Dasatinib

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. 1) ] . 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. 5 Dose Adjustment for Adverse Reactions Myelosuppression In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy.

Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications for adult and pediatric patients are summarized in Tables 3 and 4, respectively. 0 × 10 9 /L and platelets ≥50 × 10 9 /L.

Resume treatment with dasatinib tablets at the original starting dose if recovery occurs in ≤7 days. 5 × 10 9 /L for >7 days, repeat Step 1 and resume dasatinib tablets at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue dasatinib tablets (for patients resistant or intolerant to prior therapy including imatinib).

5 × 10 9 /L or Platelets <10 × 10 9 /L Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 0 × 10 9 /L and platelets ≥20 × 10 9 /L and resume at the original starting dose. If recurrence of cytopenia, repeat Step 1 and resume dasatinib tablets at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode).

If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.

Table 4:

Dose Adjustments for Neutropenia and Thrombocytopenia in Pediatric Patients with Ph+ CML Dose (maximum dose per day) If cytopenia persists for more than 3 weeks, check if cytopenia is related to leukemia (marrow aspirate or biopsy).

0 x 10 9 /L and platelets ≥75 x 10 9 /L and resume at the original starting dose or at a reduced dose. If cytopenia recurs, repeat marrow aspirate/biopsy and resume dasatinib tablets at a reduced dose. Original Starting Dose One-Level Dose Reduction Two-Level Dose Reduction Tablets 40 mg 20 mg ** 60 mg 40 mg 20 mg 70 mg 60 mg 50 mg 100 mg 80 mg 70 mg *ANC: absolute neutrophil count ** lower tablet dose not available For pediatric patients with chronic phase CML, if Grade ≥ 3 neutropenia or thrombocytopenia recurs during complete hematologic response (CHR), interrupt dasatinib tablets and resume at a reduced dose.

Implement temporary dose reductions for intermediate degrees of cytopenia and disease response as needed. For pediatric patients with Ph+ ALL, if neutropenia and/or thrombocytopenia result in a delay of the next block of treatment by more than 14 days, interrupt dasatinib tablets and resume at the same dose level once the next block of treatment is started.

If neutropenia and/or thrombocytopenia persist and the next block of treatment is delayed another 7 days, perform a bone marrow assessment to assess cellularity and percentage of blasts. 5 x 10 9 /L), at which time treatment may be resumed at full dose.

If marrow cellularity is >10%, resumption of treatment with dasatinib tablets may be considered. Non-Hematologic Adverse Reactions For adults with Ph+ CML and ALL, and pediatric patients with Ph+ CML, if a severe non-hematologic adverse reaction develops with dasatinib tablets use, treatment must be withheld until the adverse reaction has resolved or improved.

Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence [see Warnings and Precautions (5) ] . For pediatric patients with Ph+ ALL, interrupt treatment for cases of grade ≥ 3 non-hematologic adverse reactions with the exception of liver function test abnormalities, and resume at a reduced dose when resolved to grade ≤1.

For elevated direct bilirubin over 5 times the institutional upper limit of normal (ULN), interrupt treatment until improvement to baseline or grade ≤1. For elevated AST/ALT over 15 times the institutional ULN, interrupt treatment until improvement to baseline or grade <1.

For recurrent liver function test abnormalities as above, reduce the dose if this adverse reaction recurs after reinitiation of dasatinib tablets. Dose reduction recommendations are described in Table 5.

Table 5:

Dose Adjustments for Non-Hematologic Toxicities in Pediatric Patients Dose (maximum dose per day) If a non-hematologic toxicity grade 2 occurs, consider interrupting dasatinib tablets if no recovery despite symptomatic therapy; once recovered to grade ≤1, resume at the original starting dose.

Resume dasatinib tablets at a reduced dose for recurrent events. If a non-hematologic toxicity grade 3 occurs, stop dasatinib tablets until recovery to grade ≤1 and then resume at a reduced dose. If direct bilirubin is >5 ULN or AST/ALT >15 ULN, interrupt dasatinib tablets until recovery to grade ≤1 and then resume dasatinib tablets at the original starting dose.

Resume dasatinib tablets at a reduced dose for recurrent hepatotoxicity. 6 Duration of Treatment In clinical studies, treatment with dasatinib tablets in adults and in pediatric patients with chronic phase CML was continued until disease progression or until no longer tolerated by the patient.

