALL

The safety and effectiveness of dasatinib in combination with chemotherapy have been demonstrated in pediatric patients one year and over with newly diagnosed Ph+ ALL. Use of dasatinib in pediatric patients is supported by evidence from one pediatric study. There are no data in children under 1 year of age. One case of grade 1 osteopenia was reported.

The safety profile of dasatinib in pediatric subjects was comparable to that reported in studies in adult subjects

[see

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
^aIncludes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. ^bIncludes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. ^cAdverse reaction of special interest with <10% frequency. ^dIncludes 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

^aIncludes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction.

^bIncludes 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)
^aIncludes 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
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

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
Adverse Reaction	Percent (%) of Patients
^aRandomized 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
^aIncludes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. ^bIncludes 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
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

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
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
CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10⁹/L, Grade 4 <0.5 × 10⁹/L); thrombocytopenia (Grade 3 ≥25–<50 × 10⁹/L, Grade 4 <25 × 10⁹/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 × 10⁹/L, Grade 4 <0.5 × 10⁹/L); thrombocytopenia (Grade 3 ≥25–<50 × 10⁹/L, Grade 4 <25 × 10⁹/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.

and Clinical Studies (

14.3 CML in Pediatric Patients

Table 20: Efficacy of Dasatinib in Pediatric Patients with CP-CML Cumulative Response Over Time by Minimum Follow-Up Period

	3 months	6 months	12 months	24 months
CCyR (95% CI)
Newly diagnosed	43.1%	66.7%	96.1%	96.1%
(N = 51)^a	(29.3, 57.8)	(52.1, 79.2)	(86.5, 99.5)	(86.5, 99.5)
Prior imatinib	45.7%	71.7%	78.3%	82.6%
(N = 46)^b	(30.9, 61.0)	(56.5, 84.0)	(63.6, 89.1)	(68.6, 92.2)
MCyR (95% CI)
Newly diagnosed	60.8%	90.2%	98.0%	98.0%
(N = 51)^a	(46.1, 74.2)	(78.6, 96.7)	(89.6, 100)	(89.6, 100)
Prior imatinib	60.9%	82.6%	89.1%	89.1%
(N = 46)^b	(45.4, 74.9)	(68.6, 92.2)	(76.4, 96.4)	(76.4, 96.4)
MMR (95% CI)
Newly diagnosed	7.8%	31.4%	56.9%	74.5%
(N = 51)^a	(2.2, 18.9)	(19.1, 45.9)	(42.2, 70.7)	(60.4, 85.7)
Prior imatinib	15.2%	26.1%	39.1%	52.2%
(N = 46)^b	(6.3, 28.9)	(14.3, 41.1)	(25.1, 54.6)	(36.9, 67.1)

^aPatients from pediatric study of newly diagnosed CP-CML receiving oral tablet formulation

^bPatients from pediatric studies of imatinib-resistant or -intolerant CP-CML receiving oral tablet formulation

With a median follow-up of 4.5 years in newly diagnosed patients, the median durations of CCyR,

MMR by month 24 and 0.03+ to 72.5+ months for subjects who achieved MMR at any time), where ‘+’ indicates a censored observation.

In the Phase II pediatric study, 1 newly diagnosed patient and 2 imatinib-resistant or -intolerant patients progressed to blast phase CML.

14.4 Ph+ ALL in Pediatric Patients

The efficacy of dasatinib in combination with chemotherapy was evaluated in a single cohort (cohort 1) of Study CA180372 (NCT01460160), a multicenter, multiple-cohort study of pediatric patients with newly diagnosed B-cell precursor Ph+ ALL. The 78 patients in cohort 1 received dasatinib at a daily dose of 60 mg/m²for up to 24 months, in combination with chemotherapy. The backbone chemotherapy regimen was the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol.

Patients had a median age of 10.4 years (range 2.6 to 17.9 years) and included 20 patients (25%) 2 to 6 years of age, 37 patients (46%) 7 to 12 years of age, and 24 patients (30%) 13 to 17 years of age. Eighty-two percent of patients were white, and 55% were male. Thirty-two patients (41%) had a white blood cell count (WBC) of ≥50,000 mcl at diagnosis, and 17 patients (22%) had extramedullary disease.

Efficacy was established on the basis of 3-year event-free survival (EFS), defined as the time from the start of dasatinib to lack of complete response at the end of the third high risk block, relapse, secondary malignancy, or death from any cause. The 3-year EFS binary rate for patients on Study CA180372 was 64.1% (95% CI: 52.4, 74.7). At the end of induction, 75 patients (96%) had a bone marrow with <5% lymphoblasts, and 76 patients (97%) achieved this by the end of consolidation.

)]

Monitor bone growth and development in pediatric patients

[see

5.10 Effects on Growth and Development in Pediatric Patients

[ see Adverse Reactions (6.1)and Use in Specific Populations (8.4)]

. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.

Monitor bone growth and development in pediatric patients.

Pediatric Patients with Difficulty Swallowing Tablets

Five patients with Ph+ ALL 2 to 10 years of age received at least one dose of dasatinib tablet dispersed in juice on Study CA180372. The exposure for dispersed tablets was 36% lower as compared to intact tablets in pediatric patients

[see

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/m²to 120 mg/m²once daily, taken with or without food. The pharmacokinetics showed dose proportionality with a dose-related increase in exposure. The mean T_maxwas 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/m², 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_maxof 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_maxof dasatinib by 42%.

Transporters

Dasatinib is not an inhibitor of P-gp

in vitro

]

. Due to the limited available clinical data, it is unclear whether dispersing dasatinib tablets significantly alters the safety and/or efficacy of dasatinib.

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

[see Use in Specific Populations (

8.1 Pregnancy

Risk Summary

Based on limited human data, dasatinib can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib. Animal reproduction studies in rats have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates. Skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses. These findings occurred at dasatinib plasma concentrations below those in humans receiving therapeutic doses of dasatinib

[see Data]

. Advise a pregnant woman of the potential risk to a fetus.

The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Transplacental transfer of dasatinib has been reported. Dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. Hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib. These adverse pharmacologic effects on the fetus are similar to adverse reactions observed in adult patients and may result in fetal harm or neonatal death

[see Warnings and Precautions ]

Data

Human Data

Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy.

Animal Data

In nonclinical studies at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m²/day] and rabbit: 0.5 mg/kg/day [6 mg/m²/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•h/mL and 44 ng•h/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. In a pre- and postnatal development study in rats, administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at maternal exposures that were below the exposures in patients treated with dasatinib at the recommended labeling dose.

8.3 Females and Males of Reproductive Potential

Dasatinib can cause fetal harm when administered to a pregnant woman

[ see Use in Specific Populations (8.1)]

Contraception

Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with dasatinib and for 30 days after the last dose.

Infertility

Based on animal data, dasatinib may result in damage to female and male reproductive tissues

[ see Nonclinical Toxicology (13.1)]

)]

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