Dasatinib, a kinase inhibitor, is an antineoplastic agent.1, 2, 3
Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia
Dasatinib is used for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adults who are in the chronic phase of the disease.1, 19, 39 Dasatinib is used for the treatment of Ph+ CML in adults who are in the chronic, accelerated, or myeloid or lymphoid blast phase of the disease after failure (secondary to resistance or intolerance) of prior therapy including imatinib.1, 2, 39 Dasatinib also is used for the treatment of Ph+ CML in pediatric patients 1 year of age or older who are in the chronic phase of the disease.1 Dasatinib is designated an orphan drug by FDA for use in the treatment of CML.4
Adult Patients: Newly Diagnosed Philadelphia Chromosome-Positive Chronic Phase CML
The current indication for use of dasatinib in the treatment of Ph+ chronic phase CML is based on results from an open-label, randomized, phase 3 study (Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients [DASISION]) in adults with newly diagnosed chronic phase Ph+ CML.1, 19, 28
In this study, 519 patients who had been diagnosed with chronic phase Ph+ CML within the previous 3 months and who had received no prior therapies for CML (except hydroxyurea or anagrelide) were randomized to receive either dasatinib (100 mg once daily) or imatinib (400 mg once daily) until disease progression or unacceptable toxicity occurred.1, 19 The interim analysis was performed after a minimum follow-up of 12 months.19 At the time of the analysis, patients in both treatment groups had received a median of 14 months of treatment.19
Confirmed complete cytogenetic response (defined as 2 consecutive assessments at least 28 days apart documenting complete eradication of Ph+ metaphases in cells from a bone marrow sample) was the primary efficacy end point.1, 19 Confirmed complete cytogenetic response or major molecular response (defined as a Bcr-Abl transcript level of 0.1% or less in peripheral blood) was reported within 12 months of treatment initiation in 77 or 52%, respectively, of patients receiving dasatinib and 66 or 34%, respectively, of those receiving imatinib.1, 19 Disease progression (i.e., transformation from chronic phase to accelerated or blast phase CML) occurred by the data cutoff in 1.9% of patients receiving dasatinib and 3.5% of those receiving imatinib.19
When results were stratified by prognosis (according to Hasford risk score, a CML-specific prognostic indicator based on age, spleen size, and platelet, basophil, eosinophil, and peripheral blast counts),19, 20 dasatinib or imatinib therapy resulted in complete cytogenetic response within 12 months of treatment initiation in 94 or 76%, respectively, of low-risk patients and 78 or 64%, respectively, of high-risk patients.19
Nausea, vomiting, rash, myalgia, muscle inflammation, and grade 3 or 4 hypophosphatemia occurred more frequently in patients receiving imatinib, while grade 3 or 4 thrombocytopenia occurred more frequently in those receiving dasatinib.19 Fluid retention (including superficial edema) also occurred more frequently in patients receiving imatinib, although pleural effusion was reported only in patients receiving dasatinib.19
At a final 5-year follow up of the DASISION study, 61 or 63% of dasatinib- or imatinib-treated patients, respectively, remained on initial therapy.28 The 5-year major molecular response rate was 76% in patients receiving dasatinib and 64% in patients receiving imatinib.28 Progression-free survival (85%) and estimated 5-year overall survival (90-91%) were similar in both treatment groups.28 Disease progression (i.e., transformation from chronic phase to accelerated or blast phase CML) at 5 years occurred in 4.6% of those receiving dasatinib and in 7.3% of those receiving imatinib.28 No new safety signals were observed in either treatment group.28
Adult Patients: Philadelphia Chromosome-Positive Chronic Phase CML Following Prior Treatment Failure
FDA approval of dasatinib for the treatment of chronic phase CML after failure of prior therapy including imatinib was based principally on results of phase 2 studies evaluating safety and efficacy of the drug at a dosage of 70 mg twice daily.13, 14, 18 In a subsequent phase 3, randomized, open-label study, safety and efficacy of dasatinib administered at various dosages once or twice daily were evaluated in 670 patients with chronic phase CML following failure of imatinib therapy.1, 11 Major cytogenetic response (defined as elimination or substantial reduction [by at least 65%] of Ph+ hematopoietic cells) was the primary efficacy end point in these studies.1, 11, 13, 14 In the phase 3 study, resistance to imatinib was defined as failure to achieve a complete hematologic response after 3 months, major cytogenetic response after 6 months, complete cytogenetic response after 12 months, and a reduction in leukocyte count after 4 or more weeks of therapy; loss of a previous major cytogenetic response, molecular response (with concurrent increase of 10% or more in Ph+ metaphases), or complete hematologic response; or evidence of a new mutation in the Bcr-Abl kinase domain.11 In the phase 3 study, imatinib intolerance was defined as toxicity (grade 3 or worse) that occurred at an imatinib dosage of 400 mg or more daily and resulted in discontinuance of the drug.11
In the phase 3 study, patients were randomized to receive dasatinib 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily;1, 11 the median duration of treatment was 22 months.1 The 4 dasatinib dosing regimens had similar efficacy, but patients receiving dasatinib 100 mg once daily experienced less toxicity than did those receiving dasatinib 70 mg twice daily.1, 11 Among patients receiving dasatinib 100 mg once daily, 92% achieved a complete hematologic response, 63% achieved a major cytogenetic response, and 50% achieved a complete cytogenetic response; the median time to achieve a major cytogenetic response was 2.9 months.1 Severe myelosuppression and drug discontinuance or dosage reduction because of adverse reactions were reported less frequently with dasatinib 100 mg once daily than with other dosing regimens.11
In one phase 2, open-label, noncomparative study in patients with chronic phase CML following failure of imatinib therapy, complete hematologic, major cytogenetic, and complete cytogenetic responses were reported with dasatinib therapy (70 mg twice daily) in 91, 59, and 49%, respectively, of patients at a median follow-up of approximately 15 months; the median 15-month progression-free and overall survival rates were 90 and 96%, respectively.14 In a phase 2, open-label, randomized study, patients with chronic phase CML whose disease was resistant to conventional doses of imatinib (400-600 mg daily) were randomized to receive dasatinib 70 mg twice daily or imatinib 400 mg twice daily.13 At 15 months' follow-up, complete hematologic, major cytogenetic, and complete cytogenetic responses were reported in 93, 52, and 40%, respectively, of patients receiving dasatinib compared with 82, 33, and 16%, respectively, of those receiving high-dose imatinib.13
