Dasatinib

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.

• Chronic phase CML in adults: 100 mg once daily. (
  2 DOSAGE AND ADMINISTRATION

  • Chronic phase CML in adults: 100 mg once daily.
  • Accelerated phase CML, myeloid or lymphoid blast phase CML or Ph+ ALL in adults: 140 mg once daily.
  • Administer orally, with or without a meal. Do not crush, cut or chew tablets.

  2.1 Dosage of Dasatinib in Adult Patients

  The recommended starting dosage of dasatinib for chronic phase CML in adults is 100 mg administered orally once daily. The recommended starting dosage of dasatinib 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 can be taken with or without a meal, either in the morning or in the evening.

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  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 dose increase. If the dose of dasatinib is increased, monitor the patient carefully for toxicity

  [see Drug Interactions ]

  .

  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 must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to:

  • 40 mg daily for patients taking dasatinib 140 mg daily.
  • 20 mg daily for patients taking dasatinib 100 mg daily.
  • 20 mg daily for patients taking dasatinib 70 mg daily.

  For patients taking dasatinib 60 mg or 40 mg daily, consider interrupting dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating dasatinib.

  These reduced doses of dasatinib 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 is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the dasatinib dose is increased

  [see Drug Interactions ]

  .

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  2.4 Dose Escalation in Adults with CML and Ph+ ALL

  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.

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  2.5 Dose Adjustment for Adverse Reactions

  Myelosuppression

  In clinical studies, myelosuppression was managed by dose interruption, dose reduction or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications for adult patients are summarized in Table 3.

  Table 3 Dose Adjustments for Neutropenia and Thrombocytopenia in Adults

  *ANC: absolute neutrophil count
  Chronic Phase CML (starting dose 100 mg once daily)	ANC*< 0.5 × 109/L or Platelets < 50 × 109/L	1.      Stop dasatinib until ANC ≥ 1 × 109/L and platelets ≥ 50 × 109/L.
  		2.      Resume treatment with dasatinib 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 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 (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 × 109/L or Platelets < 10 × 109/L	1.      Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2.      If cytopenia is unrelated to leukemia, stop dasatinib until ANC ≥ 1 × 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 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.

  Non-Hematologic Adverse Reactions

  For adults with Ph+ CML and ALL if a severe nonhematologic 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 ]

  .

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  2.6 Duration of Treatment

  In clinical studies, treatment with dasatinib in adults 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.

  Dasatinib is a hazardous product. Follow applicable special handling and disposal procedures.¹

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
  )
• Accelerated phase CML, myeloid or lymphoid blast phase CML or Ph+ ALL in adults: 140 mg once daily. (
  2 DOSAGE AND ADMINISTRATION

  • Chronic phase CML in adults: 100 mg once daily.
  • Accelerated phase CML, myeloid or lymphoid blast phase CML or Ph+ ALL in adults: 140 mg once daily.
  • Administer orally, with or without a meal. Do not crush, cut or chew tablets.

  2.1 Dosage of Dasatinib in Adult Patients

  The recommended starting dosage of dasatinib for chronic phase CML in adults is 100 mg administered orally once daily. The recommended starting dosage of dasatinib 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 can be taken with or without a meal, either in the morning or in the evening.

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  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 dose increase. If the dose of dasatinib is increased, monitor the patient carefully for toxicity

  [see Drug Interactions ]

  .

  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 must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to:

  • 40 mg daily for patients taking dasatinib 140 mg daily.
  • 20 mg daily for patients taking dasatinib 100 mg daily.
  • 20 mg daily for patients taking dasatinib 70 mg daily.

  For patients taking dasatinib 60 mg or 40 mg daily, consider interrupting dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating dasatinib.

  These reduced doses of dasatinib 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 is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the dasatinib dose is increased

  [see Drug Interactions ]

  .

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  2.4 Dose Escalation in Adults with CML and Ph+ ALL

  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.

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  2.5 Dose Adjustment for Adverse Reactions

  Myelosuppression

  In clinical studies, myelosuppression was managed by dose interruption, dose reduction or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications for adult patients are summarized in Table 3.

  Table 3 Dose Adjustments for Neutropenia and Thrombocytopenia in Adults

  *ANC: absolute neutrophil count
  Chronic Phase CML (starting dose 100 mg once daily)	ANC*< 0.5 × 109/L or Platelets < 50 × 109/L	1.      Stop dasatinib until ANC ≥ 1 × 109/L and platelets ≥ 50 × 109/L.
  		2.      Resume treatment with dasatinib 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 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 (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 × 109/L or Platelets < 10 × 109/L	1.      Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2.      If cytopenia is unrelated to leukemia, stop dasatinib until ANC ≥ 1 × 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 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.

  Non-Hematologic Adverse Reactions

  For adults with Ph+ CML and ALL if a severe nonhematologic 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 ]

  .

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  2.6 Duration of Treatment

  In clinical studies, treatment with dasatinib in adults 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.

  Dasatinib is a hazardous product. Follow applicable special handling and disposal procedures.¹

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
  )
• Administer orally, with or without a meal. Do not crush, cut or chew tablets. (
  2 DOSAGE AND ADMINISTRATION

  • Chronic phase CML in adults: 100 mg once daily.
  • Accelerated phase CML, myeloid or lymphoid blast phase CML or Ph+ ALL in adults: 140 mg once daily.
  • Administer orally, with or without a meal. Do not crush, cut or chew tablets.

  2.1 Dosage of Dasatinib in Adult Patients

  The recommended starting dosage of dasatinib for chronic phase CML in adults is 100 mg administered orally once daily. The recommended starting dosage of dasatinib 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 can be taken with or without a meal, either in the morning or in the evening.

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  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 dose increase. If the dose of dasatinib is increased, monitor the patient carefully for toxicity

  [see Drug Interactions ]

  .

