Dasatinib

Pronunciation: da-SA-ti-nib
Class: Tyrosine kinase inhibitor

Trade Names

Sprycel
- Tablets, oral 20 mg
- Tablets, oral 50 mg
- Tablets, oral 70 mg
- Tablets, oral 80 mg
- Tablets, oral 100 mg
- Tablets, oral 140 mg

Pharmacology

Inhibits growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines that overexpress the kinase BCR-ABL.

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Pharmacokinetics

Absorption

T max is between 0.5 and 6 h. Administration 30 min following a high-fat meal resulted in a 14% increase in mean AUC of dasatinib; this effect is not clinically relevant.

Distribution

Vd is 2,505 L, suggesting extensive distribution in extravascular space. Protein binding is 96% and for the active metabolite, 93%.

Metabolism

Extensively metabolized by CYP3A4 to an active metabolite, which is equipotent to dasatinib. Also metabolized by flavin-containing monooxygenase-3 and uridine diphosphate-glucuronosyltransferase enzymes.

Elimination

Terminal half-life is 3 to 5 h. Excretion is primarily in the feces (85%) and urine (4%).

Special Populations

Renal Function Impairment

There are no studies in patients with impaired renal function; however, only 4% of the drug and its metabolites are excreted by the kidney.

Hepatic Function Impairment

Patients with moderate hepatic impairment had decreases in dose-normalized C max and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had decreases in dose-normalized C max and AUC of 43% and 28%, respectively, compared with healthy controls. Dose adjustment is not necessary in patients with hepatic impairment.

Gender

There are no clinically relevant effects of gender on the pharmacokinetics of dasatinib.

Age

There are no clinically relevant effects of age on the pharmacokinetics of dasatinib.

Indications and Usage

Treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase Philadelphia chromosome–positive (Ph+) CML with resistance or intolerance to prior therapy, including imatinib; treatment of adults with newly diagnosed Ph+ CML in chronic phase; treatment of adults with Ph+ ALL with resistance or intolerance to prior therapy.

Contraindications

None well documented.

Dosage and Administration

Accelerated Phase Chronic Myeloid Leukemia, Myeloid or Lymphoid Blast Phase Chronic Myeloid Leukemia, or Ph+ Acute Lymphoblastic Leukemia
Adults

PO Start with 140 mg once daily. May escalate dosage to 180 mg once daily in patients who do not achieve a hematologic or cytogenetic response.

Chronic Phase Chronic Myeloid Leukemia
Adults

PO Start with 100 mg once daily. May escalate dosage to 140 mg once daily in patients who do not achieve a hematologic or cytogenetic response.

Coadministration With Strong CYP3A4 Inhibitors
Adults

PO Selection of an alternate drug with no or minimal enzyme inhibition potential is recommended. If a strong CYP3A4 inhibitor must be coadministered, consider a dosage decrease of dasatinib to 20 mg daily for patients taking dasatinib 100 mg daily, and a dosage decrease to 40 mg daily for patients taking dasatinib 140 mg daily.

Coadministration With Strong CYP3A4 Inducers
Adults

PO Selection of an alternate drug with no or minimal enzyme induction potential is recommended. If a strong CYP3A4 inducer must be coadministered, consider increasing the dosage of dasatinib and carefully monitor the patient for toxicity.

Dose Adjustments for Neutropenia and Thrombocytopenia
Adults Chronic Phase Chronic Myeloid Leukemia

PO Starting dosage is 100 mg once daily. If absolute neutrophil count (ANC) is less than 0.5 × 10 9 /L or platelet count is less than 50 × 10 9 /L, stop dasatinib until ANC is at least 1 × 10 9 /L and platelets are at least 50 × 10 9 /L. Resume treatment at the original starting dose if recovery occurs in 7 days or less. If platelets are less than 25 × 10 9 /L or there is recurrence of ANC less than 0.5 × 10 9 /L for more than 7 days, stop dasatinib until ANC is at least 1 × 10 9 /L and platelets are at least 50 × 10 9 /L. Then, resume treatment at 80 mg once daily for second episode. For a third episode, further reduce dosage to 50 mg once daily (for newly diagnosed patients) or discontinue dasatinib (for patients resistant or intolerant to prior therapy, including imatinib).