Pediatric Patients: Philadelphia Chromosome-Positive Chronic Phase CML
The current indication for use of dasatinib in the treatment of pediatric patients 1 year of age and older with chronic phase Ph+ CML is based on results of a phase 1 dose-ranging study and a phase 2, open-label, single-arm study.1, 29, 30 In these studies, 51 patients with newly diagnosed CML in the chronic phase and 46 patients who were resistant to or could not tolerate imatinib received dasatinib therapy; 91 of the 97 patients received dasatinib 60 mg/m2 (maximum dose 100 mg) once daily.1, 29, 30 Therapy was continued until disease progression or unacceptable toxicity occurred.1, 29, 30
The median age of newly diagnosed and imatinib-intolerant/resistant patients was 12.8 years (range, 1.9-17.8 years) and 13.5 years (range, 2-20 years), respectively.1 The median duration of follow-up was 4.5 years in patients with newly diagnosed chronic phase CML and 5.2 years in imatinib-resistant or -intolerant patients.1 A trend toward increased complete cytogenetic response, major cytogenetic response, and major molecular response was observed in both newly diagnosed and imatinib-resistant or -intolerant patients over 3-24 months (see Table 1).1 Median time to response for complete cytogenetic response, major cytogenetic response, and major molecular response was 5.5, 3, and 8.9 months, respectively, in patients with newly diagnosed chronic phase CML, and 3.3, 2.9, and 8.3 months, respectively, in imatinib-resistant or -intolerant patients.1 At a median duration of follow-up of 4.5 or 5.2 years in newly diagnosed or imatinib-resistant or -intolerant patients, respectively, the median duration of complete cytogenetic response, major cytogenetic response, and major molecular response could not be estimated because more than half of the responding patients had not progressed at the time of data cut-off.1 Disease progression (i.e., transformation from chronic phase to blast phase CML) during the phase 2 study occurred in 3 patients (1 newly diagnosed patient and 2 imatinib-resistant or -intolerant patients).1
Complete cytogenetic response | 3 months | 6 months | 12 months | 24 months |
|---|---|---|---|---|
Newly diagnosed | 43.1% | 66.7% | 96.1% | 96.1% |
Previously treated with imatinib | 45.7% | 71.7% | 78.3% | 82.6% |
Major cytogenetic response | 3 months | 6 months | 12 months | 24 months |
Newly diagnosed | 60.8% | 90.2% | 98% | 98% |
Previously treated with imatinib | 60.9% | 82.6% | 89.1% | 89.1% |
Major molecular response | 3 months | 6 months | 12 months | 24 months |
Newly diagnosed | 7.8% | 31.4% | 56.9% | 74.5% |
Previously treated with imatinib | 15.2% | 26.1% | 39.1% | 52.2% |
Accelerated Phase or Blast Phase CML
Adult Patients: Previously Treated Philadelphia Chromosome-Positive Accelerated or Myeloid or Lymphoid Blast Phase CML
Initial FDA approval of dasatinib for the treatment of accelerated phase Ph+ CML or Ph+ CML in myeloid or lymphoid blast crisis in patients who failed prior therapy including imatinib was based principally on results of phase 2 studies evaluating safety and efficacy of the drug at a dosage of 70 mg twice daily.16, 17, 18 In a subsequent phase 3, multicenter, randomized, open-label study, safety and efficacy of dasatinib administered once or twice daily were evaluated in 611 adults with CML in accelerated, myeloid blast, or lymphoid blast phase who were intolerant of or had disease that was resistant to prior therapy including imatinib.1, 12 Major hematologic response, a primary efficacy end point in the studies, was defined as complete hematologic response or no evidence of leukemia; major cytogenetic response included complete and partial responses.1, 12, 16, 17
In the phase 3 study, patients were randomized to receive dasatinib 140 mg once daily or 70 mg twice daily;1, 12 the median duration of treatment was approximately 6 months.1 The once-daily and twice-daily regimens had comparable efficacy as measured by rates of major hematologic response.1, 12 Major hematologic and cytogenetic responses were reported with dasatinib 140 mg once daily in 66 and 39%, respectively, of patients in the accelerated phase of CML;1, 12 28 and 28%, respectively, of those in the myeloid blast phase;1 and 42 and 52%, respectively, of those in the lymphoid blast phase.1 The median time to achieve a major hematologic response with dasatinib 140 mg once daily was 1.9 months for those in the accelerated1, 12 or myeloid blast phase of CML1 and 1.8 months for those in the lymphoid blast phase.1
In a phase 2, open-label, noncomparative study in patients in the accelerated phase of the disease, major hematologic and cytogenetic responses were reported with dasatinib therapy (70 mg twice daily) in 64 and 33%, respectively, of patients at 8 months' follow-up.17 In phase 2, open-label, noncomparative studies in patients in blast crisis, major hematologic and cytogenetic responses were reported with dasatinib therapy (70 mg twice daily) in 34 and 33%, respectively, of patients in the myeloid blast phase and in 35 and 52%, respectively, of patients in the lymphoid blast phase after at least 12 months' follow-up; median overall survival and progression-free survival were 11.8 and 6.7 months, respectively, for patients in the myeloid blast phase and 5.3 and 3 months, respectively, for those in the lymphoid blast phase.16
Adult Patients: Chronic Phase CML
Some experts recommend imatinib, nilotinib, or dasatinib for the first-line treatment of chronic phase CML; selection of the tyrosine kinase inhibitor should be based on patient preference and factors such as age, comorbidities, and expected tolerability of therapy.36 Following confirmation of Bcr-Abl 1 positivity, therapy with a tyrosine kinase inhibitor should be initiated immediately.36 The risk of transformation to advanced or blast phase disease is lower in Sokal non-low risk patients treated with dasatinib or nilotinib.36
Some experts state that dasatinib should be avoided in patients at risk of developing pleural effusions (e.g., patients with existing lung disorders or uncontrolled hypertension).36 If treatment failure occurs during tyrosine kinase inhibitor therapy, a bone marrow biopsy should be performed to evaluate CML phase and clonal changes; therapy may be switched to an alternative tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib) or stem cell transplantation may be considered.36
