Dasatinib (Sprycel) is a second-generation tyrosine kinase inhibitor that selectively inhibits BCR/ABL, SRC, Ephrins, and GFR. It is indicated for the treatment of chronic myeloid leukemia in patients resistant or intolerant to first-line therapies and Philadelphia chromosome-positive acute lymphoblastic leukemia.

Indications of Dasatinib (Sprycel):

• Acute lymphoblastic leukemia:

  • Adult:
    • It is indicated for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia in adult patients with resistance or intolerance to prior therapy.
  • Pediatric:
    • It is indicated for the treatment of newly diagnosed Ph+ acute lymphoblastic leukemia in combination with chemotherapy in pediatric patients ≥1 year of age.

• Chronic myeloid leukemia:

  • Adult:
    • It is indicated for treating newly diagnosed Ph+ chronic myeloid leukemia (CML) in chronic phase;
    • treatment of chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy, including imatinib.
  • Pediatric:
    • It is used for treating Ph+ CML in chronic phase in pediatric patients ≥1 year of age.

• Off Label Use of Dasatinib in Adults:

  • Gastrointestinal stromal tumor (GIST)

Note: The effect of discontinuation on long-term disease outcome after achieving cytogenetic response (including complete cytogenetic response) or major molecular response is not known.

Dasatinib (Sprycel) dose in adults:

Dasatinib (Sprycel) Treatment dose of Philadelphia chromosome-positive (Ph+) Acute lymphoblastic leukemia:

• 140 mg per oral once daily until disease progression or unacceptable toxicity occurs.
• Consider a dose escalation to 180 mg once daily in patients not achieving hematologic or cytogenetic response at recommended initial dosage.

Dasatinib (Sprycel) Treatment dose of Ph+ Chronic myelogenous leukemia, newly diagnosed in chronic phase:

• 100 mg per oral once daily until disease progression or unacceptable toxicity occurs.
• Consider a dose escalation to 140 mg once daily in patients not achieving hematologic or cytogenetic response at recommended initial dosage.

Dasatinib (Sprycel) Treatment dose of Ph+ CML, (resistant or intolerant): 

• Chronic phase:

  • 100 mg per oral once daily until disease progression or unacceptable toxicity occurs.
  • Consider a dose escalation to 140 mg once daily in patients not achieving hematologic or cytogenetic response at recommended initial dosage.

• Accelerated or blast phase:

  • 140 mg per oral once daily until disease progression or unacceptable toxicity occurs.
  • Consider a dose escalation to 180 mg once daily in patients not achieving hematologic or cytogenetic response at recommended initial dosage.

Dasatinib (Sprycel) Treatment dose of Gastrointestinal stromal tumors (GIST): 

• 70 mg per oral twice daily.
• Missed doses: If a dose is missed, take the next regularly scheduled dose, 2 doses should not be taken at the same time.

Dasatinib (Sprycel) Dosage adjustment for concomitant strong CYP3A4 inhibitors:

• Concomitant administration with strong CYP3A4 inhibitors and grapefruit juice should be avoided.
• A dose reduction of dasatinib from 140 mg once daily to 40 mg once daily or from 100 mg once daily to 20 mg once daily or from 70 mg once daily to 20 mg once daily with careful monitoring should be done if combination with a strong CYP3A4 inhibitor cannot be avoided.
• If taking dasatinib 60 mg or 40 mg once daily, dasatinib should be withheld until the strong CYP3A4 inhibitor is discontinued allowing a washout period of 1 week before restarting dasatinib.
• If reduced dasatinib dose is not tolerated, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib therapy temporarily until the concomitant inhibitor use is discontinued.
• A washout period of ~1 week before adjusting dasatinib dose upward should be given after a strong CYP3A4 inhibitor is stopped.

Dasatinib (Sprycel) Dosage adjustment for concomitant strong CYP3A4 inducers:

• Concomitant administration with strong CYP3A4 inducers and St John's wort should be avoided.
• Dose increment of dasatinib with close monitoring is required if concomitant administration with a strong CYP3A4 inducer cannot be avoided.

