dasatinib (Rx)

Brand and Other Names:Sprycel
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 20mg
  • 50mg
  • 70mg
  • 80mg
  • 100mg
  • 140mg

Chronic Myeloid Leukemia

Also see Administration

Newly diagnosed

  • Indicated for newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase
  • Start 100 mg PO qDay (morning or evening)
  • May increase to 140 mg qDay if inadequate response

Advanced CML

  • Indicated for treatment of chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
  • Start 140 mg PO qDay
  • May increase to 180 mg qDay if inadequate response

Acute Lymphoblastic Leukemia

Indicated for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy

Start 140 mg PO qDay

May increase to 180 mg PO qDay if inadequate response

Dosage Modifications

Hepatic Impairment

  • Mild-to-moderate (Child Pugh A to B): No dosage adjustment necessary
  • Severe (Child Pugh C): Decreases mean Cmax by 43% and in mean AUC by 28% compared to normal liver function subjects

Gastric acid reducing agents

  • Do not administer H2 antagonists or proton pump inhibitors with dasatinib; consider the use of antacids in place of H2 antagonists or proton pump inhibitors
  • Administer the antacid at least 2 hr prior to or 2 hr after dasatinib dose
  • Avoid simultaneous administration of dasatinib with antacids

Concomitant strong CYP3A4 inducers

  • Avoid use
  • If coadministration of strong CYP3A4 inducer is unavoidable, consider increasing dasatinib dose and monitor for toxicity

Concomitant strong CYP3A4 inhibitors

  • Avoid use
  • Recommend an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible
  • Recommended dosage adjustment if concomitant strong CYP3A4 inhibitors must be administered
    • Patient currently taking 140 mg PO qDay: Decrease to 40 mg PO qDay
    • Patient currently taking 100 mg PO qDay: Decrease to 20 mg PO qDay
    • Patient currently taking 70 mg PO qDay: Decrease to 20 mg PO qDay
    • Patients currently taking 40 or 60 mg PO qDay: Hold treatment until inhibitor is discontinued
    • If therapy is not tolerated after dose reduction, either discontinue strong CYP3A4 inhibitor or interrupt dasatinib until inhibitor is discontinued; allow a washout period of ~1 week after inhibitor is stopped before increasing dose of dasatinib

Dose adjustments for neutropenia and thrombocytopenia

  • ANC <0.5 X 10^9 or platelets <10 X 10^9
  • Chronic Phase CML
    • Hold treatment until ANC ≥1.0 X 10^9/L and platelets ≥50 X 10^9/L
    • Resume treatment at original starting dose if recovery occurs in ≤7 days
    • If platelets <25 x 10^9/L or recurrence of ANC <0.5 x 10^9/L for >7 days, hold treatment until ANC ≥1.0 X 10^9/L and platelets ≥50 X 10^9/L and resume at a reduced dose of 80 mg PO qDay for second episode
    • For third episode, further reduce dose to 50 mg PO qDay (for newly diagnosed patients) or discontinue dasatinib (for patients resistant or intolerant to prior therapy including imatinib)
  • Accelerated phase CML, blast phase CML and Ph+ ALL
    • Check if cytopenia is related to leukemia (marrow aspirate or biopsy)
    • If cytopenia is unrelated to leukemia, hold dasatinib until ANC ≥1 X 10^9/L and platelets ≥20 X 10^9/L and resume at original starting dose
    • Recurrence of cytopenia, check if cytopenia is related to leukemia and resume dasatinib at a reduced dose of 100 mg PO qDay (second episode) or 80 mg PO qDay (third episode)
    • If cytopenia is related to leukemia, consider dose escalation to 180 mg PO qDay

Dosing Considerations

In clinical studies, dasatinib in adults, children, and adolescents patients was continued until disease progression or unacceptable toxicity

The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response or major molecular response has not been established

Dosage Forms & Strengths

tablet

  • 20mg
  • 50mg
  • 70mg
  • 80mg
  • 100mg
  • 140mg

Acute Lymphoblastic Leukemia

Indicated for patients (≥1 year) with newly diagnosed Ph+ ALL in combination with chemotherapy

Begin therapy on or before day 15 of induction chemotherapy, when diagnosis is confirmed and continue for 2 years