Philadelphia Chromosome-Positive Acute Lymphocytic Leukemia
Dasatinib is used for the treatment of Ph+ acute lymphocytic (lymphoblastic) leukemia (ALL) in adults following failure (secondary to resistance or intolerance) of prior therapy.1, 2, 39 Dasatinib is designated an orphan drug by FDA for use in this condition.4 Dasatinib is also used in combination with chemotherapy for the treatment of pediatric patients 1 year of age and older with newly diagnosed Ph+ ALL.1, 39
Adult Patients: Philadelphia Chromosome-Positive ALL Following Prior Treatment Failure
Safety and efficacy of dasatinib for the treatment of Ph+ ALL in adults who failed prior treatment have been evaluated in a phase 2, open-label, noncomparative study and a phase 3, randomized study in patients with Ph+ ALL who were intolerant of or had disease that was resistant to prior therapy including imatinib.1, 15 A total of 130 patients were enrolled in the 2 studies, and the median duration of therapy was about 3 months.1, 15 Major hematologic response, the primary efficacy end point in the 2 studies, was defined as complete hematologic response or no evidence of leukemia.1, 15
In the phase 2 study, treatment with dasatinib 70 mg twice daily resulted in a major hematologic response in 42% of patients.15 At a minimum follow-up of 8 months, median duration of major hematologic response had not yet been reached (range: 1.9 to more than 8.7 months).15 Median progression-free survival was 3.3 months.15
In the phase 3 study, patients were randomized to receive either once-daily or twice-daily dasatinib therapy (140 mg once daily or 70 mg twice daily).1, 12 Major hematologic response was reported in 38% of patients receiving dasatinib 140 mg once daily; the median duration of response was 4.6 months.1 Median progression-free survival was 4 months for those receiving the once-daily regimen and 3.1 months for those receiving the twice-daily regimen.1
Pediatric Patients: Newly Diagnosed Philadelphia Chromosome-Positive ALL in Combination with Chemotherapy
Safety and efficacy of dasatinib in combination with chemotherapy for the treatment of newly diagnosed Ph+ ALL in pediatric patients 1 year of age or older have been evaluated in a cohort of 78 patients with newly diagnosed B-cell Ph+ ALL in a phase 2, multicenter, single-arm study.1, 31 Patients in this cohort received dasatinib 60 mg/m2 for up to 24 months in combination with chemotherapy (AIEOP-BFM ALL 2000 regimen).1, 31
In the cohort of patients with newly diagnosed B-cell Ph+ ALL, the median age of patients was 10.4 years (range 2.6-17.9); 25% were 2-6 years of age, 46% were 7-12 years of age, and 30% were 13-17 years of age.1 Most patients (82%) were white, 55% were male, 41% had a WBC count of 50,000/mm3 or greater at diagnosis, and 22% had extramedullary disease.1 At 3 years, event-free survival (defined as the time from initiation of therapy to lack of complete response at the end of the third high-risk block, relapse, secondary malignancy or death from any cause) rate was 64.1%.1 At the end of induction, 96% of patients had <5% lymphoblasts in bone marrow and 97% achieved <5% lymphoblasts by the end of consolidation therapy.1
Adult Patients: Philadelphia Chromosome-Positive ALL Following Prior Treatment Failure
Although there is no universally accepted treatment protocol and evidence based on randomized controlled trials is lacking, there is consensus on the general approach to managing patients with relapsed or refractory ALL.1 Some experts recommend prolonged monitoring of Bcr-Abl transcript levels and resistance mutation screening in patients with persistent minimal residual disease or re-increasing minimal residual disease level; therapy with a second- or third-generation tyrosine kinase inhibitor should be offered to high risk patients with Ph+ ALL.37 Patients with imatinib-refractory Ph+ ALL may respond to nilotinib or dasatinib while patients with T315I Bcr-Abl mutation-positive Ph+ ALL may respond to ponatinib therapy.37 Tyrosine kinase inhibitors have been shown to have a more favorable toxicity profile in elderly patients compared to repeated cycles of conventional cytotoxic chemotherapy.37 Long-term survival has not been demonstrated with tyrosine kinase inhibitor therapy post-relapse; the majority of patients undergo allogeneic stem cell transplantation.37
Dasatinib has also been used in the treatment ofNoonan syndrome†associated with hypertrophic cardiomyopathy.4, 32, 33 Noonan syndrome is a multifaceted disorder characterized by short stature, craniofacial dysmorphism, and cardiac abnormalities.27 Dasatinib is designated an orphan drug by FDA for use in this condition.4
Dasatinib has also been used in the treatment ofgastrointestinal stromal tumors (GIST)†.34, 35
Dispensing and Administration Precautions
Administer orally once daily.1 The drug should be administered at about the same time each day, either in the morning or evening, and may be administered without regard to food.1 Swallow tablets whole and do not cut, chew, or crush.1, 10, 39
If a dose of dasatinib is missed, take the next dose at its regular time.1 Do not take two doses at the same time.1
Store all tablet preparations at 20-25°C (excursions permitted between 15-30°C).1, 39
Adult Patients: Newly Diagnosed Philadelphia Chromosome-Positive Chronic Phase CML
The recommended initial adult dosage of dasatinib for the treatment of newly diagnosed Ph+ chronic myelogenous leukemia (CML) in the chronic phase is 100 mg once daily.1, 39 In patients who do not achieve a hematologic or cytogenetic response at the recommended initial dosage, dosage may be increased to 140 mg once daily.1, 39
The optimal duration of dasatinib therapy has not been clearly established.1, 39 In clinical trials, treatment generally was continued until evidence of disease progression or until no longer tolerated by the patient.1, 10, 19, 39 The effect of discontinuance of treatment after achievement of a cytogenetic response has not been established.1, 39
Adult Patients: Philadelphia Chromosome-Positive Chronic Phase CML Following Prior Treatment Failure
The recommended initial adult dosage of dasatinib for the treatment of previously treated Ph+ CML in the chronic phase is 100 mg once daily.1, 39 In patients who do not achieve a hematologic or cytogenetic response at the recommended initial dosage, dosage may be increased to 140 mg once daily.1, 39
The optimal duration of dasatinib therapy has not been clearly established.1, 39 In clinical trials, treatment generally was continued until evidence of disease progression or until no longer tolerated by the patient.1, 10, 11, 39 The effect of discontinuance of treatment after achievement of a cytogenetic response has not been established.1, 39