Dasatinib (Sprycel) dose in children:

Dasatinib (Sprycel) Treatment dose of newly diagnosed Philadelphia chromosome-positive (Ph+) Acute lymphoblastic leukemia:

Note:

• Dasatinib should be given concurrently with chemotherapy.
• Dose escalation is not recommended.
• Dasatinib should be started on or before day 15 of induction chemotherapy and treatment should be continued for 2 years.
• The dose should be recalculated every 3 months or as clinically necessary depending on changes in body weight.

• Children weighing ≥10 kg and Adolescents:

  • 10 to <20 kg: 40 mg per oral once daily.
  • 20 to <30 kg: 60 mg per oral once daily.
  • 30 to <45 kg: 70 mg per oral once daily.
  • ≥45 kg: 100 mg per oral once daily.

Dasatinib (Sprycel) Treatment dose of Chronic myelogenous leukemia, Philadelphia chromosome-positive (Ph+), chronic phase:

Note:

• Dasatinib should be continued until disease progression or unacceptable toxicity.
• The dose should be recalculated every 3 months or as clinically necessary based on changes in body weight.

• Children weighing ≥10 kg and Adolescents:

  • 10 to <20 kg:
    • Initial: 40 mg per oral once daily;
    • may escalate the dose to 50 mg once daily if the hematologic or cytogenetic response is not achieved.
  • 20 to <30 kg:
    • Initial: 60 mg per oral once daily;
    • may escalate the dose to 70 mg once daily if the hematologic or cytogenetic response is not achieved.
  • 30 to <45 kg:
    • Initial: 70 mg per oral once daily;
    • may escalate the dose to 90 mg once daily if the hematologic or cytogenetic response is not achieved.
  • ≥45 kg:
    • Initial: 100 mg per oral once daily;
    • may escalate the dose to 120 mg once daily if the hematologic or cytogenetic response is not achieved.

Dasatinib (Sprycel) Dosage adjustment for concomitant strong CYP3A4 inhibitors:

• Concomitant administration with strong CYP3A4 inhibitors and grapefruit juice should be avoided.
• Dose reduction of dasatinib with close monitoring is necessary if concomitant administration with a strong CYP3A4 inhibitor cannot be avoided.
• Dosing adjustment based on pharmacokinetic data; specific clinical data area lacking; monitor patients closely.
• If reduced dasatinib dose is not tolerated, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib therapy temporarily until the concomitant inhibitor use is discontinued.
• A washout period of about a week should be given before adjusting dasatinib dose upward following the discontinuation of strong CYP3A4 inhibitor.

Dasatinib (Sprycel) Dosage adjustment for concomitant strong CYP3A4 inducers:

• Concomitant administration with strong CYP3A4 inducers and St John's wort should be avoided.
• Increment in dasatinib dose with close monitoring is necessary if concomitant administration with a strong CYP3A4 inducer cannot be avoided.

Dasatinib (Sprycel) Dosing adjustment for toxicity:

• Hematologic toxicity:

  • Children and Adolescents:
    • Adjustments are specific for indications.
  • Note: Growth factor support may be considered in patients with resistant myelosuppression.

    • Acute lymphoblastic leukemia, Philadelphia chromosome-positive (Ph+ ALL):

      • If a delay of the next block of treatment occurs by >14 days due to neutropenia or thrombocytopenia, interrupt dasatinib treatment and resume at the same level once the next block of treatment is started.
      • If neutropenia and/or thrombocytopenia persist and the next block of treatment is delayed another 7 days, perform a bone marrow assessment to assess cellularity and blast percentage.
      • If marrow cellularity is <10%, interrupt dasatinib treatment until ANC >500/mm³ and then resume dasatinib at the full dose.
      • Dasatinib should be resumed if marrow cellularity is >10%.