Recommended initial dosage based on body weight

  • <10 kg: Not recommended
  • 10 to <20 kg: 40 mg PO qDay
  • 20 to <30 kg: 60 mg PO qDay
  • 30 to <45 kg: 70 mg PO qDay
  • ≥45 kg: 100 mg PO qDay

Chronic Myeloid Leukemia

Indicated for patients (≥1 year) with Ph+ CML in chronic phase

Recommended initial dosage based on body weight

  • <10 kg: Not recommended
  • 10 to <20 kg: 40 mg PO qDay
  • 20 to <30 kg: 60 mg PO qDay
  • 30 to <45 kg: 70 mg PO qDay
  • ≥45 kg: 100 mg PO qDay

Recommended dose escalation if hematological or cytogenetic response is not achieved

  • Starting dose 40 mg PO qDay: May increase 50 mg PO qDay
  • Starting dose 60 mg PO qDay: May increase 70 mg PO qDay
  • Starting dose 70 mg PO qDay: May increase 90 mg PO qDay
  • Starting dose 100 mg PO qDay: May increase 120 mg PO qDay

Also see Administration

Dosage Modifications

Hepatic impairment

  • Mild-to-moderate (Child Pugh A to B): No dosage adjustment necessary
  • Severe (Child Pugh C): Decreases mean peak plasma concentration by 43% and in mean AUC by 28% compared to normal liver function subjects

Gastric acid reducing agents

  • Do not administer H2 antagonists or proton pump inhibitors with dasatinib; consider the use of antacids in place of H2 antagonists or proton pump inhibitors
  • Administer the antacid at least 2 hr prior to or 2 hr after dasatinib dose
  • Avoid simultaneous administration of dasatinib with antacids

Concomitant strong CYP3A4 inducers

  • Avoid use
  • If coadministration of strong CYP3A4 inducer is unavoidable, consider increasing dasatinib dose and monitor for toxicity

Concomitant strong CYP3A4 inhibitors

  • Avoid use
  • Recommend an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible
  • Recommended dosage adjustment if concomitant strong CYP3A4 inhibitors must be administered
    • Patient currently taking 140 mg PO qDay: Decrease to 40 mg PO qDay
    • Patient currently taking 100 mg PO qDay: Decrease to 20 mg PO qDay
    • Patient currently taking 70 mg PO qDay: Decrease to 20 mg PO qDay
    • Patients currently taking 40 or 60 mg PO qDay: Hold treatment until inhibitor is discontinued
    • If therapy is not tolerated after dose reduction, either discontinue strong CYP3A4 inhibitor or interrupt dasatinib until inhibitor is discontinued; allow a washout period of ~1 week after inhibitor is stopped before increasing dose of dasatinib

Dose adjustments for neutropenia and thrombocytopenia

  • Cytopenia persists for >3 weeks, check if cytopenia is related to leukemia (marrow aspirate or biopsy)
  • Cytopenia is unrelated to leukemia, stop treatment until ANC ≥1 X 10^9/L and platelets ≥75 X 10^9/L and resume at original starting dose or at a reduced dose
  • Cytopenia recurs, repeat marrow aspirate/biopsy and resume at a reduced dose
  • Patients with chronic phase CML: If Grade ≥3 neutropenia or thrombocytopenia recurs during complete hematologic response (CHR), interrupt treatment and resume at a reduced dose; implement temporary dose reductions for intermediate degrees of cytopenia and disease response as needed
  • Patients with Ph+ ALL: Neutropenia and/or thrombocytopenia delays next block of treatment by > 14 days; interrupt dose and resume at the same dose level once the next block of treatment is started
  • Patients with Ph+ ALL: Neutropenia and/or thrombocytopenia persist and next block of treatment is delayed another 7 days; perform a bone marrow assessment to assess cellularity and percentage of blasts; if marrow cellularity <10%, interrupt treatment until ANC >500/mcL; if marrow cellularity >10%, consider resumption of treatment
  • One-level dose reduction
    • Starting dose 40 mg PO qDay: May increase 20mg PO qDay
    • Starting dose 60 mg PO qDay: May increase 40 mg PO qDay
    • Starting dose 70 mg PO qDay: May increase 60 mg PO qDay
    • Starting dose 100 mg PO qDay: May increase 80 mg PO qDay
  • Two-level dose reduction
    • Starting dose 40 mg PO qDay: Lower tablet dose not available
    • Starting dose 60 mg PO qDay: May increase 20 mg PO qDay
    • Starting dose 70 mg PO qDay: May increase 50 mg PO qDay
    • Starting dose 100 mg PO qDay: May increase 70 mg PO qDay

