Dasatinib Dailymed

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)

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 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 tablet 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

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

Chronic Phase CML (starting dose 100 mg once daily)	ANC*< 0.5 X 109/L or Platelets < 50 x 109/L	1. Stop dasatinib tablets until ANC ≥1.0 × 109/L and platelets ≥50 × 109/L.2. Resume treatment with dasatinib tablets at the original starting dose if recovery occurs in ≤7 days.3. If platelets <25 × 109/L or recurrence of ANC <0.5 × 109/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 X 109/L or Platelets < 10 x 109/L	1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy).2. If cytopenia is unrelated to leukemia, stop dasatinib tablets until ANC ≥1.0 × 109/L and platelets ≥20 × 109/L and resume at the original starting dose.3. If recurrence of cytopenia, repeat Step 1 and resume dasatinib tablets at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode).4. If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.

*ANC: absolute neutrophil count  

Table 4: Dose Adjustments for Neutropenia and Thrombocytopenia in Pediatric Patients with Ph+ CML

		Dose (maximum dose per day)
1. If cytopenia persists for more than 3 weeks, check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukemia, stop dasatinib tablets until ANC* ≥1.0 × 109/L and platelets ≥75 × 109/L and resume at the original starting dose or at a reduced dose. 3. If cytopenia recurs, repeat marrow aspirate/biopsy and resume dasatinib tablets at a reduced dose.		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/microL (0.5 x 10⁹/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.

For adults with Ph+ CML and ALL, and pediatric patients with Ph+ CML, if a severe non-hematologic adverse reaction develops with dasatinib 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)
1.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.		Original Starting Dose	One-LevelDose Reduction	Two-LevelDose Reduction
2. If a non-hematologic toxicity grade 3 occurs, stop dasatinib tablets until recovery to grade ≤1 and then resume at a reduced dose	Tablets	40 mg	20 mg	**
		60 mg	40 mg	20 mg
		70 mg	60 mg	50 mg
		100 mg	80 mg	70 mg
3. 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.

** lower tablet dose not available

2.6 Duration of Treatment

In clinical studies, treatment with dasatinib 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 a hazardous product. Follow applicable special handling and disposal procedures.¹

• Myelosuppression and Bleeding Events: Severe thrombocytopenia, neutropenia, and anemia may occur. Use caution if used concomitantly with medications that inhibit platelet function or anticoagulants. Monitor complete blood counts regularly. Transfuse and interrupt dasatinib when indicated. ( 2.5, 5.1, 5.2 )
• Fluid Retention: Fluid retention, sometimes severe, including pleural effusions. Manage with supportive care measures and/or dose modification. (2.5 , 5.3 )
• Cardiovascular Toxicity: Monitor patients for signs or symptoms and treat appropriately. (5.4 )
• Pulmonary Arterial Hypertension (PAH): Dasatinib may increase the risk of developing PAH which may be reversible on discontinuation.  Consider baseline risk and evaluate patients for signs and symptoms of PAH during treatment. Stop dasatinib if PAH is confirmed. (5.5)
• QT Prolongation: Use dasatinib with caution in patients who have or may develop prolongation of the QT interval. (5.6)
• Severe Dermatologic Reactions: Individual cases of severe mucocutaneous dermatologic reactions have been reported. (5.7)
• Tumor Lysis Syndrome: Tumor lysis syndrome has been reported. Maintain adequate hydration and correct uric acid levels prior to initiating therapy with dasatinib. (5.8)
• Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of potential risk to fetus and to use effective contraception. (5.9, 8.1, 8.3)
• Effects on Growth and Development in Pediatric Patients: epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia have been reported. Monitor bone growth and development in pediatric patients. (5.10)
• Hepatotoxicity: Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. (5.11)

5.1 Myelosuppression

Treatment with dasatinib is associated with severe (NCI CTCAE Grade 3 or 4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML [see Adverse Reactions (6.1)].

In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated.

In pediatric patients with Ph+ ALL treated with dasatinib tablets in combination with chemotherapy, perform CBCs prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery.

Myelosuppression is generally reversible and usually managed by withholding dasatinib temporarily and/or dose reduction [see Dosage and Administration (2.5) ].