    • Chronic myelogenous leukemia, Philadelphia chromosome-positive :

      • If cytopenia (eg, neutropenia, thrombocytopenia) persists for >3 weeks, determine if the cytopenia is due to leukemia by performing a marrow aspirate or biopsy.
      • If cytopenia is unrelated to leukemia, withhold dasatinib until ANC ≥1,000/mm³, and platelets ≥75,000/mm³, dasatinib should be given at the original starting dose or at a reduced dose.
      • If cytopenia recurs, repeat marrow aspirate/biopsy and dose reduction of dasatinib is required.
      • Note:
        • If ≥ grade 3 neutropenia or thrombocytopenia recurs during complete hematologic response, interrupt dasatinib therapy and resume at a reduced dose.
        • Temporary dose reductions for intermediate degrees of cytopenia and disease response may be used as needed.

      • Recommended dose reductions for neutropenia and thrombocytopenia in Ph+ CML:

        • If the original starting dose is 40 mg daily, dose reduction to 20 mg once daily (one-level dose reduction) should be done, further dose reductions cannot be made due to available tablet sizes.
        • If the original starting dose is 60 mg once daily, the dose can be reduced to 40 mg once daily (one-level dose reduction), and then to 20 mg once daily (two-level dose reduction).
        • If the original starting dose is 70 mg once daily, dose reduction to 60 mg once daily (one-level dose reduction), and then to 50 mg once daily (two-level dose reduction) might be done.
        • If the original starting dose is 100 mg once daily, dose reduction to 80 mg once daily (one-level dose reduction), and then to 70 mg once daily (two-level dose reduction) should be done.

• Nonhematologic toxicity:

• Recommendations exclude altered liver enzymes.

  • Ph+ ALL:

    • Grade 2 toxicity:
      • If no recovery despite symptomatic management, consider interrupting dasatinib therapy;
      • once recovered to ≤ grade 1, resume at the original starting dose.
      • For recurrent events, the dose reduction of dasatinib is required(see the following dose reductions).
    • Grade ≥3 toxicity:
      • Dasatinib should be withheld until recovered to grade 1 or lower and resumed at a reduced dose (see the following dose reductions).

  • Recommended dose reductions for non-hematologic toxicities Ph+ ALL:

    • If the original starting dose is 40 mg daily, may reduce dose to 20 mg once daily (one-level dose reduction); further dose reductions cannot be made due to available tablet sizes.
    • If the original starting dose is 60 mg once daily, may reduce dose to 40 mg once daily (one-level dose reduction), and then to 20 mg once daily (two-level dose reduction).
    • If the original starting dose is 70 mg once daily, may reduce dose to 60 mg once daily (one-level dose reduction), and then to 50 mg once daily (two-level dose reduction).
    • If the original starting dose is 100 mg once daily, may reduce dose to 80 mg once daily (one-level dose reduction), and then to 70 mg once daily (two-level dose reduction).

  • Ph+ CML:

    • Severe nonhematologic toxicity:
      • Therapy should be withheld until toxicity improvement or resolution.
      • Once resolved, treatment should be resumed at a reduced dose based on the event severity and recurrence.

• All indications: Management of other nonhematologic toxicities:

  • Dermatologic toxicities:

    • Treatment with antihistamines or topical or systemic steroids,dose reduction, or discontinuation might be needed.
    • In the case of a dasatinib-related severe mucocutaneous reaction, therapy should be withdrawn.

  • Fluid retention:

    • Diuretics, short courses of corticosteroids, and/or supportive care should be given.
    • Thoracocentesis or oxygen supply is required in severe pleural effusions, consider dose reduction or treatment interruption.

  • Pleural effusion:

    • For the first episode of grade 3 pleural effusion, withhold treatment until resolves to grade 1 or lower and consider corticosteroids (eg, prednisone for 3 to 4 days), diuretics, thoracentesis, and/or pleurodesis;
    • may resume dasatinib at a decreased dose (one-level dose reduction) when effusion resolves.
    • In the case of recurrent pleural effusion, initiate supportive therapy, withhold therapy, and resume at the next lower dose level (two-level dose reduction) or discontinue therapy.

