Dasatinib (Monograph)
Brand names: Phyrago, Sprycel
Drug class: Antineoplastic Agents
Introduction
Antineoplastic agent; a kinase inhibitor.
Uses for Dasatinib
Chronic Myelogenous Leukemia (CML)
Treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) CML in adults who are in the chronic phase of the disease.
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.
Treatment of Ph+ CML in pediatric patients ≥1 year of age who are in the chronic phase of the disease (Sprycel only).
Designated an orphan drug by FDA for use in the treatment of CML.
Acute Lymphocytic (Lymphoblastic) Leukemia (ALL)
Treatment of Philadelphia chromosome-positive (Ph+) ALL in adults following failure (secondary to resistance or intolerance) of prior therapy.
In combination with chemotherapy for the treatment of newly diagnosed Ph+ ALL in pediatric patients ≥1 year of age (Sprycel only).
Designated an orphan drug by FDA for use in the treatment of ALL.
Dasatinib Dosage and Administration
General
Pretreatment Screening
-
Obtain CBC.
-
Correct electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia) prior to initiating therapy.
-
Correct uric acid levels prior to initiating therapy.
-
Monitor transaminases at baseline.
Patient Monitoring
- Adult Patients
-
Adults with CML in chronic phase: Monitor CBC every 2 weeks during the first 3 months of therapy and then every 3 months (or as clinically indicated) thereafter.
-
Adults with accelerated phase CML or Ph+ ALL: Monitor CBC weekly during the first 2 months of therapy and monthly (or as clinically indicated) thereafter.
-
Monitor electrolytes, particularly potassium and magnesium, periodically during therapy.
-
Monitor for signs and symptoms of cardiac toxicity.
-
Monitor transaminases monthly or as clinically indicated during therapy.
- Pediatric Patients
-
Pediatric patients with CML in chronic phase: Monitor CBC every 2 weeks during the first 3 months of therapy and then every 3 months (or as clinically indicated) thereafter.
-
Pediatric patients with Ph+ ALL: Monitor CBC as clinically indicated; during consolidation chemotherapy, obtain CBC every 2 days until recovery.
-
Monitor electrolytes, particularly potassium and magnesium, periodically during therapy.
-
Monitor for signs and symptoms of cardiac toxicity.
-
Monitor bone growth and development.
-
Monitor transaminases monthly or as clinically indicated during therapy.
Dispensing and Administration Precautions
- Handling and Disposal
-
Consult specialized references for procedures for proper handling (e.g., use of gloves) and disposal of antineoplastics.
-
Dasatinib may cause fetal harm; pregnant females should not handle crushed or broken dasatinib tablets.
Other General Considerations
-
Maintain adequate hydration throughout therapy.
Administration
Oral Administration
Administer orally once daily without regard to meals.
Administer at the same time each day.
Swallow tablets whole; do not cut, chew, or crush.
If a dose is missed, take the next dose at its regular time. Do not take two doses at the same time.
Dosage
Pediatric Patients
CML
Chronic Phase
OralPediatric patients ≥1 year of age: Dosage is based on body weight as described in Table 1. Recalculate dosage every 3 months or more frequently if necessary to account for changes in body weight.
Tablet dosing not recommended in pediatric patients weighing <10 kg.
In clinical studies, treatment was continued until evidence of disease progression or until no longer tolerated by the patient.
Effect of discontinuance of treatment after achievement of a complete cytogenetic response not established.
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, increase dasatinib dosage as described in Table 2.
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 |
ALL
Oral
Pediatric patients ≥1 year of age: Dosage is based on body weight as described in Table 3. Recalculate dosage every 3 months or more frequently if necessary to account for changes in body weight. In clinical studies, treatment was continued for 2 years.
Initiate therapy on or before day 15 of induction chemotherapy. Dosage escalations are not recommended for pediatric Ph+ ALL since dasatinib is administered in combination with chemotherapy.
Tablet dosing not recommended in pediatric patients weighing <10 kg.
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 |
Systemic exposure of dasatinib following administration of dasatinib tablets dispersed in juice was 36% lower compared to intact tablets in 5 patients 2–10 years of age with Ph+ ALL. Efficacy and safety of dispersing dasatinib tablets not established.
Dosage Modification for Toxicity
Nonhematologic Adverse Effects
OralIn pediatric patients with Ph+ CML, if a severe nonhematologic adverse reaction occurs, withhold dasatinib until the toxicity has resolved or improved. Thereafter, resume therapy, as appropriate, at a reduced dosage depending on severity and recurrence.
In pediatric patients with Ph+ ALL, temporarily interrupt 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 original dosage or reduced dosage (following a subsequent episode) as described in Table 4. 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 4.