5) has not been established. 4)] . Dasatinib tablets are hazardous products. Follow applicable special handling and disposal procedures. 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 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.

3)].

Table 1:

Dosage of Dasatinib Tablets for Pediatric Patients a Body Weight (kg) b Daily Dose (mg) 10 to less than 20 40 mg 20 to less than 30 60 mg 30 to less than 45 70 mg at least 45 100 mg a For pediatric patients with Ph+ ALL, begin dasatinib tablets therapy on or before day 15 of induction chemotherapy, when diagnosis is confirmed and continue for 2 years.

b Tablet dosing is not recommended for patients weighing less than 10 kg. 4 for recommendations on dose escalation in adults with CML and Ph+ ALL, and pediatric patients with CML. 3 Dose Modification Strong CYP3A4 Inducers Avoid the use of concomitant strong CYP3A4 inducers and St.

John’s wort. If patients must be coadministered a strong CYP3A4 inducer, consider a dasatinib tablets dose increase. 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. 1) ] . 5 Dose Adjustment for Adverse Reactions Myelosuppression In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy.

Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications for adult and pediatric patients are summarized in Tables 3 and 4, respectively. 0 × 10 9 /L and platelets ≥50 × 10 9 /L.

Resume treatment with dasatinib tablets at the original starting dose if recovery occurs in ≤7 days. 5 × 10 9 /L for >7 days, repeat Step 1 and resume dasatinib tablets at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue dasatinib tablets (for patients resistant or intolerant to prior therapy including imatinib).

5 × 10 9 /L or Platelets <10 × 10 9 /L Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 0 × 10 9 /L and platelets ≥20 × 10 9 /L and resume at the original starting dose. If recurrence of cytopenia, repeat Step 1 and resume dasatinib tablets at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode).

If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.

Table 4:

Dose Adjustments for Neutropenia and Thrombocytopenia in Pediatric Patients with Ph+ CML Dose (maximum dose per day) If cytopenia persists for more than 3 weeks, check if cytopenia is related to leukemia (marrow aspirate or biopsy).

0 x 10 9 /L and platelets ≥75 x 10 9 /L and resume at the original starting dose or at a reduced dose. If cytopenia recurs, repeat marrow aspirate/biopsy and resume dasatinib tablets at a reduced dose. Original Starting Dose One-Level Dose Reduction Two-Level Dose Reduction Tablets 40 mg 20 mg ** 60 mg 40 mg 20 mg 70 mg 60 mg 50 mg 100 mg 80 mg 70 mg *ANC: absolute neutrophil count ** lower tablet dose not available For pediatric patients with chronic phase CML, if Grade ≥ 3 neutropenia or thrombocytopenia recurs during complete hematologic response (CHR), interrupt dasatinib tablets and resume at a reduced dose.

Implement temporary dose reductions for intermediate degrees of cytopenia and disease response as needed. For pediatric patients with Ph+ ALL, if neutropenia and/or thrombocytopenia result in a delay of the next block of treatment by more than 14 days, interrupt dasatinib tablets and resume at the same dose level once the next block of treatment is started.

If neutropenia and/or thrombocytopenia persist and the next block of treatment is delayed another 7 days, perform a bone marrow assessment to assess cellularity and percentage of blasts. 5 x 10 9 /L), at which time treatment may be resumed at full dose.

If marrow cellularity is >10%, resumption of treatment with dasatinib tablets may be considered. Non-Hematologic Adverse Reactions For adults with Ph+ CML and ALL, and pediatric patients with Ph+ CML, if a severe non-hematologic adverse reaction develops with dasatinib tablets use, treatment must be withheld until the adverse reaction has resolved or improved.

Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence [see Warnings and Precautions (5) ] . For pediatric patients with Ph+ ALL, interrupt treatment for cases of grade ≥ 3 non-hematologic adverse reactions with the exception of liver function test abnormalities, and resume at a reduced dose when resolved to grade ≤1.

For elevated direct bilirubin over 5 times the institutional upper limit of normal (ULN), interrupt treatment until improvement to baseline or grade ≤1. For elevated AST/ALT over 15 times the institutional ULN, interrupt treatment until improvement to baseline or grade <1.

For recurrent liver function test abnormalities as above, reduce the dose if this adverse reaction recurs after reinitiation of dasatinib tablets. Dose reduction recommendations are described in Table 5.

