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Dasatinib (Dasanib)

Dasatinib (Dasanib)

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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.




DOSAGE AND ADMINISTRATION

• Dosage of Dasatinin in Adult Patients:
-The recommended starting dosage of Dasatinib for chronic phase CML in adults is 100 mg 
administered orally once daily. 
-The recommended starting dosage of Dsatinib for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults is 140 mg administered orally once daily. Tablets should not be crushed, cut, or chewed; they should be swallowed whole. 
Dasatinib can be taken with or without a meal, either in the morning or in the evening.
• Dosage of Dasatinib in Pediatric Patients with CML or Ph+ ALL :
The recommended starting dosage for pediatrics is based on body weight as shown in Table 1. The 
recommended dose should be administered orally once daily with or without food. Recalculate the 
dose every 3 months based on changes in body weight, or more often if necessary.
Do not crush, cut or chew tablets. Swallow tablets whole. There are additional administration 
considerations for pediatric patients who have difficulty swallowing tablets.

INDICATIONS
• newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
• adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. 
• adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. 
• pediatric patients 1 year of age and older with Ph+ CML in chronic phase.
• pediatric patients 1 year of age and older with newly diagnosed Ph+ ALL in combination with chemotherapy.
WARNINGS AND PRECAUTIONS
• Myelosuppression
Treatment with Dasatinib is associated with severe (NCI CTCAE Grade 3 or 4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patinibents with chronic phase CML.
In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated.
In pediatric patients with Ph+ ALL treated with SPRYCEL in combination with chemotherapy, perform CBCs prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery.
Myelosuppression is generally reversible and usually managed by withholding Dasatinib temporarily and/or dose reduction.
• Bleeding-Related Events
Dasatinib can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving Dasatinib. The incidence of Grade 3/4 hemorrhage, occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage  occurred  in  0.4%  of  adult patients. The  most  frequent  site  of  hemorrhage was gastrointestinal. Most bleeding events in clinical studies were associated with severe thrombocytopenia. In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro.
Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage.
• Fluid Retention
Dasatinib may cause fluid retention. After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), Grade 3 or 4 fluid retention was reported in 5% of patients, including 3% of patients with Grade 3 or 4 pleural effusion. In adult patients with newly diagnosed or imatinib-resistant or -intolerant chronic phase CML, Grade 3 or 4 fluid retention occurred in 6% of patients treated with Dasatinib at the recommended dose (n=548). In adult patients with advanced phase CML or Ph+ ALL treated with Dasatinib at the recommended dose (n=304), Grade 3 or 4 fluid retention was reported in 8% of patients, including Grade 3 or 4 pleural effusion reported in 7% of patients. In pediatric patients with chronic phase CML, cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients.
Evaluate patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough, promptly with a chest x-ray or additional diagnostic imaging as appropriate. Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids. Severe pleural effusion may require thoracentesis and oxygen therapy. Consider dose reduction or treatment interruption.
• Cardiovascular Events
Dasatinib can cause cardiac dysfunction. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial in adults (n=258), the following cardiac adverse reactions occurred: cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac-related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.
•Pulmonary Arterial Hypertension
Dasatinib may increase the risk of developing pulmonary arterial hypertension (PAH) in adult and pediatric patients which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of Dasatinib. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating Dasatinib and during treatment. If PAH is confirmed, Dasatinib should be permanently discontinued.
• QT Prolongation
Dasationib may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to and during Dasatinib administration.
• Severe Dermatologic Reactions
Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with Dasatinib. Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified.
• Tumor Lysis Syndrome
Tumor lysis syndrome has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease. Due to potential for tumor lysis syndrome, maintain adequate hydration, correct uric acid levels prior to initiating therapy with Dasatinib, and monitor electrolyte levels. Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently.
• Embryo-Fetal Toxicity
Based on limited human data, Dasatinib can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects of Dasatinib including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to Dasatinib. Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception, during treatment with Dasatinib and for 30 days after the final dose.
• Effects on Growth and Development in Pediatric Patients
In pediatric trials of Dastatinib in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.
Monitor bone growth and development in pediatric patients.
DRUG INTERACTIONS
•Strong CYP3A4 Inhibitors
The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a SPRYCEL dose reduction.
•Strong CYP3A4 Inducers
The coadministration of Dasatinib with strong CYP3A inducers may decrease dasatinib concentrations. Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a Dasatinib dose increase.
•Gastric Acid Reducing Agents
The coadministration of Dasatinib with a gastric acid reducing agent may decrease the concentrations of dasatinib. Decreased dasatinib concentrations may reduce efficacy.
Do not administer H2 antagonists or proton pump inhibitors with Dasatinib. Consider the use of antacids in place of H2 antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of Dasatinib. Avoid simultaneous administration of Dasatinib with antacids.