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Dasatinib; Uses, Dosage, Side Effects, Interactions, Pregnancy

Dasatinib Anhydrous is an orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently, because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations. SRC-family protein-tyrosine kinases interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways; tumorigenic forms can occur through altered regulation or expression of the endogenous protein and by way of virally-encoded kinase genes.

Dasatinib is a chemotherapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Dasatinib belongs to the class of medications called protein-tyrosine kinase inhibitors Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+). It is taken by mouth. Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML). The main targets of Dasatinib, are BCR-ABL, SRC, Ephrins and GFR.

Mechanism of Action of Dasatinib

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase. In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

Indications of Dasatinib

Acute lymphoblastic leukemia
Chronic myelogenous leukemia
Leukemia
Acute lymphoblastic leukaemias
Chronic myeloid leukemia
Newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase.
Chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate.
Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.
Dasatinib is also used to treat people with chronic myeloid leukemia and people with acute lymphoblastic leukemia who are positive for the Philadelphia chromosome.
For the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy. Also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.

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Contra Indications of Dasatinib

Anemia, bone marrow suppression, neutropenia, thrombocytopenia. …
Anticoagulant therapy, bleeding, GI bleeding, intracranial bleeding. …
Edema, pericardial effusion, pleural effusion.

Dosage of Dasatinib

Strengths: 70 mg; 20 mg; 50 mg; 100 mg; 80 mg; 140 mg

Leukemia

Chronic Phase CML

100 mg orally once a day

Accelerated Phase CML, Myeloid or Lymphoid Blast Phase CML, Ph+ ALL

140 mg orally once a day

Side Effects of Dasatinib

The most common

More common

Fast or irregular heartbeat
appetite loss
changes in nails
constipation
fatigue
fever
Back pain
dizziness
headache
increased cough
Acid or sour stomach
decreased appetite
Agitation
chest congestion
chest pain
cold sweats
confusion
decreased sexual ability or desire
stomach or abdominal cramps, gas, or pain
trouble sleeping

Less common

bleeding gums
blood in the urine or stools
chest pain
diarrhea
Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
difficulty in moving
muscle stiffness
redness of the face, neck, arms and occasionally, upper chest
lack or loss of strength
muscle spasm
difficult or labored breathing
dry mouth
headache
irritability
lack or loss of strength
loose stools
loss of interest or pleasure
muscle stiffness
night sweats
passing gas
stomach discomfort, upset, or pain
swollen joints
trouble concentrating
increased blood pressure

Drug Interactions of Dasatinib

Dasatinib may interact with following drugs, supplyments & may change the efficacy of drugs

alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
“azole” antifungal medications (e.g., fluconazole, itraconazole, ketoconazole)
beta-blockers (e.g., atenolol, propranolol, metoprolol)
barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine, )
carbamazepine
chloroquine
corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
cyclosporine
dantrolene
“gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
losartan
macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
metronidazole
mirtazapine
montelukast
ondansetron
carbamazepine
phenytoin
progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
proton pump inhibitors (PPIs;e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
sildenafil
“statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
tadalafil
tetracycline
theophylline
tocilizumab
tolterodine
tramadol
other selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, sertraline)
5-HT3 antagonists (e.g., granisetron, ondansetron)
tamsulosin
tapentadol
thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
tramadol
tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine,
other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
tetracycline
tocilizumab
vemurafenib
trimethoprim
vaccines
warfarin

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Pregnancy & Lactation

FDA Pregnancy Category D

Pregnancy

This medication should not be used during pregnancy or by women who are planning to become pregnant. If it is taken by a woman who is pregnant, it may harm the developing baby. Women should avoid becoming pregnant while taking dasatinib. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if dasatinib passes into breast milk. Due to the potential for serious harm to a baby, if they are exposed to this medication, breast-feeding must be stopped before starting this medication. The safety and effectiveness of using this medication have not been established for children less than 18 years of age.