Dose adjustments for nonhematologic adverse reactions

  • Ph+ CML: Severe nonhematologic adverse reaction develops: Withhold treatment until the event resolves or improves; resume as appropriate at a reduced dose depending on severity and recurrence of the event
  • Ph+ ALL: Interrupt treatment for cases of Grade >3 nonhematologic adverse reactions with the exception of liver function test abnormalities, and resume at a reduced dose when resolved to Grade ≤1; if direct bilirubin is >5x ULN or AST/ALT >15x ULN, interrupt therapy until recovery to Grade ≤1 and then resume treatment at original starting dose or at a reduced dose for recurrent events
  • One-level dose reduction
    • Starting dose 40 mg PO qDay: May increase 20mg PO qDay
    • Starting dose 60 mg PO qDay: May increase 40 mg PO qDay
    • Starting dose 70 mg PO qDay: May increase 60 mg PO qDay
    • Starting dose 100 mg PO qDay: May increase 80 mg PO qDay
  • Two-level dose reduction
    • Starting dose 40 mg PO qDay: Lower tablet dose not available
    • Starting dose 60 mg PO qDay: May increase 20 mg PO qDay
    • Starting dose 70 mg PO qDay: May increase 50 mg PO qDay
    • Starting dose 100 mg PO qDay: May increase 70 mg PO qDay
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Interactions

Interaction Checker

and dasatinib

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Fluid retention, incl CHF, pulm edema, pleural effusion (50%)

            Diarrhea (49%)

            Headache (40%)

            Hemorrhage (40%)

            Fatigue (39%)

            Pyrexia (39%)

            Skin rash (35%)

            Infection (34%)

            Nausea (34%)

            Dyspnea (32%)

            Cough (28%)

            Pain (26%)

            Abdominal pain (25%)

            Vomiting (22%)

            Anorexia (19%)

            Arthralgia (19%)

            Asthenia (19%)

            Constipation (14%)

            Dizziness (14%)

            Musculoskeletal pain (14%)

            Weight loss (14%)

            Chest pain (13%)

            Neuropathy (13%)

            Myalgia (12%)

            Abdominal distention (11%)

            Arrhythmia (11%)

            Chills (11%)

            Pneumonia (11%)

            Pruritus (11%)

            Weight gain (11%)

            1-10% (selected)

            Anemia

            Febrile neutropenia

            Thrombocytopenia

            Mucosal inflammation

            Postmarketing Reports

            Cardiac disorders: Atrial fibrillation/atrial flutter

            Vascular disorders: Thrombosis/embolism (including pulmonary embolism, deep vein thrombosis)

            Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, pulmonary arterial hypertension

            Dermatologic reactions: Stevens-Johnson syndrome, erythema multiforme

            Infections: Hepatitis B virus reactivation

            Renal and urinary disorders: Nephrotic syndrome

            Blood and lymphatic system disorders: Thrombotic microangiopathy

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            Warnings

            Contraindications

            None

            Cautions

            Hypokalemia, hypomagnesemia, congenital QT interval prolongation, hepatic impairment

            Use with caution in patients who have or may develop prolongation of QT interval

            Cardiac adverse reactions were reported in 5.8% of 258 patients including cardiomyopathy (1.6%), congestive heart failure, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction; monitor patients for signs or symptoms and treat appropriately

            Tumor lysis syndrome reported; maintain adequate hydration and correct uric acid levels prior to initiating therapy

            Risk of fluid retention and pleural/pericardial effusion; manage with supportive care measures and/or dose modification

            Embryofetal toxicity reported (see Pregnancy)

            In pediatric trials of dasatinib in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported, including epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia; monitor bone growth and development in pediatric patients

            Myelosuppression including severe thrombocytopenia, neutropenia and anemia

            • May manage by dose interruption, dose reduction, or discontinuation of therapy
            • Hematopoietic growth factor has been used with resistant myelosuppression