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 4.
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 |
Hematologic Adverse Effects
OralTemporary interruption, dosage reduction, or discontinuance is indicated in patients experiencing severe neutropenia and/or thrombocytopenia. Hematopoietic growth factor has been used in patients with resistant myelosuppression.
In pediatric patients with Ph+ CML experiencing persistent (>3 weeks) neutropenia or thrombocytopenia unrelated to leukemia (as determined by bone marrow aspirate or biopsy), withhold treatment. Treatment may be resumed at the original starting dosage or at a reduced dosage as described in Table 5 when ANC resolves to ≥1000/mm3 and platelet counts resolve to ≥75,000/mm3. If neutropenia or thrombocytopenia recurs, repeat bone marrow aspirate or biopsy and resume dasatinib at a reduced dosage (Table 5).
Original Starting Dose |
One-level Dose |
Two-level Dose |
---|---|---|
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 |
In pediatric patients with chronic phase CML experiencing grade 3 or higher neutropenia or thrombocytopenia during complete hematologic response, temporarily withhold therapy and resume at a reduced dosage. Temporary dosage reductions may be necessary for intermediate degrees of cytopenia and disease response.
Pediatric patients with Ph+ ALL: If neutropenia and/or thrombocytopenia delay the next cycle by >14 days, interrupt dasatinib therapy and resume at the same dosage once the next cycle starts. 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. If marrow cellularity is less than 10%, interrupt treatment untilANC >500/mm3, at which time treatment may be resumed at full dosage. If bone marrow cellularity is greater than 10%, consider resuming therapy.
Dosage Modification for Concomitant Therapy with CYP3A4 Inducers or Inhibitors
Dosage modifications are necessary when dasatinib is used concomitantly with strong inducers or inhibitors of CYP3A4 (see Drugs Affecting Hepatic Microsomal Enzymes under Drug Interactions).
Adults
CML
Chronic Phase
OralRecommended initial dosage is 100 mg once daily. If hematologic or cytogenetic response is not achieved, increase dosage to 140 mg once daily.
In clinical studies, treatment was continued until evidence of disease progression or until no longer tolerated by the patient.
Optimal duration of therapy has not been established.
Effect of discontinuance of treatment after achievement of a complete cytogenetic response not established.
Accelerated or Myeloid or Lymphoid Blast Phase
OralRecommended initial dosage is 140 mg once daily. If hematologic or cytogenetic response is not achieved, increase dosage to 180 mg once daily.
In clinical studies, treatment was continued until evidence of disease progression or until no longer tolerated by the patient.
Optimal duration of therapy has not been established.
Effect of discontinuance of treatment after achievement of a complete cytogenetic response not established.
ALL
Oral
Recommended initial dosage is 140 mg once daily. If hematologic or cytogenetic response is not achieved, increase dosage to 180 mg once daily.
Optimal duration of therapy has not been established.
Effect of discontinuance of treatment after achievement of a complete cytogenetic response not established.
Dosage Modification for Toxicity
Nonhematologic Adverse Effects
OralIf a severe nonhematologic adverse reaction occurs, withhold dasatinib until the toxicity has resolved or improved. Thereafter, resume therapy, as appropriate, at a reduced dosage depending on severity and recurrence.
Hematologic Adverse Effects
OralTemporary interruption, dosage reduction, or discontinuance is indicated in patients experiencing severe neutropenia and/or thrombocytopenia. Hematopoietic growth factor has been used in patients with resistant myelosuppression.
Adults with Chronic Phase CML: Dasatinib therapy should be withheld if ANC decreases to less than 500/mm3 or platelet counts decrease to less than 50,000/mm3. 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.
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. 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.
Following a third episode of neutropenia or thrombocytopenia, in which ANC decreases to less than 500/mm3for 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. However, dasatinib should be discontinued following a third such episode in patients receiving the drug following failure of prior therapy including imatinib.
Adults with Accelerated Phase or Blast Phase CML: Dasatinib therapy should be withheld 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). 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. Treatment should again be withheld if the ANC decreases to less than 500/mm3 or platelet counts decrease to less than 10,000/mm3. 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.
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), consider dosage escalation to 180 mg once daily.
Adults with Ph+ALL: Withhold therapy 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). 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. Treatment should again be withheld if ANC decreases to less than 500/mm3 or platelet counts decrease to less than 10,000/mm3. 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.
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), consider dosage escalation to 180 mg once daily.
Dosage Modification for Concomitant Therapy with CYP3A4 Inducers or Inhibitors
Dosage modifications are necessary when dasatinib is used concomitantly with strong inducers or inhibitors of CYP3A4 (see Drugs Affecting Hepatic Microsomal Enzymes under Drug Interactions).