Adult Patients: Philadelphia Chromosome-Positive Accelerated or Myeloid or Lymphoid Blast Phase CML Following Prior Treatment Failure
The recommended initial adult dosage of dasatinib for the treatment of advanced (e.g., accelerated phase, myeloid or lymphoid blast phase) CML after failure of prior therapy (including imatinib) is 140 mg once daily.1, 39 In patients who do not achieve a hematologic or cytogenetic response at the recommended initial dosage, dosage may be increased to 180 mg once daily.1, 39
The optimal duration of dasatinib therapy has not been established.1, 39 In clinical trials, treatment generally was continued until evidence of disease progression or until no longer tolerated by the patient.1, 10, 12, 39 The effect of discontinuance of treatment after achievement of a cytogenetic response has not been established.1, 39
Pediatric Patients: Philadelphia Chromosome-Positive Chronic Phase CML
The recommended initial dosage of dasatinib for the treatment of chronic phase CML in pediatric patients 1 year of age or older is based on body weight (see Table 2).1, 39 The dosage should be recalculated every 3 months or more frequently if necessary to account for changes in body weight.1, 39
Tablet dosing is not recommended for pediatric patients weighing <10 kg.1, 39
In clinical studies, treatment was continued until disease progression or until no longer tolerated by the patient.1, 39 The effect of discontinuance of treatment after achievement of a cytogenetic response has not been established.1, 39
Body Weight (kg) | Recommended Starting Dosage |
|---|---|
10 to <20 | 40 mg once daily |
20 to <30 | 60 mg once daily |
30 to <45 | 70 mg once daily |
≥45 | 100 mg once daily |
In patients who do not achieve a hematologic or cytogenetic response at the recommended initial dosage, the dasatinib dosage may be increased as described in Table 3.1, 39
Starting Dosage | Escalated Dosage |
|---|---|
40 mg once daily | 50 mg once daily |
60 mg once daily | 70 mg once daily |
70 mg once daily | 90 mg once daily |
100 mg once daily | 120 mg once daily |
Adult Patients: Philadelphia Chromosome-Positive ALL Following Prior Treatment Failure
The recommended initial adult dosage of dasatinib for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL) after failure of prior therapy is 140 mg once daily.1, 39 In patients who do not achieve a hematologic or cytogenetic response at the recommended initial dosage, dosage may be increased to 180 mg once daily.1, 39
The optimal duration of dasatinib therapy has not been clearly established.1, 39 In clinical trials, treatment generally was continued until evidence of disease progression or unacceptable toxicity was observed.1, 39 The effect of discontinuance of treatment after achievement of a cytogenetic response has not been established.1, 39
Pediatric Patients: Newly Diagnosed Philadelphia Chromosome-Positive ALL in Combination with Chemotherapy
The recommended initial dosage of dasatinib for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) ALL (in combination with chemotherapy) in pediatric patients is based on body weight (see Table 4).1, 39 The dosage should be recalculated every 3 months or more frequently if necessary to account for changes in body weight.1, 39
Dasatinib therapy should be started on or before day 15 of induction chemotherapy.1, 39 Dosage escalations are not recommended for pediatric Ph+ ALL since dasatinib is administered in combination with chemotherapy.1, 39
Tablet dosing is not recommended for pediatric patients weighing <10 kg.1, 39
The manufacturer recommends continuing therapy for 2 years in pediatric patients with Ph+ ALL.1, 39
Body Weight (kg) | Recommended Starting Dosage |
|---|---|
10 to <20 | 40 mg once daily |
20 to <30 | 60 mg once daily |
30 to <45 | 70 mg once daily |
≥45 | 100 mg once daily |
In Study CA180372, at least 1 dose of the tablet formulation of dasatinib was dispersed in juice and administered to 5 patients (2-10 years of age) with Ph+ ALL.1, 39 The systemic exposure of dasatinib following administration of dispersed tablets was 36% lower compared to intact tablets.1, 39 Because data are limited, efficacy and safety of dispersing dasatinib tablets have not been established.1, 39
Temporary interruption, dosage reduction, or discontinuance of dasatinib therapy is indicated in patients experiencing severe neutropenia and/or thrombocytopenia.1, 10, 39 Hematopoietic growth factor has been used in patients with resistant myelosuppression associated with dasatinib therapy.1, 39
Adult Patients: Chronic Phase CML : Dasatinib therapy should be withheld in patients in the chronic phase of CML if absolute neutrophil counts (ANC) decrease to less than 500/mm3 or platelet counts decrease to less than 50,000/mm3.1, 39 Treatment may be resumed at the original starting dosage of 100 mg once daily if ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 50,000/mm3 in 7 days or less.1, 39
Following a second episode of neutropenia or thrombocytopenia, in which ANC decreases to less than 500/mm3 for longer than 7 days or platelet counts decrease to less than 25,000/mm3, treatment should again be withheld.1, 39 Treatment may be resumed at a reduced dosage of 80 mg once daily when ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 50,000/mm3.1, 39
Following a third episode of neutropenia or thrombocytopenia, in which ANC decreases to less than 500/mm3 for longer than 7 days or platelet counts decrease to less than 25,000/mm3, treatment should again be withheld in patients receiving dasatinib for newly diagnosed disease; treatment in these patients may be resumed at a reduced dosage of 50 mg once daily when ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 50,000/mm3.1, 39 However, dasatinib should be discontinued following a third such episode in patients receiving the drug following failure of prior therapy including imatinib.1, 39
Adult Patients: Accelerated Phase or Blast Phase CML : Dasatinib therapy should be withheld in patients in the accelerated phase or blast phase of CML if ANC decreases to less than 500/mm3 or platelet counts decrease to less than 10,000/mm3 and the cytopenia is unrelated to leukemia (as determined by bone marrow aspirate or biopsy).1, 39 Treatment may be resumed at the original starting dosage of 140 mg once daily when ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 20,000/mm3.1, 39 Treatment should again be withheld if the ANC decreases to less than 500/mm3 or platelet counts decrease to less than 10,000/mm3.1, 39 Treatment may be resumed at a reduced dosage of 100 mg once daily (following a second episode) or 80 mg once daily (following a third episode) when ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 20,000/mm3.1, 39