            Patients with chronic phase CML and pediatric Ph+ ALL

            • Perform complete blood cell counts (CBCs) every 2 weeks for 12 weeks, then q3Months thereafter, or as clinically indicated
            • Perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated in patients with advanced phase CML or Ph+ ALL

            Pediatric patients with Ph+ ALL treated in combination with chemotherapy

            • Perform CBCs prior to start of each block of chemotherapy and as clinically indicated
            • During consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery

            Bleeding

            • Can cause serious and fatal bleeding; incidence of Grade 3/4 hemorrhage, most commonly gastrointestinal, reported, requiring treatment interruptions and transfusions
            • Most bleeding events associated with severe thrombocytopenia; also shown to cause platelet dysfunction in vitro
            • Concomitant medications that inhibit platelet function or anticoagulants may increase risk of hemorrhage
            • Severe hemorrhage may require treatment interruption and transfusion

            Pulmonary arterial hypertension

            • Increased risk of developing pulmonary arterial hypertension (PAH)
            • May be reversible upon discontinuation of therapy
            • Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiation and during treatment
            • If PAH confirmed permanently discontinue therapy

            Severe mucocutaneous dermatologic reactions

            • Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, reported
            • Discontinue permanently in patients who experience severe mucocutaneous reaction during treatment if no other etiology can be identified

            Drug interactions overview

            • Avoid concomitant CYP3A4 inducers/inhibitors
            • If unavoidable, consider dose modification as appropriate (see Dosage Modifications)
            • Coadministration of dasatinib with a gastric acid reducing agent may decrease the concentrations of dasatinib and reduce efficacy (see Dosage Modifications)
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            Pregnancy & Lactation

            Pregnancy

            Based on limited human data, dasatinib can cause fetal harm when administered to a pregnant woman; adverse pharmacologic effects (eg, hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia) have been reported with maternal exposure to dasatinib

            Animal reproduction studies in rats have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates; skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses; these findings occurred at dasatinib plasma concentrations below those in humans receiving therapeutic doses of dasatinib

            Advise a pregnant woman of the potential risk to a fetus

            Transplacental transfer of dasatinib has been reported

            Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraceptive methods, during treatment with dasatinib and for 30 days after the final dose

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

            Lactation

            No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production

            However, dasatinib is present in the milk of lactating rats

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Multi-kinase inhibitor that inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-Kit, EPHA2 and PDGFR-beta kinases; tyrosine kinase inhibition possibly blocks angiogenesis and cellular proliferation

            Absorption

            Peak plasma time: 0.5-6 hr

            Peak plasma concentration: 82.2 ng/mL (100 mg PO qDay)

            AUC: 397 ng/mL·hr (100 mg PO qDay)

            High-fat meal increased mean AUC of dasatinib following a single dose of 100 mg by 14%

            Distribution

            Protein Bound: 96% (dasatinib); 93% (active metabolites)

            Vd: 2505 L

            Metabolism

            Metabolism: extensively metabolized primarily by CYP3A4

            Enzymes inhibited: CYP3A4 (weak)

            Dasatinib is a P-gp substrate

            Elimination

            Half-Life: 3-5 hr

            Clearance: 363.8 l/hr

            Excretion: Feces (85%); urine (4%)

            Pharmacogenomics

            Tyrosine kinase inhibitors (TKIs) inhibit activity of BCR-ABL fusion protein, resulting in both hematologic response (ie, normal cell counts in the peripheral blood and normal bone marrow morphology), as well as cytogenetic response (ie, disappearance or reduction of the Philadelphia [Ph] chromosome)

            NCCN clinical practice guidelines recommends TKIs in CML with confirmed BCR-ABL transcripts in bone marrow or evidence of translocation on cytogenetics

            Genetic testing laboratories

            • The following companies currently offer FISH and/or transcript quantification testing for BCR-ABL
            • Asuragen (http://www.asuragen.com/)
            • Dako (http://www.dakousa.com/)
            • Invitrogen (http://www.invitrogen.com/)
            • Ipsogen (http://www.ipsogen.com)
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            Administration

            Oral Administration

            Take with or without meals, either in the morning or evening

            Swallow tablet whole; do not cut, crush, or chew

            Follow special handling and disposal procedures

            Personnel who are pregnant should avoid exposure to crushed or broken tablets

            Storage

            Tablets: Store at room temperature at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            • Compare formulary status to other drugs in the same class.
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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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