Special Populations
Hepatic Impairment
No specific dosage recommendations at this time.
Renal Impairment
No specific dosage recommendations at this time.
Geriatric Patients
No specific dosage recommendations at this time.
Cautions for Dasatinib
Contraindications
-
None.
Warnings/Precautions
Hematologic Effects
Myelosuppression (principally severe neutropenia, anemia, and thrombocytopenia) occurs commonly and is usually reversible; more frequent in patients in the accelerated or blast phase of CML and in those with Ph+ ALL than in patients in the chronic phase of CML.
Temporary suspension of therapy or dosage reduction may be required if hematologic toxicity occurs, or discontinuation of treatment.
In patients with chronic phase CML, perform CBC every 2 weeks during the first 3 months of therapy and then every 3 months (or as clinically indicated) thereafter. In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly during the first 2 months of therapy and monthly (or as clinically indicated) thereafter.
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.
Hemorrhage
Risk of severe hemorrhage, including potentially fatal CNS or GI hemorrhage; usually associated with severe thrombocytopenia.
Severe hemorrhage may require treatment interruption and transfusions.
Use with caution in patients receiving anticoagulants or drugs that inhibit platelet function.
Fluid Retention
Risk of potentially severe fluid retention (i.e., pleural effusion, pericardial effusion, pulmonary edema, ascites, generalized edema).
Fluid retention generally managed with supportive care (e.g., diuretics, short course of corticosteroids).
Evaluate 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) by chest radiograph. Severe pleural effusion may require thoracentesis and oxygen therapy. Consider dosage reduction or interruption of therapy if fluid retention occurs.
Cardiac Effects
May cause cardiac dysfunction or prolongation of the QT interval.
Use 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). Correct hypokalemia or hypomagnesemia prior to administration of dasatinib.
Pulmonary Arterial Hypertension (PAH)
May increase risk for development of PAH. May occur at any time after initiation of therapy (e.g., 8–60 months); reported most often in patients with comorbidities or receiving other drugs concomitantly. May be reversible upon discontinuance of dasatinib.
Evaluate patient for manifestations of cardiopulmonary disease before and during dasatinib therapy. Consider PAH in any patient with dyspnea, fatigue, hypoxia, and fluid retention; however, exclude other etiologies of dyspnea prior to initiating invasive diagnostic procedures for PAH.
Interruption of therapy accompanied by monitoring for improvement may be considered if PAH is suspected. If PAH is confirmed (e.g., by cardiac catheterization), permanently discontinue the drug.
Severe Dermatologic Reactions
May cause severe dermatological reactions, including Stevens-Johnson syndrome and erythema multiforme.
Permanently discontinue in patients experiencing a severe dermatological reaction during treatment and no other etiology for the reaction can be identified.
Tumor Lysis Syndrome
May increase risk of tumor lysis syndrome, generally in patients with imatinib-resistant disease in an advanced phase.
Due to potential for tumor lysis syndrome, maintain adequate hydration, correct uric acid levels prior to initiating therapy with dasatinib, and monitor electrolyte levels during therapy. 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.
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; embryofetal toxicity and teratogenicity have been reported in humans. Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
Females of reproductive potential and males with such female partners should use effective forms of contraception during therapy and for 30 days after the last dose.
Females who are pregnant should not handle crushed or broken dasatinib tablets.
Effects on Growth and Development of Pediatric Patients
May affect bone growth and development in pediatric patients.
Monitor bone growth and development during therapy in pediatric patients.
Hepatotoxicity
Hepatotoxicity with increases in bilirubin, AST, ALT, and alkaline phosphatase reported. Monitor transaminases at baseline and monthly or as clinically indicated during therapy. Reduce or withhold the dasatinib dose or permanently discontinue therapy based on hepatotoxicity severity. When administered with chemotherapy, transaminase elevations and hyperbilirubinemia reported. Monitor hepatic function when dasatinib is used in combination with chemotherapy.
Lactose-intolerant Patients
140-mg daily dosage of dasatinib (Sprycel) contains 189 mg of lactose monohydrate; 100-mg daily dosage of dasatinib (Sprycel) contains 135 mg of lactose monohydrate. Dasatinib (Phyrago) tablets do not contain lactose.
Specific Populations
Pregnancy
May cause fetal harm.
Lactation
Not known whether dasatinib is distributed into human milk. Discontinue nursing because of potential risk to nursing infants.
Pediatric Use
Monitor bone growth and development in pediatric patients.