If patients in the accelerated phase or blast phase of CML have reductions in ANC to less than 500/mm3 or reductions in platelet counts to less than 10,000/mm3 and the cytopenia is related to leukemia (as determined by bone marrow aspirate or biopsy), the manufacturer recommends that an escalation in dasatinib dosage to 180 mg once daily be considered.1, 39
Adult Patients: Philadelphia Chromosome-Positive ALL : Dasatinib therapy should be withheld in patients with Ph+ ALL if ANC decreases to less than 500/mm3 or platelet counts decrease to less than 10,000/mm3 and the cytopenia is unrelated to leukemia (as determined by marrow aspirate or biopsy).1, 39 Treatment may be resumed at the original starting dosage of 140 mg once daily when ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 20,000/mm3.1, 39 Treatment should again be withheld if ANC decreases to less than 500/mm3 or platelet counts decrease to less than 10,000/mm3.1, 39 Treatment may be resumed at a reduced dosage of 100 mg once daily (following a second episode) or 80 mg once daily (following a third episode) when ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 20,000/mm3.1, 39
If patients with Ph+ ALL have reductions in ANC to less than 500/mm3 or reductions in platelet counts to less than 10,000/mm3 and the cytopenia is related to leukemia (as determined by marrow aspirate or biopsy), the manufacturer recommends that an increase in dasatinib dosage to 180 mg once daily be considered.1, 39
Pediatric Patients: Philadelphia Chromosome-Positive CML : Dasatinib therapy should be withheld in patients with Ph+ CML experiencing persistent (lasting longer than 3 weeks) neutropenia or thrombocytopenia unrelated to leukemia (as determined by bone marrow aspirate or biopsy).1, 39 Treatment may be resumed at the original starting dosage or at a reduced dosage when ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 75,000/mm3 (see Table 5).1, 39 If neutropenia or thrombocytopenia recurs, repeat bone marrow aspirate or biopsy and resume dasatinib at a reduced dosage (see Table 5).1, 39
Original Starting Dose | One-level Dose Reduction | Two-level Dose Reduction |
|---|---|---|
40 mg | 20 mg | Lower tablet strength not available |
60 mg | 40 mg | 20 mg |
70 mg | 60 mg | 50 mg |
100 mg | 80 mg | 70 mg |
For pediatric patients with chronic phase CML, dasatinib therapy should be withheld in patients who experience grade 3 or higher neutropenia or thrombocytopenia during complete hematologic response.1, 39 Treatment may be resumed at a reduced dosage.1, 39 Temporary dosage reductions may be necessary for intermediate degrees of cytopenia and disease response.1, 39
Pediatric Patients: Philadelphia Chromosome-Positive ALL : If neutropenia and/or thrombocytopenia delay the next cycle by more than 14 days, interrupt dasatinib therapy and resume at the same dosage once the next cycle starts.1, 39 If neutropenia and/or thrombocytopenia persist and the next cycle is further delayed by 7 days, perform a bone marrow assessment to assess cellularity and percentage of blasts.1, 39 If bone marrow cellularity is less than 10%, interrupt treatment until ANC exceeds 500/mm3, at which time treatment may be resumed at full dosage.1, 39 If bone marrow cellularity is greater than 10%, consider resuming therapy.1, 39
Adult Patients : Dasatinib therapy should be withheld in adults with Ph+ CML and ALL experiencing severe adverse nonhematologic reactions; once the adverse reaction has resolved or improved, treatment may be resumed as appropriate at a reduced dosage depending on the severity and recurrence.1, 39
Pediatric Patients : Dasatinib therapy should be withheld in pediatric patients with Ph+ CML experiencing severe adverse nonhematologic reactions; once the adverse reaction has resolved or improved, treatment may be resumed as appropriate at a reduced dosage depending on the severity and recurrence.1, 39
In pediatric patients with Ph+ ALL, consider temporarily interrupting therapy if grade 2 nonhematologic toxicity occurs if no recovery despite symptomatic therapy; when the toxicity improves to grade 1 or less, resume therapy at the original dosage or reduced dosage (following a subsequent episode) as described in Table 6.1, 39 If grade 3 nonhematologic toxicity occurs, temporarily interrupt therapy; when toxicity resolves to grade 1 or less, resume therapy at a reduced dosage as described in Table 6.1, 39
In pediatric patients with Ph+ ALL who experience elevated direct bilirubin concentrations >5 times the ULN or AST/ALT concentration >15 times the ULN occurs, temporarily interrupt therapy; when hepatotoxicity resolves to grade 1 or less, resume therapy at the original dosage or reduced dosage (following a subsequent episode) as described in Table 6.1, 39
Original Starting Dose | One-level Dose Reduction | Two-level Dose Reduction |
|---|---|---|
40 mg | 20 mg | Lower tablet strength not available |
60 mg | 40 mg | 20 mg |
70 mg | 60 mg | 50 mg |
100 mg | 80 mg | 70 mg |
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of dasatinib with strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 should be avoided.1, 39 If such concomitant therapy cannot be avoided, reduction of dasatinib dosage should be considered.1, 39 If concomitant use of a strong CYP3A4 inhibitor and dasatinib at a dosage of 140 mg daily cannot be avoided, consider reducing the dosage of dasatinib to 40 mg daily.1, 39 If concomitant use of a strong CYP3A4 inhibitor and dasatinib at a dosage of 70 or 100 mg daily cannot be avoided, consider reducing the dosage of dasatinib to 20 mg daily.1, 39 If dasatinib is not tolerated following dosage reduction, either the CYP3A4 inhibitor must be discontinued or dasatinib therapy must be interrupted until treatment with the CYP3A4 inhibitor is completed.1, 39 Upon discontinuance of the CYP3A4 inhibitor, approximately 1 week should elapse before the dasatinib dosage is increased.1, 39 If use of a strong CYP3A4 inhibitor is necessary in patients receiving dasatinib at a dosage of 40 or 60 mg daily, consider temporarily interrupting dasatinib until the CYP3A4 inhibitor is discontinued; approximately 1 week should elapse before dasatinib therapy is restarted.1, 39
Concomitant use of dasatinib with strong CYP3A4 inducers should be avoided.1, 39 If such concomitant therapy cannot be avoided, an increase in dasatinib dosage should be considered based on pharmacokinetic considerations.1, 39 If the dosage is increased, the patient should be monitored closely for toxicity.1, 39
No specific dosage recommendations at this time.1
No specific dosage recommendations at this time.1
No specific dosage recommendations at this time.1