Table 5:

Dose Adjustments for Non-Hematologic Toxicities in Pediatric Patients Dose (maximum dose per day) If a non-hematologic toxicity grade 2 occurs, consider interrupting dasatinib tablets if no recovery despite symptomatic therapy; once recovered to grade ≤1, resume at the original starting dose.

Resume dasatinib tablets at a reduced dose for recurrent events. If a non-hematologic toxicity grade 3 occurs, stop dasatinib tablets until recovery to grade ≤1 and then resume at a reduced dose. If direct bilirubin is >5 ULN or AST/ALT >15 ULN, interrupt dasatinib tablets until recovery to grade ≤1 and then resume dasatinib tablets at the original starting dose.

Resume dasatinib tablets at a reduced dose for recurrent hepatotoxicity. Original Starting Dose One-Level Dose Reduction Two-Level Dose Reduction Tablets 40 mg 20 mg ** 60 mg 40 mg 20 mg 70 mg 60 mg 50 mg 100 mg 80 mg 70 mg ** lower tablet dose not available Myelosuppression In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy.

Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications for adult and pediatric patients are summarized in Tables 3 and 4, respectively. 0 × 10 9 /L and platelets ≥50 × 10 9 /L.

Resume treatment with dasatinib tablets at the original starting dose if recovery occurs in ≤7 days. 5 × 10 9 /L for >7 days, repeat Step 1 and resume dasatinib tablets at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue dasatinib tablets (for patients resistant or intolerant to prior therapy including imatinib).

5 × 10 9 /L or Platelets <10 × 10 9 /L Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 0 × 10 9 /L and platelets ≥20 × 10 9 /L and resume at the original starting dose. If recurrence of cytopenia, repeat Step 1 and resume dasatinib tablets at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode).

If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily.

Table 4:

Dose Adjustments for Neutropenia and Thrombocytopenia in Pediatric Patients with Ph+ CML Dose (maximum dose per day) If cytopenia persists for more than 3 weeks, check if cytopenia is related to leukemia (marrow aspirate or biopsy).

0 x 10 9 /L and platelets ≥75 x 10 9 /L and resume at the original starting dose or at a reduced dose. If cytopenia recurs, repeat marrow aspirate/biopsy and resume dasatinib tablets at a reduced dose. Original Starting Dose One-Level Dose Reduction Two-Level Dose Reduction Tablets 40 mg 20 mg ** 60 mg 40 mg 20 mg 70 mg 60 mg 50 mg 100 mg 80 mg 70 mg *ANC: absolute neutrophil count ** lower tablet dose not available For pediatric patients with chronic phase CML, if Grade ≥ 3 neutropenia or thrombocytopenia recurs during complete hematologic response (CHR), interrupt dasatinib tablets and resume at a reduced dose.

Implement temporary dose reductions for intermediate degrees of cytopenia and disease response as needed. For pediatric patients with Ph+ ALL, if neutropenia and/or thrombocytopenia result in a delay of the next block of treatment by more than 14 days, interrupt dasatinib tablets and resume at the same dose level once the next block of treatment is started.

If neutropenia and/or thrombocytopenia persist and the next block of treatment is delayed another 7 days, perform a bone marrow assessment to assess cellularity and percentage of blasts. 5 x 10 9 /L), at which time treatment may be resumed at full dose.

If marrow cellularity is >10%, resumption of treatment with dasatinib tablets may be considered. Non-Hematologic Adverse Reactions For adults with Ph+ CML and ALL, and pediatric patients with Ph+ CML, if a severe non-hematologic adverse reaction develops with dasatinib tablets use, treatment must be withheld until the adverse reaction has resolved or improved.

Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence [see Warnings and Precautions (5) ] . For pediatric patients with Ph+ ALL, interrupt treatment for cases of grade ≥ 3 non-hematologic adverse reactions with the exception of liver function test abnormalities, and resume at a reduced dose when resolved to grade ≤1.

For elevated direct bilirubin over 5 times the institutional upper limit of normal (ULN), interrupt treatment until improvement to baseline or grade ≤1. For elevated AST/ALT over 15 times the institutional ULN, interrupt treatment until improvement to baseline or grade <1.

For recurrent liver function test abnormalities as above, reduce the dose if this adverse reaction recurs after reinitiation of dasatinib tablets. Dose reduction recommendations are described in Table 5.