  • Pulmonary arterial hypertension:

    • Therapy should be withdrawn in case of confirmed pulmonary arterial hypertension.

Dasatinib (Sprycel) Pregnancy Risk Category: X

• Dasatinib can cross the placenta with amniotic and fetal plasma concentrations comparable to those of mothers.
• Exposure to dasatinib by mothers can cause adverse effects like hydrops Fetalis, fetal Leukopenia, and thrombocytopenia.
• Effective contraception should always be used during treatment, and for at least 30 days following the last dasatinib dose.
• Avoid contact with crushed or broken tablets during pregnancy

Use of dasatinib while breastfeeding

• It is unknown if breast milk contains Dasatinib.
• Due to the potential for adverse reactions, breastfeeding is not recommended during treatment or for at least 2 weeks after the last dasatinib dose.

Dasatinib (Sprycel) Dose adjustment in renal disease:

• There are no dosage adjustments provided in the manufacturer’s labeling.
• However, <4% of dasatinib and metabolites are renally excreted.

Dasatinib (Sprycel) Dose adjustment in liver disease:

• No initial dosage adjustment is necessary; use with caution.
• Dose reduction or withdrawal is required in case of transaminitis or elevated bilirubin.

Common Side Effects of Dasatinib (Sprycel):

• Cardiovascular:

  • Facial Edema
  • Peripheral Edema

• Central Nervous System:

  • Headache
  • Fatigue
  • Pain

• Dermatologic:

  • Skin Rash
  • Pruritus

• Endocrine & Metabolic:

  • Fluid Retention

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Vomiting
  • Abdominal Pain

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Neutropenia
  • Anemia
  • Hemorrhage
  • Febrile Neutropenia

• Infection:

  • Infection

• Local:

  • Localized Edema

• Neuromuscular & Skeletal:

  • Musculoskeletal Pain
  • Limb Pain
  • Myalgia
  • Arthralgia

• Respiratory:

  • Pleural Effusion
  • Dyspnea

• Miscellaneous:

  • Fever

Rare Side Effects Of Dasatinib (Sprycel):

• Cardiovascular:

  • Cardiac Conduction Disturbance
  • Ischemic Heart Disease
  • Cardiac Disorder
  • Edema
  • Pericardial Effusion
  • Prolonged Q-T Interval On ECG
  • Cardiac Arrhythmia
  • Chest Pain
  • Flushing
  • Hypertension
  • Palpitations
  • Tachycardia

• Central Nervous System:

  • Intracranial Hemorrhage
  • Chills
  • Depression
  • Dizziness
  • Drowsiness
  • Insomnia
  • Myasthenia
  • Neuropathy
  • Peripheral Neuropathy

• Dermatologic:

  • Acne Vulgaris
  • Alopecia
  • Dermatitis
  • Eczema
  • Hyperhidrosis
  • Urticaria
  • Xeroderma

• Endocrine & Metabolic:

  • Growth Suppression
  • Hyperuricemia
  • Weight Gain
  • Weight Loss

• Gastrointestinal:

  • Constipation
  • Gastrointestinal Hemorrhage
  • Abdominal Distention
  • Change In Appetite
  • Colitis
  • Dysgeusia
  • Dyspepsia
  • Enterocolitis
  • Gastritis
  • Mucositis
  • Stomatitis

• Hematologic & Oncologic:

  • Bruise

• Hepatic:

  • Increased Serum Bilirubin
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
  • Ascites

• Infection:

  • Herpes Virus Infection
  • Sepsis

• Neuromuscular & Skeletal:

  • Muscle Spasm
  • Abnormal Bone Growth
  • Asthenia
  • Stiffness

• Ophthalmic:

  • Blurred Vision
  • Decreased Visual Acuity
  • Dry Eye Syndrome
  • Visual Disturbance

• Otic:

  • Tinnitus

• Renal:

  • Increased Serum Creatinine

• Respiratory:

  • Pulmonary Hypertension
  • Pulmonary Edema
  • Cough
  • Pneumonia
  • Pneumonitis
  • Pulmonary Infiltrates
  • Upper Respiratory Tract Infection

• Miscellaneous:

  • Soft Tissue Injury

Contraindications to Dasatinib (Sprycel):

• The US labeling of the manufacturer does not list any contraindications.