Dasatinib is commonly associated with grade 3 or 4 neutropenia, anemia, and thrombocytopenia.1 These effects are more frequent in patients in the accelerated phase or blast phase of CML and in those with Ph+ ALL than in patients in the chronic phase of CML.1 In patients with chronic phase CML, grade 3 or 4 myelosuppression has been reported less frequently with once-daily dosing (100 mg once daily) than with other (e.g., twice-daily) dosing regimens.1, 11
In patients with chronic phase CML, CBCs should be monitored every 2 weeks during the first 3 months of therapy and then every 3 months (or as clinically indicated) thereafter.1 In patients with advanced phase CML or Ph+ ALL, CBCs should be monitored weekly during the first 2 months of therapy and monthly (or as clinically indicated) thereafter.1 In pediatric patients with Ph+ ALL, perform CBC prior to the start of each block of chemotherapy and as clinically indicated; during consolidation blocks of chemotherapy, perform CBC every 2 days until recovery.1 If hematologic toxicity occurs, temporarily interrupt therapy and reduce dosage of dasatinib or discontinue treatment.1
Severe hemorrhage, usually associated with severe thrombocytopenia, has occurred in patients receiving dasatinib.1 Severe CNS hemorrhage, in some cases fatal, has been reported in less than 1% of patients.1 Severe hemorrhage (grade 3 or 4) has been reported in 5.8% of patients and generally has required treatment interruption and transfusions.1 Grade 5 hemorrhage has been reported in 0.4% of patients.1 The most common site of hemorrhage was GI.1 Dasatinib also has been shown to cause platelet dysfunction in vitro.1
Caution should be used in patients receiving anticoagulants or drugs that inhibit platelet function.1
Severe fluid retention has been reported in adult and pediatric patients receiving dasatinib in clinical trials.1 Grade 3 or 4 fluid retention has been reported in 5% of adult patients with newly diagnosed chronic phase CML, 6% of adult patients with newly diagnosed imatinib-intolerant or -resistant chronic phase CML, and 8% of adult patients with advanced phase CML or Ph+ ALL.1 Grade 1 or 2 fluid retention was reported in 10.3% of pediatric patients with chronic phase CML in clinical trials.1 Grade 3 or 4 pleural effusion has been reported in 3% of adult patients with newly diagnosed chronic phase CML and in 7% of adult patients with advanced phase CML or Ph+ ALL.1
Patients developing symptoms suggestive of pleural effusion or other fluid retention (e.g., new or worsening dyspnea on exertion or at rest, dry cough, pleuritic chest pain) should be evaluated by chest radiograph.1 Severe pleural effusion may require thoracentesis and oxygen therapy.1 Fluid retention associated with dasatinib usually can be managed with supportive care (e.g., diuretics, short course of corticosteroids).1 Consider dosage reduction or interruption of therapy if fluid retention occurs.1
Dasatinib may cause cardiac dysfunction.1 At 5 years of follow-up in a clinical trial comparing dasatinib and imatinib in adults with newly diagnosed chronic phase CML, cardiac ischemic events, cardiac-related fluid retention, and conduction system abnormalities (e.g., arrhythmia, palpitations) occurred in 3.9, 8.5, and 7% of patients receiving dasatinib, respectively, and in 1.6, 3.9, and 5% of patients receiving imatinib.1 Two cases (0.8%) of peripheral arterial occlusive disease occurred in patients receiving imatinib and transient ischemic attack occurred in 2 (0.8%) patients receiving dasatinib.1
Patients should be monitored for manifestations of cardiac dysfunction, and appropriate treatment should be provided if cardiac dysfunction occurs.1
Prolongation of the QT Interval
Dasatinib may cause prolongation of the QT interval.1 The drug should be used with caution in patients who have or may develop prolongation of the QT interval (e.g., hypokalemia, hypomagnesemia, congenital long QT syndrome, use of drugs known to prolong QT interval, cumulative high-dose anthracycline therapy).1 Hypokalemia or hypomagnesemia should be corrected prior to administration of dasatinib.1
Pulmonary Arterial Hypertension
Dasatinib may increase the risk for development of pulmonary arterial hypertension (PAH) in adult and pediatric patients.1, 21 Cases of PAH, including some cases attributed to dasatinib and confirmed by cardiac catheterization, have been reported during postmarketing experience in patients receiving the drug.1, 21, 22, 23, 24, 25 Development of PAH has been reported at various time intervals (e.g., 8-60 months) after initiation of dasatinib therapy.1, 21, 22, 23, 24, 25 The mechanism of this adverse effect is unknown;22, 24 however, reported cases of PAH have occurred most often in patients with comorbidities or receiving other drugs concomitantly.21 In some cases, improvement in hemodynamic and clinical parameters was observed following discontinuance of dasatinib therapy.1, 21, 22, 23, 24 In one case, PAH recurred following treatment with another tyrosine kinase inhibitor, nilotinib.25
Patients should be evaluated for manifestations of underlying cardiopulmonary disease before and during dasatinib therapy.1, 21 PAH should be considered in any patient presenting with dyspnea, fatigue, hypoxia, and fluid retention; however, other etiologies of dyspnea should be excluded prior to initiating invasive diagnostic procedures for PAH.1, 21 Since PAH may be reversible following discontinuance of dasatinib, interruption of therapy accompanied by monitoring for improvement may be considered if PAH is suspected.21 If a diagnosis of PAH is confirmed (e.g., by cardiac catheterization), the drug should be permanently discontinued.1, 21
Dasatinib may cause severe dermatological reactions, including Stevens-Johnson syndrome and erythema multiforme.1
Permanently discontinue dasatinib in patients who experience a severe dermatological reaction during treatment and no other etiology for the reaction can be identified.1
Dasatinib may increase the risk of tumor lysis syndrome, generally in patients with imatinib-resistant disease in an advanced phase.1
Due to the potential for tumor lysis syndrome, maintain adequate hydration, correct uric acid levels prior to initiating therapy with dasatinib, and monitor electrolyte levels during therapy.1 Patients with advanced phase disease and/or high tumor burden may be at an increased risk of tumor lysis syndrome and should be monitored more frequently.1
Fetal/Neonatal Morbidity and Mortality
Dasatinib may cause fetal harm; embryofetal toxicity and teratogenicity have been reported in humans.1
Dasatinib has been shown to cross the placenta.1 Dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.1 Hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib.1 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.1 Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects to the fetus when administered during pregnancy.1