Table 5:

Dose Adjustments for Non-Hematologic Toxicities in Pediatric Patients Dose (maximum dose per day) If a non-hematologic toxicity grade 2 occurs, consider interrupting dasatinib tablets if no recovery despite symptomatic therapy; once recovered to grade ≤1, resume at the original starting dose.

Resume dasatinib tablets at a reduced dose for recurrent events. If a non-hematologic toxicity grade 3 occurs, stop dasatinib tablets until recovery to grade ≤1 and then resume at a reduced dose. If direct bilirubin is >5 ULN or AST/ALT >15 ULN, interrupt dasatinib tablets until recovery to grade ≤1 and then resume dasatinib tablets at the original starting dose.

Resume dasatinib tablets at a reduced dose for recurrent hepatotoxicity. 6 Duration of Treatment In clinical studies, treatment with dasatinib tablets in adults and in pediatric patients with chronic phase CML was continued until disease progression or until no longer tolerated by the patient.

5) has not been established. 4)] . Dasatinib tablets are hazardous products. Follow applicable special handling and disposal procedures. 1

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.

1 months are presented in Table 11. 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%). 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%). 4% of pediatric patients. Chronic Myeloid Leukemia (CML) Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of adult patients are shown in Table 6 for newly diagnosed patients with chronic phase CML and Tables 8 and 10 for CML patients with resistance or intolerance to prior imatinib therapy.

Table 6:

Adverse Reactions Reported in ≥10% of Adult Patients with Newly Diagnosed Chronic Phase CML (minimum of 60 months follow-up) All Grades Grade 3/4 Dasatinib (n=258) Imatinib (n=258) Dasatinib (n=258) Imatinib (n=258) Adverse Reaction Percent (%) of Patients a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction.

b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage.

Fluid retention 38 45 5 1 Pleural effusion 28 1 3 0 Superficial localized edema 14 38 0 <1 Pulmonary hypertension 5 <1 1 0 Generalized edema 4 7 0 0 Pericardial effusion 4 1 1 0 Congestive heart failure/cardiac dysfunction a 2 1 <1 <1 Pulmonary edema 1 0 0 0 Diarrhea 22 23 1 1 Musculoskeletal pain 14 17 0 <1 Rash b 14 18 0 2 Headache 14 11 0 0 Abdominal pain 11 8 0 1 Fatigue 11 12 <1 0 Nausea 10 25 0 0 Myalgia 7 12 0 0 Arthralgia 7 10 0 <1 Hemorrhage c 8 8 1 1 Gastrointestinal bleeding 2 2 1 0 Other bleeding d 6 6 0 <1 CNS bleeding <1 <1 0 <1 Vomiting 5 12 0 0 Muscle spasms 5 21 0 <1 A comparison of cumulative rates of adverse reactions reported in ≥10% of patients with minimum follow-up of 1 and 5 years in a randomized trial of newly diagnosed patients with chronic phase CML treated with dasatinib are shown in Table 7.

Table 7:

Adverse Reactions Reported in ≥10% of Adult Patients with Newly Diagnosed Chronic Phase CML in the Dasatinib-Treated Arm (n=258) Minimum of 1 Year Follow-up Minimum of 5 Years Follow-up All Grades Grade 3/4 All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Fluid retention 19 1 38 5 Pleural effusion 10 0 28 3 Superficial localized edema 9 0 14 0 Pulmonary hypertension 1 0 5 1 Generalized edema 2 0 4 0 Pericardial effusion 1 <1 4 1 Congestive heart failure/cardiac 2 <1 2 <1 dysfunction a Pulmonary edema <1 0 1 0 Diarrhea 17 <1 22 1 Musculoskeletal pain 11 0 14 0 Rash b 11 0 14 0 Headache 12 0 14 0 Abdominal pain 7 0 11 0 Fatigue 8 <1 11 <1 Nausea 8 0 10 0 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction.

b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. 1%); 1 death in each group was assessed by the investigator as related to study therapy.

Table 8:

Adverse Reactions Reported in ≥10% of Adult Patients with Chronic Phase CML Resistant or Intolerant to Prior Imatinib Therapy (minimum of 84 months follow-up) a Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular.