Pediatric labeled indications are approved for Sprycel tablets. However, due to marketing exclusivity rights, the Phyrago preparation is not labeled for pediatric indications.
Safety and efficacy not established in patients <18 years of age with previously treated Ph+ accelerated or myeloid or lymphoid blast phase CML.
Safety and efficacy of dasatinib (Sprycel) monotherapy evaluated in pediatric patients ≥1 year of age with newly diagnosed chronic phase CML. Safety and efficacy of dasatinib (Sprycel) also demonstrated in pediatric patients ≥1 year of age with newly diagnosed Ph+ ALL. No data in pediatric patients <1 year of age.
Adverse effects on bone growth and development and grade 1 osteopenia reported in pediatric patients. Overall, safety profile in pediatric patients is comparable to that reported in adult patients.
Systemic exposure of dasatinib following administration of dasatinib tablets dispersed in juice was 36% lower compared to intact tablets in 5 patients 2–10 years of age with Ph+ ALL. Efficacy and safety of dispersing dasatinib tablets not been established.
Geriatric Use
No substantial difference in efficacy relative to younger adults, but patients ≥65 years of age are more likely to experience toxicity.
Hepatic Impairment
Reduced peak plasma concentration and AUC of dasatinib in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) as compared to patients with normal hepatic function.
Renal Impairment
Renal impairment not expected to decrease dasatinib clearance.
Creatinine clearance of 21.6 mL/minute had no clinically relevant effect on the pharmacokinetics of dasatinib.
Common Adverse Effects
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, musculoskeletal pain.
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, altered state of consciousness.
Drug Interactions
Metabolized principally by CYP3A4; weak inhibitor of CYP3A4.
Does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1; does not induce human CYP isoenzymes.
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma dasatinib concentrations). Consider alternative drugs with no or less enzyme inhibition potential. If concomitant use with a strong CYP3A4 inhibitor cannot be avoided, consider reducing dasatinib dosage to 20 mg daily (if current dosage is 70 or 100 mg daily) or to 40 mg daily (if current dosage is 140 mg daily) based on pharmacokinetic considerations (no clinical data with these dosage adjustments available). In patients taking a current dasatinib dosage of 40 or 60 mg, consider interrupting dasatinib therapy until the inhibitor is discontinued. If dasatinib is not tolerated following dosage reduction, discontinue the CYP3A4 inhibitor or interrupt dasatinib therapy until treatment with the CYP3A4 inhibitor is completed. Upon discontinuance of a potent CYP3A4 inhibitor, allow approximately 1 week to elapse before increasing dasatinib dosage.
Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma dasatinib concentrations). Avoid concomitant use of strong CYP3A4 inducers; consider alternative drugs with no or less enzyme induction potential. If concomitant therapy cannot be avoided, consider increase in dasatinib dosage and closely monitor patient for toxicity.
Drugs Affecting Coagulation
Potential for bleeding; use anticoagulants and drugs that inhibit platelet function concomitantly with caution.
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP3A4: Potential pharmacokinetic interaction (increased plasma substrate concentrations).
Specific Drugs and Foods
Drug or Food |
Interaction |
Comments |
---|---|---|
Antacids (e.g., calcium carbonate, aluminum and magnesium hydroxides) |
Possible decreased plasma dasatinib concentrations, secondary to apparent pH-dependence of dasatinib solubility Dasatinib AUC unchanged when administered 2 hours after antacid (aluminum and magnesium hydroxides) but decreased 55% when administered concomitantly with antacid |
Administer antacids ≥2 hours before or ≥2 hours after a dose of dasatinib |
Anticoagulants (e.g., warfarin) |
Possible increased risk of hemorrhage |
Use concomitantly with caution |
Antifungals, azoles (i.e., itraconazole, ketoconazole, voriconazole) |
Possible increased plasma dasatinib concentrations and increased exposure to dasatinib Ketoconazole: Increased dasatinib AUC by fivefold and peak concentration by fourfold |
Avoid concomitant use if possible; if concomitant therapy necessary, closely monitor for toxicity and consider reducing dasatinib dosage |
Grapefruit juice |
Possible increased plasma dasatinib concentrations |
Avoid concomitant use |
Histamine H2-receptor antagonists (e.g., cimetidine, famotidine, ranitidine) |
Possible decreased plasma dasatinib concentrations, secondary to apparent pH-dependence of dasatinib solubility Famotidine: Decreased dasatinib AUC and peak concentration by 61–63% when given 10 hours before dasatinib |
Concomitant use not recommended |
Proton-pump inhibitors (e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) |
Possible decreased plasma dasatinib concentrations, secondary to apparent pH-dependence of dasatinib solubility Omeprazole: Decreased dasatinib AUC and peak concentration by 42–43% when given 22 hours before dasatinib |
Concomitant use not recommended |
Rifamycins (rifabutin, rifampin) |
Possible decreased plasma dasatinib concentrations and AUC of dasatinib Rifampin: Decreased dasatinib AUC and peak concentration by 81–82% |
Avoid concomitant use if possible; if concomitant therapy necessary, consider increasing dasatinib dosage and closely monitor for toxicity |
St. John’s wort (Hypericum perforatum) |
Potential for unpredictable decreases in plasma dasatinib concentrations |
Concomitant use not recommended |
Dasatinib Pharmacokinetics
Absorption
Bioavailability
Bioavailability of dispersed tablets is estimated to be 36% lower in pediatric patients.