Canadian labeling

• Hypersensitivity to dasatinib and any other component of this formulation
• Breastfeeding

Warnings and precautions

• Suppression of bone marrow

  • Dasatinib may cause bone marrow suppression, including anemia, thrombocytopenia and neutropenia.
  • Temporary withdrawal or reduction of doses can reverse the condition.
  • Patients with advanced chronic myeloid (CML) or Ph+ acute lymphoblastic (ALL) are more likely to experience myelosuppression.
  • Monitoring blood counts is required every two weeks for 12 weeks, and then every three months thereafter (for chronic phase CML), or every other week for the first 2 years (for all phases) or as needed (for accelerated phase CML or ALL).
  • Before each block of chemotherapy is initiated, blood counts should be checked.
  • If necessary, follow-up care should be taken. During the consolidation blocks of chemotherapy, blood counts should be checked every two days.

• Cardiovascular adverse events

  • Dasatinib can cause cardiac dysfunction, including ischemia and cardiac fluid retention-related events.
  • You should monitor your symptoms and signs of cardiac dysfunction.
  • Regular blood pressure monitoring is essential during therapy.
  • If necessary, antihypertensive therapy should be administered to reduce the chance of cardiotoxicity.

• Dermatologic toxicities:

  • The severe mucocutaneous dermatologic reactions that Dasatinib therapy can cause, such as Stevens Johnson syndrome or erythema multifide, are possible. If severe reactions occur, therapy should be stopped.

• Fluid retention

  • Fluid retention that presents with edema, fluid retention, pleural, and pericardial effusions can lead to pulmonary hypertension.
  • Pleural effusion can be caused by hypertension, cardiac history, and twice daily administration schedule.
  • Grade >=2 effusions should not be treated. After symptoms subside, it may be necessary to reduce doses.
  • Grade 3-4 fluid retention/pleural effusion in adults is quite common, while grade 1 or 2 fluid retention may occur in children.
  • For evaluation, you should immediately order a CXR.
  • For severe fluid retention, treatment interruption, or dose reduction, support therapy may be required with oxygen therapy, corticosteroids or diuretics, or thoracentesis.
  • A decreased frequency of fluid retention is associated with once-daily dosing.
  • Patients with pulmonary or cardiovascular disease should be treated with extreme caution.

• Hemorrhage

  • It is possible to experience life-threatening bleeding, such as CNS hemorhage grades 3 and higher.
  • The gastrointestinal area was the most common site of hemorhage.
  • In cases of grade 3 or 4, transfusion and therapy discontinuation is required.
  • Clinical studies showed that bleeding was most commonly caused by severe thrombocytopenia. However, dasatinib can also cause platelet dysfunction.
  • Concomitant anticoagulants or medications that inhibit platelet function increase the risk of bleeding.

• Hypertension in the pulmonary arterial system:

  • Adult and pediatric patients who have received dasatinib can be at increased risk of pulmonary arterial hypertension.
  • This can happen after any treatment period, even after more than 12 months.
  • It is important to evaluate the cause of the condition before you start treatment. e
  • Patients with severe dyspnea or fatigue, hypoxia, fluid retention, and severe dyspnea should not be treated.
  • The treatment should be stopped immediately after a PAH diagnosis has been confirmed.

• Extension of QT

  • QT interval prolongation may occur with dasatinib. There are reports of QTcF >500msec in some patients.
  • Patients with long QT syndrome, those taking antiarrhythmic medication or any other medications that cause QT prolongation, potassium-wasting diuretics, or patients who have received cumulative high-dose Anthracycline therapy are at higher risk.
  • Hypokalemia and hypomagnesemia must be corrected before therapy can begin.