Accelerated Phase Chronic Myeloid Leukemia, Blast Phase Chronic Myeloid Leukemia, and Ph+ Acute Lymphoblastic Leukemia

PO Starting dosage is 140 mg once daily. If ANC is less than 0.5 × 10 9 /L or platelet count is less than 10 × 10 9 /L, check if cytopenia is related to leukemia. If unrelated to leukemia, stop dasatinib until ANC is at least 1 × 10 9 /L and platelets are at least 20 × 10 9 /L. Then, resume treatment at the original starting dose. If recurrence of cytopenia occurs, check if cytopenia is related to leukemia; if unrelated to leukemia, stop dasatinib until ANC is at least 1 × 10 9 /L and platelets are at least 20 × 10 9 /L, and resume dasatinib at a dosage of 100 mg once daily (second episode) or 80 mg once daily (third episode). If cytopenia is related to leukemia, consider escalating the dasatinib dosage to 180 mg once daily.

General Advice

  • May be given without regard to meals.
  • Instruct patients to swallow tablets whole and not to crush or cut.
  • If a severe nonhematological adverse reaction develops, treatment must be withheld until the event has resolved or improved. Thereafter, treatment can be resumed as appropriate, at a reduced dose, depending on the initial severity of the event.
  • Dasatinib is considered a cytotoxic agent. Follow safe handling procedures when preparing, administering, or dispensing dasatinib.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Antacids (eg, aluminum-magnesium hydroxide, calcium carbonate)

Based on nonclinical data, if antacid therapy cannot be avoided, administer the antacid at least 2 h before or after dasatinib.

CYP3A4 inducers (eg, carbamazepine, dexamethasone, rifabutin, rifampin, phenobarbital, phenytoin, St. John's wort)

May reduce dasatinib plasma levels, decreasing the therapeutic effect. Avoid concurrent use. If dasatinib must be administered with a strong CYP3A4 inducer, consider increasing the dose of dasatinib and carefully monitoring for toxicity.

CYP3A4 inhibitors (eg, atazanavir, clarithromycin, erythromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

May elevate dasatinib plasma concentrations, increasing the risk of adverse reactions. Avoid concurrent use with strong CYP3A4 inhibitors. If dasatinib must be administered with a CYP3A4 inhibitor, closely monitor for toxicity and consider reducing the dasatinib dosage to 20 mg daily in patients taking 100 mg daily and to 40 mg daily in patients taking 140 mg daily. When the strong inhibitor is discontinued, allow a 1-wk washout period before increasing the dasatinib dose.

CYP3A4 substrates (eg, alfentanil, cisapride, cyclosporine, ergot derivatives [eg, dihydroergotamine, ergotamine], fentanyl, pimozide, quinidine, simvastatin, sirolimus, tacrolimus)

Plasma levels may be altered by dasatinib; therefore, use with caution.

H 2 antagonists (eg, famotidine), proton pump inhibitors (eg, omeprazole)

May reduce dasatinib plasma levels, decreasing the therapeutic effect. Concomitant use is not recommended.

QT interval–prolonging drugs (eg, anthracyclines [eg, doxorubicin cumulative high-dose therapy], antiarrhythmic agents [eg, amiodarone], chlorpromazine, cisapride, droperidol, halofantrine, methadone, paliperidone, pimozide, tricyclic antidepressants [eg, amitriptyline, imipramine], ziprasidone)

Because of the risk for QT prolongation, coadminister dasatinib with drugs that prolong the QT interval with caution. Carefully monitor the patient.

Adverse Reactions

Cardiovascular

CHF/cardiac dysfunction (4%); pericardial effusion (3%); arrhythmia (including flushing, hypertension, palpitations, tachycardia) (1% to less than 10%); atrial fibrillation/atrial flutter, thrombosis/embolism (including deep vein thrombosis, pulmonary embolism) (postmarketing).

CNS

Headache (33%); fatigue (24%); CNS bleeding (3%); asthenia, depression, dizziness, dysgeusia, insomnia, neuropathy (including peripheral neuropathy), somnolence (1% to less than 10%).

Dermatologic

Rash (21%); acne, alopecia, dermatitis (including eczema), dry skin, hyperhydrosis, pruritus, urticaria (1% to less than 10%).