Pregnancy should be avoided during therapy.1 Females of reproductive potential and males with such female partners should be advised to use an effective contraceptive method during therapy and for 30 days after the last dose.1 If dasatinib is used during pregnancy or the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Females who are pregnant should not handle crushed or broken dasatinib tablets.1
Effects on Growth and Development of Pediatric Patients
Dasatinib has been associated with adverse reactions related to bone growth and development.1 In clinical trials of pediatric patients with chronic phase CML who received at least 2 years of dasatinib therapy, 5 patients (5.2%) developed epiphyses delayed fusion, osteopenia, growth retardation, or gynecomastia; 1 case of osteopenia and 1 case of gynecomastia resolved during therapy.1
Monitor bone growth and development during therapy in pediatric patients.1
Dasatinib may cause hepatotoxicity with increases in bilirubin, AST, ALT, and alkaline phosphatase.1 Monitor transaminases at baseline and monthly or as clinically indicated during therapy.1 Based on severity of hepatotoxicity, reduce or withhold the dasatinib dose or permanently discontinue therapy.1 Transaminase elevations and hyperbilirubinemia have occurred when dasatinib was administered concomitantly with chemotherapy.1 Monitor hepatic function when dasatinib is used in combination with chemotherapy.1
Each 140-mg daily dosage of dasatinib film-coated tablets (Sprycel®) contains 189 mg of lactose monohydrate and each 100-mg daily dosage of dasatinib film-coated tablets (Sprycel®) contains 135 mg of lactose monohydrate.1 Dasatinib (Phyrago®) tablets do not contain lactose.39
Dasatinib has been shown to cause fetal harm when administered to pregnant females.1
Females who are pregnant should not handle crushed or broken dasatinib tablets.1
It is not known whether dasatinib is distributed into human milk.1 Because of the potential for serious adverse reactions from dasatinib in breast-fed infants, a decision should be made whether to discontinue breast-feeding or the drug, taking into account the importance of the drug to the female; breast-feeding is not recommended during therapy and for 2 weeks after the last dose.1
Monitor bone growth and development in pediatric patients.1, 39
Safety and efficacy of dasatinib have not been established in patients younger than 18 years of age with previously treated Ph+ accelerated or myeloid or lymphoid blast phase CML.1, 39
Safety and efficacy of dasatinib monotherapy have been evaluated in pediatric patients at least 1 year of age with newly diagnosed chronic phase CML.1, 39 Safety and efficacy of dasatinib also have been demonstrated in pediatric patients at least 1 year of age with newly diagnosed Ph+ ALL.1, 39 There are no data in pediatric patients under 1 year of age.1, 39
In pediatric patients with newly diagnosed chronic phase CML, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients.1, 39 In pediatric patients with newly diagnosed Ph+ ALL, one patient experienced grade 1 osteopenia.1, 39 Overall, the safety profile of dasatinib in pediatric patients was comparable to that reported in adult patients.1, 39
In Study CA180372, at least 1 dose of the tablet formulation of dasatinib was dispersed in juice and administered to 5 patients (2-10 years of age) with Ph+ ALL.1, 39 The systemic exposure of dasatinib following administration of dispersed tablets was 36% lower compared to intact tablets.1, 39 Because data are limited, efficacy and safety of dispersing dasatinib tablets has not been established.1, 39
When the total number of patients studied in clinical trials of dasatinib is considered, 23% were 65 years of age or older and 5% were 75 years of age or older.1 Although no overall differences in efficacy were observed between geriatric and younger patients, patients 65 years of age or older are more likely to experience toxicity.1
Peak plasma concentration and AUC of dasatinib were lower in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) than in those with normal hepatic function.1
Renal excretion of unchanged dasatinib and its metabolites is minimal (less than 4%).1
Creatinine clearance of 21.6 mL/minute had no clinically relevant effect on the pharmacokinetics of dasatinib.1
Adverse effects reported in 15% or more of adult patients receiving dasatinib as monotherapy include myelosuppression, fluid retention, diarrhea, headache, rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain.1, 39
Adverse effects reported in 30% or more of pediatric patients receiving dasatinib in combination with chemotherapy include mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, edema, infection, hypotension, decreased appetite, hypersensitivity, dyspnea, epistaxis, peripheral neuropathy, and altered state of consciousness.1, 39
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Inhibitors of Cytochrome P-450 (CYP) 3A4 Isoenzyme
Pharmacokinetic interactions (increased plasma dasatinib concentrations) may occur during concomitant use of dasatinib and strong CYP3A4 inhibitors; concomitant use of a single-20 mg dose of dasatinib and ketoconazole (twice daily) increased peak plasma concentrations and AUC of dasatinib by 4- and 5-fold, respectively.1
Concomitant use of dasatinib with these drugs or with grapefruit juice should be avoided.1 If such concomitant therapy cannot be avoided, reduction of dasatinib dosage should be considered.1 If concomitant use of a strong CYP3A4 inhibitor and dasatinib at a dosage of 140 mg daily cannot be avoided, consider reducing the dosage of dasatinib to 40 mg daily.1 If concomitant use of a strong CYP3A4 inhibitor and dasatinib at a dosage of 70 or 100 mg daily cannot be avoided, consider reducing the dosage of dasatinib to 20 mg daily.1 If dasatinib is not tolerated following dosage reduction, either the CYP3A4 inhibitor must be discontinued or dasatinib therapy must be interrupted until treatment with the CYP3A4 inhibitor is completed.1 Upon discontinuance of the CYP3A4 inhibitor, approximately 1 week should elapse before the dasatinib dosage is increased.1 If use of a strong CYP3A4 inhibitor is necessary in patients receiving dasatinib at a dosage of 40 or 60 mg daily, consider temporarily interrupting dasatinib until the CYP3A4 inhibitor is discontinued; approximately 1 week should elapse before dasatinib therapy is restarted.1
