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Drugs reference index «Dasatinib»

Dasatinib


Dasatinib

Pronunciation: (da-SA-ti-nib)Class: Protein-tyrosine kinase inhibitor

Trade Names:Sprycel- Tablets 20 mg- Tablets 50 mg- Tablets 70 mg- Tablets 100 mg

Pharmacology

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

Pharmacokinetics

Absorption

T max is between 0.5 and 6 h.

Distribution

Vd is 2,505 L, suggesting extensive distribution in extravascular space. Protein binding 96%; 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 fecal (85%) and 4% in urine.

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

There are no studies in patients with impaired hepatic function.

Indications and Usage

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

Contraindications

None known.

Dosage and Administration

Chronic phaseCML Adults

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

Accelerated phase CML, myeloid, or lymphoid blast CML phase, or (Ph+) ALL Adults

Start with 70 mg in the morning and evening. May escalate dosage to 100 mg twice daily in patients who do not achieve a hematologic or cytogenetic response.

Coadministration With Strong CYP3A4 InhibitorsAdults

PO Selection of an alternate drug with no or minimal enzyme inhibition potential is recommended. If a strong CYP3A4 inhibitor must be coadministered, consider decreasing the dosage of dasatinib to 20 mg daily.

Coadministration With Strong CYP3A4 InducersAdults

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 ThrombocytopeniaAdults Chronic phase CML

PO Starting dosage 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. Then resume treatment at the original starting dose if recovery occurs in 7 days or less. If platelets are less than 25 × 10 9 /L and/or recurrence of ANC is 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 twice daily (second episode) or discontinue (third episode).

Accelerated phase CML, blast phase CML, and Ph+ ALL

PO Starting dosage 70 mg twice 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, check if cytopenia is related to leukemia, and resume dasatinib at a dosage of 50 mg twice daily (second episode) or 40 mg twice daily (third episode). If cytopenia is related to leukemia, consider escalating the dasatinib dosage to 100 mg twice daily.

General Advice

  • May be given without respect to meals.
  • Tablets should be swallowed whole. Do not crush or cut.
  • If a 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.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Antacids

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, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort)

May reduce dasatinib plasma levels, decreasing the therapeutic effect. When possible, use alternative therapy.

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.

CYP3A4 substrates (eg, alfentanil, astemizole, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, quinidine, simvastatin, sirolimus, tacrolimus, terfenadine)

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. Concommitant use is not recommended.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

CHF/cardiac dysfunction (4%); arrhythmia including tachycardia, flushing, hypertension, palpitations (1% to less than 10%).

CNS

Headache (24%); fatigue (21%); asthenia, depression, dizziness, dysgeusia, insomnia, neuropathy, somnolence (1% to less than 10%); CNS bleeding (1%).

Dermatologic

Rash (22%); acne, alopecia, dermatitis, dry skin, hypertrichosis, pruritus, urticaria (1% to less than 10%).

EENT

Dry eyes, visual disorder (1% to less than 10%).

GI

Diarrhea (37%); nausea (24%); vomiting (13%); abdominal pain (10%); GI bleeding (7%); abdominal distention, anorexia, appetite disturbance, colitis, constipation, dyspepsia, enterocolitis infection, gastritis, mucosal inflammation, oral soft tissue disorder (1% to less than 10%); ascites (1%).

Hematologic-Lymphatic

Thrombocytopenia (81%); neutropenia (80%); anemia (75%); hemorrhage (21%); febrile neutropenia, pancytopenia (1% to less than 10%).

Lab Tests

Hypophosphatemia (20%); hypocalcemia (16%); elevated ALT (7%); elevated AST, elevated bilirubin (5%); hyperuricemia (1% to less than 10%); elevated creatinine (3%).

Metabolic-Nutritional

Fluid retention (37%); weight decrease, weight increase (1% to less than 10%).

Musculoskeletal

Musculoskeletal pain (14%); arthralgia, muscle inflammation, muscle weakness, myalgia (1% to less than 10%).

Respiratory

Dyspnea (20%); pulmonary edema (3%); cough; lung infiltration; pneumonia including bacterial, fungal, and viral; pneumonitis; upper respiratory tract infection/inflammation (1% to less than 10%).

Miscellaneous

Pleural effusion (23%); superficial localized edema (20%); pyrexia (13%); generalized edema, pericardial effusion (4%); chest pain; chills; contusion; herpes virus infection; infections, including bacterial, fungal, nonspecific, and viral pain (1% to less than 10%); pulmonary hypertension (1%).

Precautions

Monitor

Monitor CBC weekly for the first 2 mo, then monthly thereafter, or as clinically indicated.

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

In most studies, safety and efficacy were similar in patients 65 yr of age and older compared with younger patients. However, in 2 studies in patients with chronic phase CML, the rates of major cytogenetic response were lower in patients 65 yr of age and older.

Hepatic Function

Use with caution.

Bleeding

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

Fluid retention

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

Lactose content

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

Myelosuppression

Severe thrombocytopenia, neutropenia, and anemia 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 and severe myelosuppression.

Patient Information

  • Advise patient to read the patient information leaflet before using 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.
  • Inform patient to contact health care provider if more than the prescribed dose is accidentally taken.
  • Instruct patient regarding how to store, administer, and dispose of outdated medication.
  • Advise patient to report the following symptoms to doctor: bleeding, bruising, fever, shortness of breath, swelling, or weight gain.

Copyright © 2009 Wolters Kluwer Health.

  • Dasatinib MedFacts Consumer Leaflet (Wolters Kluwer)
  • dasatinib Advanced Consumer (Micromedex) - Includes Dosage Information
  • Sprycel Prescribing Information (FDA)
  • Sprycel Consumer Overview

See Also...

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