• Tumor lysis syndrome

  • Tumor lysis syndrome may occur in patients who are resistant to imatinib treatment or have advanced phase disease.
  • Patients with advanced-stage diseases or high tumor burdens are at greater risk.
  • Proper hydration and correction of uric acid levels are essential before therapy can begin.
  • It is important to monitor electrolyte levels closely.

• Hepatic impairment

  • Extreme caution is advised due to the high hepatic metabolism.

Dasatinib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Blood pressure
• CBC with differential counts
  • Every 2 weeks for 12 Weeks, then every 3 Months thereafter (for chronic phase CML).Or
  • Weekly for 2 months, then monthly, or as needed (for ALL or accelerated blast phase CML)
  • CBC with differential before each block of chemotherapy is initiated.
  • Then, as clinically indicated, every 2 days until the completion of consolidation blocks of chemotherapy (pediatric patients diagnosed with Ph+ ALL).
• Tests of liver function
• Electrolytes in serum
• Calcium, magnesium, and phosphorus serum
• Recommendations for thyroid function testing:
  • Pre-existing levothyroxine therapy
    • Take baseline TSH levels. Then monitor every four weeks until levels and doses of levothyroxine are stable. Finally, monitor every 2 months
  • Without preexisting thyroid hormone replacement
    • TSH at baseline, then once a month for 4 months, and then every 2 to three months thereafter
• Biopsies of bone marrow
• Fluid retention monitoring
• Watch out for symptoms and signs of cardiac dysfunction
• ECG monitoring is recommended if QT prolongation is possible.
• If symptoms of pleural effusion are present (eg, cough, dyspnea), a chest x-ray may be recommended.
• The signs and symptoms of tumor lysis syndrome.
• Monitor bone development in children.
• You must ensure that you adhere to the rules.

How to administer Dasatinib (Sprycel)?

• It should be taken orally once daily (morning or evening) without regard to food.
• It should be taken as a whole without breaking, cutting, crushing, or chewing tablets.
• In the case of GI upset, it should be taken with a meal.
• Proton pump inhibitors and H-2 receptor blockers should not be given concomitantly with dasatinib.
• Antacids should be given separated by at least 2 hours before or 2 hours after the dasatinib dose if needed.

Mechanism of action of Dasatinib (Sprycel):

• Dasatinib, an inhibitor of BCR/ABL tyrosine-kinase kinase (except for the T315I or F317V mutations), targets most imatinib resistant BCR/ABL mutations.
• Kinase inhibition stops the proliferation of leukemia cells.
• It also inhibits the SRC family (including SRC and LKC; YES, FYN; c-KIT and EPHA2); as well as platelet-derived growth factors receptor (PDGFRb).

Protein binding:

• Dasatinib: ~96%;
• Active metabolite: 93%

Bioavailability:

• The adjusted geometric mean ratio was 0.84 for AUC in healthy adults who received tablets dispersed in juice (compared with intact tablets).

Metabolism:

• It is extensively metabolized in the liver via CYP3A4 (primarily), flavin-containing monooxygenase-3 (FOM-3), and uridine diphosphate-glucuronosyltransferase (UGT) to an active metabolite and other inactive metabolites.
• The active metabolite plays only a minor role in the pharmacology of dasatinib.

Terminal Half-life elimination:

• Adults: 3 to 5 hours
• Children: 2 to 5 hours

Time to peak plasma concentration:

• 0.5 to 6 hours

Excretion:

• Feces (~85%, 19% as unchanged drug);
• Urine (~4%, 0.1% as unchanged drug).

International Brand Names of Dasatinib:

• Sprycel
• Dasanix
• Etersa
• Liteda
• Rembre

Dasatinib Brand Names in Pakistan:

No Brands Available in Pakistan.