Pharmacokinetic interactions (decreased plasma dasatinib concentrations) may occur during concomitant use of dasatinib and strong CYP3A4 inducers, including St. John's wort ( Hypericum perforatum ).1 When dasatinib was administered with rifampin, the mean peak plasma concentration and AUC of dasatinib were decreased by 81 and 82%, respectively.1 If administration with a CYP3A4 inducer is indicated, drugs with less enzyme induction potential should be used; close monitoring for toxicity and an increase in dasatinib dosage should be considered.1 Since St. John's wort may cause unpredictable decreases in plasma dasatinib concentrations, concomitant use with dasatinib should be avoided.1
Concomitant use of dasatinib with strong CYP3A4 inducers should be avoided.1 If such concomitant therapy cannot be avoided, an increase in dasatinib dosage should be considered based on pharmacokinetic considerations.1 If the dosage is increased, the patient should be monitored closely for toxicity.1
Dasatinib, a time-dependent inhibitor of CYP3A4, may decrease the metabolic clearance of drugs that are metabolized mainly by CYP3A4.1 Dasatinib does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.1
Since dasatinib may cause severe thrombocytopenia and bleeding, anticoagulants and drugs that inhibit platelet function should be used concomitantly with caution.1
Because solubility of dasatinib is pH dependent, concomitant administration of dasatinib and antacids may reduce plasma dasatinib concentrations.1, 26 Administration of an antacid containing aluminum and magnesium hydroxides (Maalox® 30 mL) 2 hours before dasatinib (single 50-mg dose) increased peak plasma dasatinib concentrations by 26% but did not substantially alter the AUC of the drug; however, when the antacid and dasatinib were administered concomitantly, peak plasma concentrations and AUC of dasatinib were reduced by 58 and 55%, respectively.1, 26 Concomitant administration should be avoided.1, 26, 39 If antacid therapy is needed, the antacid dose should be administered at least 2 hours before or after a dose of dasatinib.1, 26, 39
Histamine H2-receptor Antagonists, Proton-pump Inhibitors
Long-term suppression of gastric acid secretion by histamine H2-receptor antagonists or proton-pump inhibitors is likely to reduce dasatinib (Sprycel®) exposure.1 When dasatinib 50 mg was administered 10 hours after famotidine (single 40-mg dose), peak plasma concentrations and AUC of dasatinib were reduced by 63 and 61%, respectively.1, 26 When dasatinib (single 100-mg dose) was administered 22 hours after omeprazole (40 mg) at steady state, peak plasma concentrations and AUC of dasatinib were reduced by 42 and 43%, respectively.1 Concomitant use of dasatinib and histamine H2-receptor antagonists or proton-pump inhibitors is not recommended.1, 26 Instead, use of antacids (administered at least 2 hours before or after a dose of dasatinib) should be considered.1
No clinically significant differences in the pharmacokinetics of dasatinib (Phyrago®) were seen following concomitant use with omeprazole or famotidine.39
Dasatinib, an inhibitor of multiple tyrosine kinases (including Bcr-Abl, the Src family [Src, Lck, Yes, Fyn], c-Kit, EphA-2, and platelet-derived growth factor [PDGF]-β), is an antineoplastic agent.1 Dasatinib is a thiazolecarboxamide that is structurally unrelated to imatinib.3
The Philadelphia chromosome, characteristic of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL), is created by a reciprocal translocation between chromosomes 9 and 22.5, 6, 7, 8, 9 Translocation between these chromosomes results in production of an abnormal protein (Bcr-Abl tyrosine kinase) that exhibits enhanced tyrosine kinase activity (i.e., increased phosphorylation of tyrosine residues);5, 6, 9 phosphorylation of tyrosine residues on growth factor receptors is thought to be important in stimulating cell proliferation and inhibiting cell death (apoptosis).6 Dasatinib inhibits Bcr-Abl tyrosine kinase, thereby inhibiting tyrosine phosphorylation of proteins involved in Bcr-Abl signal transduction.1 In vitro, the drug has been shown to inhibit the growth of CML and ALL cell lines overexpressing Bcr-Abl.1
Data from in vitro studies indicate that dasatinib may overcome imatinib resistance resulting from Bcr-Abl kinase domain mutations, activation of alternate signaling pathways involving the Src family kinases (Lyn, Hck), and multi-drug-resistance gene overexpression.1 In preclinical studies in cell-line models, dasatinib inhibited most (18 of 19) imatinib-resistant Bcr-Abl kinase domain mutant forms.2, 3
Systemic exposure to dasatinib is dose proportional over a dose range of 15-240 mg daily.1 Following oral administration, peak plasma concentrations of dasatinib are achieved at 0.5-6 hours.1 The AUC of dasatinib film-coated tablets (Sprycel®; single 100 mg dose) increased by 14% following coadministration with a high-fat meal;1 no clinically significant differences in AUC were observed after dasatinib tablets (Phyrago®) were administered with a high-fat meal.39 Dasatinib is 96% bound to plasma proteins in vitro.1 Dasatinib is extensively metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by the isoenzyme 3A4.1 An active metabolite, formed principally by CYP3A4, is approximately equipotent to dasatinib but accounts for only about 5% of total plasma concentrations of the drug.1 Following oral administration of a single radiolabeled dose of dasatinib, approximately 85% of the radioactivity was recovered in feces and 4% was recovered in urine within 10 days; unchanged drug accounted for 19% of the dose recovered in feces and 0.1% of the dose recovered in urine, with the remainder being metabolites.1 The mean terminal half-life of dasatinib film-coated tablets (Sprycel®) is 3-5 hours and 5 hours for dasatinib tablets (Phyrago®).1
The pharmacokinetics of dasatinib were evaluated in 43 pediatric patients with leukemia or solid organ tumors at oral doses ranging between 60-120 mg/m2.1 Systemic exposure to dasatinib was dose proportional.1 Following oral administration, peak plasma concentrations of dasatinib were achieved in 0.5-6 hours.1 Dasatinib clearance and volume of distribution change with body weight in pediatric patients.1 The mean terminal half-life of dasatinib was 2-5 hours.1 The bioavailability of dispersed tablets is estimated to be 36% lower when compared to that of intact tablets in pediatric patients.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 20 mg | Phyrago® | Nanocopoeia |
50 mg | Phyrago® | Nanocopoeia | ||
70 mg | Phyrago® | Nanocopoeia | ||
80 mg | Phyrago® | Nanocopoeia | ||
100 mg | Phyrago® | Nanocopoeia | ||
140 mg | Phyrago® | Nanocopoeia | ||
Tablets, film-coated | 20 mg | |||
50 mg | Sprycel® | Bristol Myers-Squibb | ||
70 mg | Sprycel® | Bristol Myers-Squibb | ||
80 mg | Sprycel® | Bristol Myers-Squibb | ||
100 mg | Sprycel® | |||
140 mg | Sprycel® | Bristol Myers Squibb |
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