  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 must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to:

  • 40 mg daily for patients taking dasatinib 140 mg daily.
  • 20 mg daily for patients taking dasatinib 100 mg daily.
  • 20 mg daily for patients taking dasatinib 70 mg daily.

  For patients taking dasatinib 60 mg or 40 mg daily, consider interrupting dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating dasatinib.

  These reduced doses of dasatinib 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 is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the dasatinib dose is increased

  [see Drug Interactions ]

  .

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  2.4 Dose Escalation in Adults with CML and Ph+ ALL

  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.

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  2.5 Dose Adjustment for Adverse Reactions

  Myelosuppression

  In clinical studies, myelosuppression was managed by dose interruption, dose reduction or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications for adult patients are summarized in Table 3.

  Table 3 Dose Adjustments for Neutropenia and Thrombocytopenia in Adults

  *ANC: absolute neutrophil count
  Chronic Phase CML (starting dose 100 mg once daily)	ANC*< 0.5 × 109/L or Platelets < 50 × 109/L	1.      Stop dasatinib until ANC ≥ 1 × 109/L and platelets ≥ 50 × 109/L.
  		2.      Resume treatment with dasatinib 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 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 (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 × 109/L or Platelets < 10 × 109/L	1.      Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2.      If cytopenia is unrelated to leukemia, stop dasatinib until ANC ≥ 1 × 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 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.

  Non-Hematologic Adverse Reactions

  For adults with Ph+ CML and ALL if a severe nonhematologic 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 ]

  .

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

  2.6 Duration of Treatment

  In clinical studies, treatment with dasatinib in adults 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.

  Dasatinib is a hazardous product. Follow applicable special handling and disposal procedures.¹

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
  )

Dasatinib Tablets, 20 mg are white to off-white, round, film-coated tablets, debossed with '1741' on one side and plain on the other side

Dasatinib Tablets, 50 mg are white to off-white, oval, film-coated tablets, debossed with '1742' on one side and plain on the other side.

Dasatinib Tablets, 70 mg are white to off-white, round, film-coated tablets, debossed with '1743' on one side and plain on the other side.

Dasatinib Tablets, 80 mg are white to off-white, oblong, film-coated tablets, debossed with '1744' on one side and plain on the other side

Dasatinib Tablets, 100 mg are white to off-white, oval, film-coated tablets, debossed with '1745' on one side and plain on the other side

Dasatinib Tablets, 140 mg are white to off-white, round, film-coated tablets, debossed with '1746' on one side and plain on the other side.

• Lactation:
  Advise women not to breastfeed. (
  8.2 Lactation

  Risk Summary

  No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed child or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing children from dasatinib, breastfeeding is not recommended during treatment with dasatinib and for 2 weeks after the last dose.
  )

• 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. (
  2.6 Duration of Treatment

  In clinical studies, treatment with dasatinib in adults 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.

  Dasatinib is a hazardous product. Follow applicable special handling and disposal procedures.¹

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
  ,
  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 ]

  .

  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.

  Myelosuppression is generally reversible and usually managed by withholding dasatinib temporarily and/or dose reduction

  [see Dosage and Administration ]

  .

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
  ,
  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 ]

  . 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.
  )
• Fluid Retention:
  Fluid retention, sometimes severe, including pleural effusions. Manage with supportive care measures and/or dose modification. (
  2.6 Duration of Treatment

  In clinical studies, treatment with dasatinib in adults 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.

  Dasatinib is a hazardous product. Follow applicable special handling and disposal procedures.¹

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
  ,
  5.3 Fluid Retention

  Dasatinib may cause fluid retention

  [see Adverse Reactions ]

  . 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.

  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 ]

  .

  Pediatric use information is approved for Bristol-Myers Squibb Company's Sprycel (dasatinib) tablets. However, due to Bristol-Myers Squibb Company's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
  )
• Cardiovascular Toxicity:
  Monitor patients for signs or symptoms and treat appropriately. (
  5.4 Cardiovascular Toxicity

  Dasatinib can cause cardiac dysfunction

  [see Adverse Reactions ]

  . 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.
  )
• 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 Pulmonary Arterial Hypertension

  Dasatinib may increase the risk of developing pulmonary arterial hypertension (PAH) in adult 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 ]

  . 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.
  )
• QT Prolongation:
  Use dasatinib with caution in patients who have or may develop prolongation of the QT interval. (
  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 ]

  . Correct hypokalemia or hypomagnesemia prior to and during dasatinib administration.
  )
• Severe Dermatologic Reactions:
  Individual cases of severe mucocutaneous dermatologic reactions have been reported. (
  5.7 Severe Dermatologic Reactions

  Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome

  [see Adverse Reactions ]

  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.
  )
• 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 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 ]

  .
  )
• Embryo-Fetal Toxicity:
  Can cause fetal harm. Advise patients of reproductive potential of potential risk to fetus and to use effective contraception. (
  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 Pregnancy

  Risk Summary

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

  [see Data]

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

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

  Clinical Considerations

  Fetal/Neonatal Adverse Reactions

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

  [see Warnings and Precautions ]

  .

  Data

  Human Data

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

  Animal Data

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

  Dasatinib can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ]

  .

  Contraception

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

  Infertility

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

  [see Nonclinical Toxicology ]

  .
  )
• 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 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 and Use in Specific Populations ]

  . Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment. Monitor bone growth and development in pediatric patients.
  )
• 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 Hepatotoxicity

  Dasatinib may cause hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase

  [see Adverse Reactions ]

  . Monitor transaminases at baseline and monthly or as clinically indicated during treatment. Reduce dose, withhold or permanently discontinue dasatinib based on severity

  [see Dosage and Administration ]

  . 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.
  )