EENT

Dry eyes, tinnitus, visual disorder (including vision blurred, visual acuity reduced, and visual disturbance) (1% to less than 10%).

GI

Diarrhea (31%); nausea (24%); vomiting (16%); abdominal pain (12%); GI bleeding (9%); abdominal distention, anorexia, appetite disturbance, colitis (including neutropenic colitis), constipation, dyspepsia, enterocolitis infection, gastritis, mucosal inflammation (including mucositis/stomatitis), oral soft tissue disorder (1% to less than 10%).

Hematologic-Lymphatic

Thrombocytopenia (85%); neutropenia (79%); anemia (74%); hemorrhage (26%); febrile neutropenia (12%); pancytopenia (1% to less than 10%).

Lab Tests

Hypophosphatemia (18%); hypokalemia (15%); hypocalcemia (12%); elevated creatinine (8%); elevated bilirubin (6%); elevated ALT (5%); elevated AST (4%).

Metabolic-Nutritional

Fluid retention (35%); weight decrease, weight increase (1% to less than 10%).

Musculoskeletal

Musculoskeletal pain (19%); myalgia (13%); arthralgia (12%); muscle inflammation (4%); muscle weakness (1% to less than 10%).

Respiratory

Pleural effusion (24%); dyspnea (20%); pulmonary edema (4%); cough, lung infiltration, pneumonia (including bacterial, fungal, and viral), pneumonitis, pulmonary hypertension, upper respiratory tract infection/inflammation (1% to less than 10%); interstitial lung disease (postmarketing).

Miscellaneous

Superficial edema (19%); pyrexia (18%); infections (including bacterial, fungal, viral, and nonspecific) (14%); generalized edema (3%); chest pain, chills, contusion, herpes virus infection, pain (1% to less than 10%).

Precautions

Monitor

Monitor CBC weekly for the first 2 mo, then monthly thereafter, or as clinically indicated. Evaluate patients who develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, by chest x-ray. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.


Pregnancy

Category D . May cause fetal harm when administered to a pregnant woman.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Patients 65 y of age and older are more likely to experience toxicity.

Hepatic Function

Use with caution.

CV effects

CV adverse reactions may occur, including cardiomyopathy, CHF , diastolic dysfunction, fatal MI, and left ventricular dysfunction.

Fertility impairment

May impair reproductive function and fertility.

Fluid retention

Fluid retention, possibly severe (eg, pleural and pericardial effusion), may occur.

Hemorrhage

Severe hemorrhage, including fatal CNS and GI hemorrhages, may occur. Use with caution in patients receiving anticoagulants or medications that may inhibit platelet function.

Lactose content

A 140 mg daily dose contains 189 mg; a 100 mg daily dose contains 135 mg.

Myelosuppression

Severe anemia, neutropenia, and thrombocytopenia may occur and can usually be managed by withholding treatment or reducing the dose.

QTc prolongation

QTc prolongation has been reported; therefore, use with caution in patients who have or may develop QTc prolongation, including patients with hypokalemia or hypomagnesemia, patients with congenital QT syndrome, or patients taking high-dose anthracycline therapy, antiarrhythmic agents, or other medicines that prolong the QT interval. Correct hypokalemia or hypomagnesemia before administering dasatinib.

Overdosage

Symptoms

Bleeding, severe myelosuppression.

Patient Information

  • Advise patient to read the patient information leaflet before using for product the first time and with each refill.
  • Advise patient to inform health care provider of lactose intolerance or heart or liver problems.
  • Advise patient to swallow the tablet whole and not to break, cut, or crush the tablet.
  • Instruct patient to take exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
  • Advise patient that if a dose is missed, to take the next scheduled dose at the regular time and not to take 2 doses at the same time.
  • Advise patient to contact health care provider if more than the prescribed dose is accidentally taken.
  • Advise patient to report the following symptoms to doctor: bleeding, bruising, fever, shortness of breath, swelling, or weight gain.
  • Inform patients that they may experience diarrhea, fatigue, headache, muscle pain, nausea, skin rash, or vomiting. If any of these symptoms are significant, advise patients to contact their health care provider.
  • Advise women of childbearing age that dasatinib may cause fetal harm and to avoid becoming pregnant. Advise patients to contact their health care provider immediately if they become pregnant while on therapy.

Copyright © 2009 Wolters Kluwer Health.

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