Onset
Following oral administration, peak plasma concentrations are attained within 0.5–6 hours in adult and pediatric patients.
Special Populations
In patients with moderate or severe hepatic impairment (Child-Pugh class B or C), peak plasma concentrations and AUC (normalized for differences in administered doses) are lower than in healthy individuals; differences not considered clinically important.
No clinically relevant effects of age and gender on pharmacokinetics.
Food
AUC of dasatinib (Sprycel; single 100-mg dose) increased by 14% following administration with a high-fat meal. No clinically significant differences observed after dasatinib (Phyrago) administration with a high-fat meal.
Distribution
Extent
Extensively distributed into the extravascular space.
Volume of distribution changes with body weight in pediatric patients.
Plasma Protein Binding
Approximately 96 and 93% for dasatinib and active metabolite, respectively.
Elimination
Metabolism
Metabolized in the liver, principally by CYP3A4, to an active metabolite and several inactive metabolites.
Elimination Route
Eliminated principally in feces (85%) mainly as metabolites and to a lesser extent in urine (4%).
Half-life
Adults: 3–5 hours for dasatinib film-coated tablets (Sprycel); 5 hours for dasatinib tablets (Phyrago).
Pediatric patients: 2–5 hours.
Stability
Storage
Oral
Tablets
20–25°C (excursions permitted between 15–30°C).
Tablets, film-coated
20–25°C (excursions permitted between 15–30°C).
Actions
-
Inhibits multiple tyrosine kinases including Bcr-Abl, the Src family (Src, Lck, Yes, Fyn), c-Kit, EphA-2, and platelet-derived growth factor (PDGFR)-β; predicted to bind to multiple conformations of the Abl kinase.
-
Inhibits Bcr-Abl tyrosine kinase, an abnormal protein created by the Philadelphia chromosome abnormality in CML and Ph+ ALL that exhibits enhanced tyrosine kinase activity (i.e., increased phosphorylation of tyrosine residues).
-
Overcomes imatinib resistance resulting from Bcr-Abl kinase domain mutations, activation of alternate signaling pathways involving the Src family kinases (Lyn, Hck), and multidrug-resistance gene overexpression.
Advice to Patients
-
Adivse patients to swallow dasatinib tablets whole with water and not to break, chew, cut, or crush the tablets. Advise patients to avoid grapefruit juice while taking the drug.
-
Advise patients that if a dose of dasatinib is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.
-
Advise patients who are taking Sprycel film-coated tablets to inform their clinician if they are lactose intolerant. Phyrago tablets do not contain lactose.
-
Advise patients to inform their clinician if they experience fever or other symptoms of infection, any bleeding or bruising, difficulty in breathing, swelling, weight gain, or increasing shortness of breath.
-
Advise patients to inform their clinician if they experience symptoms of liver problems (e.g., abdominal pain, yellowing of the skin or whites of the eyes, loss of appetite, bleeding, bruising, dark "tea-colored" urine).
-
Advise patients of other common adverse effects, including diarrhea, rash, headache, musculoskeletal pain, fatigue, and nausea.
-
Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise females and males with female partners of reproductive potential to use an effective method of contraception during and for 30 days after treatment. Females should avoid breast-feeding during dasatinib therapy and for 2 weeks after the final dose. Advise women who are pregnant to avoid handling crushed or broken dasatinib tablets.
-
Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.
-
Inform patients of other important precautionary information.
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].
Preparations
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 |
Sprycel |
Bristol Myers-Squibb |
|
50 mg |
Sprycel |
Bristol Myers-Squibb |
||
70 mg |
Sprycel |
Bristol Myers-Squibb |
||
80 mg |
Sprycel |
Bristol Myers-Squibb |
||
100 mg |
Sprycel |
Bristol Myers-Squibb |
||
140 mg |
Sprycel |
Bristol Myers Squibb |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions April 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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