5.2 Bleeding-Related Events

Dasatinib can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in ˂1% of patients receiving dasatinib. The incidence of Grade 3/4 hemorrhage occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal [see Adverse Reactions (6.1)]. Most bleeding events in clinical studies were associated with severe thrombocytopenia. In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro.

Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage.

5.3 Fluid Retention

Dasatinib may cause fluid retention [see Adverse Reactions (6.1)]. After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), Grade 3 or 4 fluid retention was reported in 5% of patients, including 3% of patients with Grade 3 or 4 pleural effusion. In adult patients with newly diagnosed or imatinib-resistant or ‑intolerant chronic phase CML, Grade 3 or 4 fluid retention occurred in 6% of patients treated with dasatinib at the recommended dose (n=548). In adult patients with advanced phase CML or Ph+ ALL treated with dasatinib at the recommended dose (n=304), Grade 3 or 4 fluid retention was reported in 8% of patients, including Grade 3 or 4 pleural effusion reported in 7% of patients. In pediatric patients with chronic phase CML, cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients.  

Evaluate patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough, promptly with a chest x-ray or additional diagnostic imaging as appropriate. Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids. Severe pleural effusion may require thoracentesis and oxygen therapy. Consider dose reduction or treatment interruption [see Dosage and Administration (2.5) ].

5.4 Cardiovascular Toxicity

Dasatinib can cause cardiac dysfunction [see Adverse Reactions (6.1)]. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial in adults (n=258), the following cardiac adverse reactions occurred: cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac-related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7 % dasatinib vs 5 % imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

5.5 Pulmonary Arterial Hypertension

Dasatinib may increase the risk of developing pulmonary arterial hypertension (PAH) in adult and pediatric patients which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention [see Adverse Reactions (6.1) ]. PAH may be reversible on discontinuation of dasatinib. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib and during treatment. If PAH is confirmed, dasatinib should be permanently discontinued.

5.6 QT Prolongation

Dasatinib may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy [see Adverse Reactions (6.1)]. Correct hypokalemia or hypomagnesemia prior to and during dasatinib administration.

5.7 Severe Dermatologic Reactions

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome [see Adverse Reactions (6.2)] and erythema multiforme, have been reported in patients treated with dasatinib. Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified.

5.8 Tumor Lysis Syndrome

Tumor lysis syndrome has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease. Due to potential for tumor lysis syndrome, maintain adequate hydration, correct uric acid levels prior to initiating therapy with dasatinib, and monitor electrolyte levels. Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently [see Adverse Reactions ( 6.1 )] .

5.9 Embryo-Fetal Toxicity

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, 8.3)].

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.

5.11 Hepatotoxicity

Dasatinib tablets may cause hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase [see Adverse Reactions (6.1)]. Monitor transaminases at baseline and monthly or as clinically indicated during treatment. Reduce dose, withhold, or permanently discontinue dasatinib tablets based on severity [see Dosage and Administration (2.5)]. When dasatinib tablets are administered in combination with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Monitor hepatic function when dasatinib tablets are used in combination with chemotherapy.

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 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 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 Apotex Corp. at 1-800-706-5575 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=2,809), 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
Rashb	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
Hemorrhagec	8	8	1	1
Gastrointestinal bleeding	2	2	1	0
Other bleedingd	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 dysfunctiona	2		<1	2		<1
Pulmonary edema		<1	0	1		0
Diarrhea		17	<1	22		1
Musculoskeletal pain		11	0	14		0
Rashb		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 rasha	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 rashb	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 × 10⁹/L, Grade 4 <0.5 × 10⁹/L); thrombocytopenia (Grade 3 ≥25 to <50× 10⁹/L, Grade 4 <25 × 10 ⁹/L); anemia (hemoglobin Grade 3 ≥65 to <80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3 to 6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3 to 10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5 to 20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7 to 6 mg/dL, Grade 4 <6 mg/dL); hypophosphatemia (Grade 3 <2 to 1 mg/dL, Grade 4<1 mg/dL); hypokalemia (Grade 3 <3 to 2.5 mmol/L, Grade 4 <2.5 mmol/L).

Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of dasatinib are shown by disease phase in Table 13.

