Dasatinib (Monograph)

Brand name: Sprycel
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
VA class: AN900
Chemical name: N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate
Molecular formula: C₂₂H₂₆C₁N₇O₂S • H₂O
CAS number: 863127-77-9

Medically reviewed by Drugs.com on Feb 14, 2022. Written by ASHP.

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 myeloid or lymphoid blast crisis, in the accelerated phase, or in the chronic 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.

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.

Designated an orphan drug by FDA for use in the treatment of acute ALL.

Other Uses

Has been used for the treatment of Noonan-syndrome^{† [off-label]} associated with hypertrophic cardiomyopathy. Designated an orphan drug by FDA for use in this condition.

Has been used for the treatment of gastrointestinal stromal tumors (GIST)^{† [off-label]}.

Dasatinib Dosage and Administration

General

Pretreatment Screening

• Complete blood cell count (CBC).

• Correct electrolyte abnormalities (e.g. hypokalemia, hypomagnesemia) prior to initiating therapy.

• Correct uric acid levels prior to initiating therapy.

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.

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.

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 (morning or evening) 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

Oral

≥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 patients who do not achieve a hematologic or cytogenetic response at the recommended initial dosage, increase dasatinib dosage as described in Table 2.

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.

Continue treatment until evidence of disease progression or until no longer tolerated by the patient.

Optimal duration of therapy has not been clearly established.

ALL

Oral

≥1 year of age (in combination with chemotherapy): 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. Continue therapy 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.

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

Nonhematologic Adverse Effects

Oral

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 the initial severity of the event.

In pediatric patients with Ph⁺ ALL, temporarily interrupt therapy if grade 2 nonhematologic toxicity occurs; when the toxicity improves to grade 1 or less, resume therapy at original dosage or reduce 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.

If elevated direct bilirubin concentrations >5 times the ULN or AST/ALT concentration >15 times the ULN occurs, temporarily interrupt therapy; when toxicity resolves to grade 1 or less, resume therapy at the original dosage or reduce dosage (following a subsequent episode) as described in Table 4.

Hematologic Adverse Effects

Oral

In patients in the chronic phase of CML experiencing grade 3 or higher neutropenia or thrombocytopenia during complete hematologic response, temporarily withhold therapy. May resume dasatinib therapy at a reduced dosage. Temporary dosage reductions may be necessary for intermediate degrees of neutropenia and thrombocytopenia and disease response.

In patients with Ph⁺ ALL experiencing persistent (>3 weeks) neutropenia or thrombocytopenia unrelated to ALL (as determined by bone marrow aspirate or biopsy). 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). 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 bone marrow cellularity is <10%, interrupt treatment with dasatinib until ANC >500/mm³. If neutropenia and/or thrombocytopenia recur and delay the next cycle by 7 days, repeat bone marrow aspirate or biopsy. If marrow cellularity is less than 10%, treatment may be resumed at the full dosage once ANC exceeds 500/mm³. If bone marrow cellularity is greater than 10%, consider resuming therapy.

Adults

CML

Chronic Phase

Oral

100 mg once daily. If hematologic or cytogenetic response is not achieved, increase dosage to 140 mg once daily.

Continue treatment until evidence of disease progression or until no longer tolerated by the patient.

Optimal duration of therapy has not been clearly established.

Accelerated Phase or Blast Crisis

Oral

140 mg once daily. If hematologic or cytogenetic response is not achieved, increase dosage to 180 mg once daily.

Continue treatment until evidence of disease progression or until no longer tolerated by the patient.

Optimal duration of therapy has not been clearly established.

ALL

Oral

140 mg once daily. If hematologic or cytogenetic response is not achieved, increase dosage to 180 mg once daily.

Continue treatment until evidence of disease progression or until no longer tolerated by the patient.

Optimal duration of therapy has not been clearly established.

Dosage Modification for Toxicity

Nonhematologic Adverse Effects

Oral

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 the initial severity of the event.

Adverse Hematologic Effects

Oral

Temporary interruption, dosage reduction, or discontinuance is indicated in patients experiencing severe neutropenia and/or thrombocytopenia (see Tables 6 and 7). Hematopoietic growth factor has been used in patients with resistant myelosuppression.

Special Populations

Hepatic Impairment

No special dosage recommendations at this time.

Renal Impairment

No special dosage recommendations at this time.

Geriatric Patients

No special dosage recommendations at this time.

Cautions for Dasatinib

Contraindications

• No known contraindications.

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.

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 advance 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.

Lactose-intolerant Patients

140-mg daily dosage contains 189 mg of lactose monohydrate; 100-mg daily dosage contains 135 mg of lactose monohydrate.

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.

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 monotherapy evaluated in pediatric patients ≥1 year of age with newly diagnosed chronic phase CML. Safety and efficacy also has been 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

Not studied in patients with hepatic impairment (ALT and/or AST >2.5 times ULN and/or total bilirubin >2 times ULN); however the drug is metabolized extensively in the liver.

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 patients receiving dasatinib as monotherapy myelosuppression, fluid retention, diarrhea, headache, rash, hemorrhage, dyspnea, fatigue, nausea, and 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, and altered state of consciousness.

Interactions for Dasatinib

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 potent 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). Consider stopping dasatinib 40 or 60 mg if a CYP3A4 inhibitor is necessary. 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 potent 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

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 (single 100-mg dose) increased by 14% following 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.

Pediatric patients: 2–5 hours.

Stability

Storage

Oral

Tablets

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

• Importance of taking only as prescribed. Take at about the same time each day; do not discontinue therapy without first consulting clinician.

• Importance of advising patients to swallow dasatinib tablets whole with water and not to break, chew, cut, or crush the tablets. Importance of not drinking grapefruit juice while taking the drug.

• Risk of severe fluid retention, bleeding, and cytopenia. Importance of immediately informing clinician if fever, any bleeding or bruising, swelling, weight gain, or increasing shortness of breath occurs.

• Importance of close medical supervision in patients receiving dasatinib.

• Importance of informing clinicians if patient is lactose intolerant.

• Importance of advising females to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Importance of advising 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. Importance of advising women who are pregnant to avoid handling crushed or broken dasatinib tablets.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

Reload page with references included

Frequently asked questions

• How long does it take Sprycel (dasatinib) to start working?
• Is Sprycel a chemotherapy drug?

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