100 mg Once Daily Chronic (n=165) Adverse Reaction All Grades Grade 3/4 Percent (%) of Patients Fluid retention 48 7 Superficial localized edema 22 0 Pleural effusion 28 5 Generalized edema 4 0 Pericardial effusion 3 1 Pulmonary hypertension 2 1 Headache 33 1 Diarrhea 28 2 Fatigue 26 4 Dyspnea 24 2 Musculoskeletal pain 22 2 Nausea 18 1 Skin rash a 18 2 Myalgia 13 0 Arthralgia 13 1 Infection (including bacterial, viral, fungal, and non-specified) 13 1 Abdominal pain 12 1 Hemorrhage 12 1 Gastrointestinal bleeding 2 1 Pruritus 12 1 Pain 11 1 Constipation 10 1 Cumulative rates of selected adverse reactions that were reported over time in patients treated with the 100 mg once daily recommended starting dose in a randomized dose-optimization trial of imatinib-resistant or -intolerant patients with chronic phase CML are shown in Table 9.

Table 9:

Selected Adverse Reactions Reported in Adult Dose Optimization Trial (Imatinib-Intolerant or -Resistant Chronic Phase CML) a Minimum of 2 Years Follow-up Minimum of 5 Years Follow-up Minimum of 7 Years Follow-up Adverse Reaction All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Percent (%) of Patients a Randomized dose-optimization trial results reported in the recommended starting dose of 100 mg once daily (n=165) population.

Diarrhea 27 2 28 2 28 2 Fluid retention 34 4 42 6 48 7 Superficial edema 18 0 21 0 22 0 Pleural effusion 18 2 24 4 28 5 Generalized edema 3 0 4 0 4 0 Pericardial effusion 2 1 2 1 3 1 Pulmonary hypertension 0 0 0 0 2 1 Hemorrhage 11 1 11 1 12 1 Gastrointestinal bleeding 2 1 2 1 2 1 Table 10: Adverse Reactions Reported in ≥10% of Adult Patients with Advanced Phase CML Resistant or Intolerant to Prior Imatinib Therapy a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure.

b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular.

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. 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. 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.

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.

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.

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.

1%. These adverse reactions are included based on clinical relevance. 1% – protein losing gastroenteropathy, ileus, acute pancreatitis, anal fistula. 1% – gait disturbance. 1% – leukocytoclastic vasculitis, skin fibrosis. 1% – acute respiratory distress syndrome, pulmonary embolism.

1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis, VIIth nerve paralysis, dementia, ataxia. 1% – aplasia pure red cell. 1% – epiphyses delayed fusion (reported at 1%–<10% in the pediatric studies), growth retardation (reported at 1%–<10% in the pediatric studies).

1%–<1% – blood creatine phosphokinase increased, gamma-glutamyltransferase increased. 2%]). 1% – diabetes mellitus. 1% – cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis.

1% – photophobia. 1% – livedo reticularis, deep vein thrombosis, embolism. 1%–<1% – anxiety, affect lability, confusional state, libido decreased. 1% – abortion. 1%–<1% – gynecomastia, menstrual disorder. Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion.

1%–<1% – vertigo, hearing loss. 1%–<1% – cholestasis, cholecystitis, hepatitis. 1% – renal impairment. 1%–<1% – hypersensitivity (including erythema nodosum). 1% – hyperthyroidism, thyroiditis. 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 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.

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. 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.

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.

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 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. 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.

8% of adult patients and generally required treatment interruptions and transfusions. 4% of adult patients. 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. 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.

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. 5) ] . 1) ] . 0% imatinib). 8%) transient ischemic attacks occurred with dasatinib.

Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. 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.

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.

1) ] . Correct hypokalemia or hypomagnesemia prior to and during dasatinib administration. 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.

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.

1) ] . 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.

3 )] . 2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). 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.

1) ]. Monitor transaminases at baseline and monthly or as clinically indicated during treatment. 5) ] . When dasatinib is administered in combination with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed.

Monitor hepatic function when dasatinib is used in combination with chemotherapy. 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 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. 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.

8% of adult patients and generally required treatment interruptions and transfusions. 4% of adult patients. 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. 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.

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. 5) ] . 1) ] . 0% imatinib). 8%) transient ischemic attacks occurred with dasatinib.

Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. 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.

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.

1) ] . Correct hypokalemia or hypomagnesemia prior to and during dasatinib administration. 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.

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.

1) ] . 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.

3 )] .