Table 13: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML in Adults: Resistance or Intolerance to Prior Imatinib Therapy

	Chronic Phase CML 100 mg Once Daily	Advanced Phase CML 140 mg Once Daily
	(n=165)	Accelerated Phase  (n=157)	Myeloid Blast Phase (n=74)	Lymphoid Blast Phase (n=33)
		Percent (%) of Patients
Hematology Parameters*
Neutropenia	36	58	77	79
Thrombocytopenia	24	63	78	85
Anemia	13	47	74	52
Biochemistry Parameters
Hypophosphatemia	10	13	12	18
Hypokalemia	2	7	11	15
Hypocalcemia	<1	4	9	12
Elevated SGPT (ALT)	0	2	5	3
Elevated SGOT (AST)	<1	0	4	3
Elevated Bilirubin	<1	1	3	6
Elevated Creatinine	0	2	8	0

CTC grades: neutropenia (Grade 3 ≥0.5 to <1 × 10⁹/L, Grade 4 <0.5 × 10⁹/L); thrombocytopenia (Grade 3 ≥25 to <50× 10⁹/L, Grade 4 <25 × 10 ⁹/L); anemia (hemoglobin Grade 3 ≥65 to <80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3 to 6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3 to 10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5 to 20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7 to 6 mg/dL, Grade 4 <6 mg/dL); hypophosphatemia (Grade 3 <2 to 1 mg/dL, Grade 4<1 mg/dL); hypokalemia (Grade 3 <3 to 2.5 mmol/L, Grade 4 <2.5 mmol/L). *Hematology parameters for 100 mg once-daily dosing in chronic phase CML reflects 60-month minimum follow-up.

Among adult patients with chronic phase CML with resistance or intolerance to prior imatinib therapy, cumulative Grade 3 or 4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%).

In the pediatric studies in CML, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults.  

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Adults  

A total of 135 adult patients with Ph+ ALL were treated with dasatinib in clinical studies. The median duration of treatment was 3 months (range 0.03 to 31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events, such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders, such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. Serious adverse reactions reported in ≥5% of patients included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), and infection (5%).

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Pediatric Patients

The safety of dasatinib tablets 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 tablets 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 tablets (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 tablets 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 tablets 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.

A dditional Pooled Data from Clinical Trials

The following additional adverse reactions were reported in adult and pediatric patients (n=2,809) in dasatinib CML clinical studies and adult patients in Ph+ ALL clinical studies at a frequency of ≥10%, 1% to <10%, 0.1% to <1%, or <0.1%. These adverse reactions are included based on clinical relevance.

Gastrointestinal Disorders:   1% to <10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1% to <1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis, gastroesophageal reflux disease; <0.1% – protein losing gastroenteropathy, ileus, acute pancreatitis, anal fistula.

General Disorders and Administration-Site Conditions:  ≥10% – peripheral edema, face edema; 1% to <10% – asthenia, chest pain, chills; 0.1% to <1% – malaise, other superficial edema, peripheral swelling; <0.1% – gait disturbance.

Skin and Subcutaneous Tissue Disorders:  1% to <10% – alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1% to <1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome, hair disorder; <0.1% – leukocytoclastic vasculitis, skin fibrosis.

Respiratory, Thoracic, and Mediastinal Disorders:   1% to <10% – lung infiltration, pneumonitis, cough; 0.1% to <1% – asthma, bronchospasm, dysphonia, pulmonary arterial hypertension; <0.1% – acute respiratory distress syndrome, pulmonary embolism.

Nervous System Disorders:  1% to <10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1% to <1% – amnesia, tremor, syncope, balance disorder; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis, VIIth nerve paralysis, dementia, ataxia.

Blood and Lymphatic System Disorders:   0.1% to <1% – lymphadenopathy, lymphopenia; <0.1% – aplasia pure red cell.

Musculoskeletal and Connective Tissue Disorders:  1% to <10% – muscular weakness, musculoskeletal stiffness; 0.1% to <1% – rhabdomyolysis, tendonitis, muscle inflammation, osteonecrosis, arthritis; <0.1% – epiphyses delayed fusion (reported at 1% to <10% in the pediatric studies), growth retardation (reported at 1% to <10% in the pediatric studies).

Investigations:   1% to <10% – weight increased, weight decreased; 0.1% to <1% – blood creatine phosphokinase increased, gamma-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