Dasatinib

Mechanism of effect

Dasatinib is a BCR-ABL tyrosine kinase inhibitor that targets most imatinib-resistant BCR-ABL mutations (except the T315I and F317V mutants) by distinctly binding to active and inactive ABL-kinase. Kinase inhibition halts proliferation of leukemia cells. It also inhibits SRC family (including SRC, LKC, YES, FYN); c-KIT, EPHA2 and platelet derived growth factor receptor (PDGFRβ).

Pharmacokinetics

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%

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

Vd: 2505 L

Metabolism: extensively metabolized primarily by CYP3A4

Enzymes inhibited: CYP3A4 (weak)

Dasatinib is a P-gp substrate

Half-Life: 3-5 hr

Clearance: 363.8 l/hr

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

Drug indications

Acute Lymphoblastic Leukemia

Dosage

-Chronic Myeloid Leukemia

Newly diagnosed

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

PEDIATRIC

-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

Drug contraindications

Breast feeding , Hypersensitivity to this drug

Side effects

anemia , Infection , Pain , Diarrhea , Headache , Nephrotic syndrome , weight decrease , nausea , chest pain , abdominal pain , vertigo , neuropathy , Stevens-Johnson syndrome , fluid retention , hemorrhage , pneumonia , atrial fibrillation , Weight increase , musculoskeletal pain , skin rush , tiredness , pulmonary arterial hypertension , Febrile Neutropenia

Interactions

Procainamide , Butalbital and Acetaminophen , Ramucirumab , lenvatinib , Apalutamide , Lopinavir and Ritonavir , Urokinase , oleandomycin , Gefitinib , Alteplase , Amiodarone , Eptifibatide , Erythromycin , Esomeprazole , Streptokinase , vorapaxar , zanubrutinib , st. john's wort , rotavirus vaccine , samarium sm 153 lexidronam , lefamulin , selpercatinib , lemborexant , fondaparinux , Pasireotide , bedaquiline , levomethadyl acetate , Typhoid vaccine (live), oral , Yellow fever vaccine , ozanimod , Oxaprozin , etodolac , Ceritinib , Ruxolitinib , conivaptan , Bepridil , Zoster Vaccines , Cabozantinib , Anisindione , Siponimod , Troleandomycin , Nabumetone , ivosidenib , Crizotinib , Tenecteplase , Edoxaban , Treprostinil , Bromfenac , Betrixaban , Drotrecogin alfa , Dexlansoprazole , Reteplase , Talimogene laherparepvec , Fedratinib , Binimetinib , inotersen , Anistreplase , Ibrutinib , Iloperidone , Baricitinib , Halofantrine , Grepafloxacin , Mibefradil , cobicistat , Delavirdine , Amisulpride , Tositumomab , Ibritumomab tiuxetan , Antithrombin III , Ardeparin , Acalabrutinib , Gatifloxacin , Efavirenz , Sulindac , Tipranavir , Tinzaparin , Telaprevir , Danaparoid , Ponatinib , Ketoprofen , fenoprofen , Diflunisal , Dalteparin , Arsenic trioxide , flurbiprofen , Golimumab , Anagrelide , Fosphenytoin , Idelalisib , Regorafenib , Ribociclib , Dofetilide , Ticagrelor , Ibutilide , Epoprostenol , Iloprost , Indinavir , Mesoridazine , Dicoumarol , Tirofiban , Abciximab , Panobinostat , Droperidol , Phenylbutazone , vemurafenib , Osimertinib , Chloroquine , sparfloxacin , Tofacitinib , vandetanib , Varicella-Zoster Vaccines , Nizatidine , Telithromycin , boceprevir , Argatroban , Lepirudin , Rubella Vaccines , Mumps vaccine , Mifepristone , Dolasetron , Certolizumab , Amprenavir , Fosamprenavir , Ivabradine , Desirudin , Bivalirudin , ritonavir , saquinavir , nelfinavir , mitotane , Apixaban , Adalimumab , Quinidine , BCG vaccine , Ziprasidone , teriflunomide , Nefazodone , dronedarone , Atazanavir , Darunavir , Aspirin , Influenza vaccine , Toremifene , Plicamycin , Rivaroxaban , escitalopram , fentanyl , sulfinpyrazone , Rifabutin , Rifapentine , Ketoconazole , cladribine , Clarithromycin , Clopidogrel , Clozapine , Enzalutamide , Heparin , Hydroxychloroquine , Warfarin , Voriconazole , Carbamazepine , Ketorolac , Mefenamic acid , Meloxicam , Moxifloxacin , Natalizumab , Nilotinib , Haloperidol , Famotidin , Phenobarbital , Phenytoin , Fingolimod , Lansoprazole , Methadone , Rifampin , Cimetidine , Sotalol , Citalopram , Cisapride , Cilostazol , Dexamethasone , Dipyridamole , Disopyramide , Diclofenac , Rabeprazole , Ranitidine , Trastuzumab , Tolmetin , Thioridazine , Ticlopidine , Deferasirox , Deferiprone , Prasugrel , Primidone , Pantoprazole , Posaconazole , Piroxicam , Pimozide , Enoxaparin , Ibuprofen , Itraconazole , Indomethacin , Infliximab , Papaverine , vemurafenib , Meningococcal conjugate vaccine , cangrelor , defibrotide

ado-cangrelor-caplacizumab-dicumarol- h1n1, , trivalent-poliovirus vaccine, live, trivalent-ranitidine bismuth citrate-smallpox vaccine

Alerts

-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

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

-Risk of fluid retention and pleural/pericardial effusion

-Embryofetal toxicity reported

-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

-Myelosuppression including severe thrombocytopenia, neutropenia and anemia

-Can cause serious and fatal bleeding. Concomitant medications that inhibit platelet function or anticoagulants may increase risk of hemorrhage

-Increased risk of developing pulmonary arterial hypertension

-Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, reported

-Severe Hepatic Impairment: Decreases mean Cmax by 43% and in mean AUC by 28% compared to normal liver function subjects

Points of recommendation

-monitor bone growth and development in pediatric patients

-Hematopoietic growth factor has been used with resistant myelosuppression

-in 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

-in 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

-Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiation and during treatment

-Discontinue permanently in patients who experience severe mucocutaneous reaction during treatment if no other etiology can be identified

-Avoid concomitant CYP3A4 inducers/inhibitors.If unavoidable, consider dose modification as appropriate

-Coadministration of dasatinib with a gastric acid reducing agent may decrease the concentrations of dasatinib and reduce efficacy

-Administer the antacid at least 2 hr prior to or 2 hr after dasatinib dose

- Advise a pregnant woman of the potential risk to a fetus

Pregnancy level

D

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

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

Use is not recommended in women who are pregnant or contemplating pregnancy.

Breast feeding warning

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

Breastfeeding is not recommended during use of this drug.

Related drugs

bosutinib , tucatinib

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Drug information of Dasatinib