Dasatinib is used for treating adult patients with:

• Newly diagnosed Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase.
• Ph+ CML in chronic, accelerated, or myeloid/lymphoid blast phases when there is resistance or intolerance to previous treatments, including imatinib.
• Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior therapy.

Dasatinib is also indicated for pediatric patients aged 1 year and older with:

• Ph+ CML in the chronic phase.
• Newly diagnosed Ph+ ALL, when used in combination with chemotherapy.

Pharmacology / Mechanism of Action:
At nanomolar concentrations, dasatinib inhibits several kinases including BCR-ABL, members of the SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Modeling studies suggest that dasatinib can bind to multiple conformations of the ABL kinase.

In vitro studies show activity against leukemic cell lines representing both imatinib-sensitive and imatinib-resistant disease variants. It inhibits proliferation of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines that overexpress BCR-ABL. Under experimental conditions, dasatinib can overcome resistance to imatinib caused by BCR-ABL kinase domain mutations, activation of alternative SRC-family signaling pathways (such as LYN and HCK), and overexpression of multidrug resistance genes.

Absorption:
Peak plasma concentration (Cmax) is reached within 0.5 to 6 hours (Tmax) after oral dosing. A high-fat meal increases the average AUC of a single 100 mg dose by about 14%. The high-fat meal contained 985 kcal, with 52% fat, 34% carbohydrates, and 14% protein.

Distribution:
The apparent volume of distribution is approximately 2505 L (CV% 93%). In vitro, dasatinib is about 96% bound to human plasma proteins, while its active metabolite is 93% bound, with no concentration dependency between 100–500 ng/mL. Dasatinib is also a P-glycoprotein (P-gp) substrate in vitro.

Elimination:
The terminal half-life ranges from 3 to 5 hours. The mean apparent oral clearance is 363.8 L/hr (CV% 81.3%).

Metabolism:
Dasatinib is mainly metabolized in the liver by CYP3A4, which is also responsible for forming its active metabolite. Other enzymes involved include flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferases (UGTs). The active metabolite, which has similar potency to dasatinib, accounts for about 5% of the total drug exposure (AUC), suggesting a minor role in overall drug effect. Several inactive oxidative metabolites are also formed.

Excretion:
Elimination occurs primarily through feces. After a single radiolabeled oral dose, about 4% of radioactivity was recovered in urine and 85% in feces within 10 days. Unchanged dasatinib accounted for 0.1% in urine and 19% in feces, while the remainder consisted of metabolites.

Dosage of Dasatinib 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 Dasatinib 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. The exposure in patients receiving a crushed tablet is lower than in those swallowing an intact tablet. 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 below chart. The recommended dose should be administered orally once daily with or without food. The dose should be recalculated every 3 months based on changes in body weight, or more often if necessary.

• Body Weight (kg): 10 to less than 20: Daily Dose 40 mg
• Body Weight (kg): 20 to less than 30: Daily Dose 60 mg
• Body Weight (kg): 30 to less than 45: Daily Dose 70 mg
• Body Weight (kg): At least 45: Daily Dose 100 mg

Pediatric Use: The safety profile of Dasatinib in pediatric subjects was comparable to that reported in studies in adult subjects with chronic phase CML. Bone growth and development in pediatric patients should be monitored

Strong CYP3A4 Inhibitors:
Co-administration of strong CYP3A4 inhibitors can increase dasatinib plasma levels. This may raise the risk of toxicity. Therefore, the combined use of strong CYP3A4 inhibitors should be avoided. If such combination cannot be avoided, a reduction in dasatinib dose should be considered.

Strong CYP3A4 Inducers:
When dasatinib is given together with strong CYP3A4 inducers, its plasma concentration may decrease, potentially reducing therapeutic effectiveness. Alternative drugs with lower enzyme-inducing potential should be used whenever possible. If co-administration is unavoidable, an increase in dasatinib dose may be required.

Gastric Acid Reducing Agents:
Use of gastric acid–reducing medications with dasatinib may lower its plasma concentration and reduce efficacy. H2-receptor antagonists and proton pump inhibitors should not be used with dasatinib. Instead, antacids may be considered. Antacids should be taken at least 2 hours before or 2 hours after dasatinib administration. Concurrent intake of dasatinib and antacids should be avoided.

Dasatinib is contraindicated in patients who have a known hypersensitivity to dasatinib itself or to any of the ingredients present in its formulation.

Important safety concerns include myelosuppression, bleeding events, fluid retention, cardiovascular complications, pulmonary arterial hypertension, QT interval prolongation, severe skin reactions, tumor lysis syndrome, and potential effects on growth and development in pediatric patients.

Dasatinib may cause harm to an unborn baby if taken during pregnancy. Women of reproductive potential should be advised to avoid becoming pregnant while receiving dasatinib, which may require the use of effective contraception during treatment and for at least 30 days after the last dose. Breastfeeding is not recommended during dasatinib therapy and should also be avoided for at least 2 weeks after the final dose.

Myelosuppression:
Dasatinib treatment is associated with severe hematologic toxicities, including Grade 3 or 4 thrombocytopenia, neutropenia, and anemia. These effects occur more frequently and earlier in patients with advanced phase CML or Ph+ ALL compared to those with chronic phase CML.

In chronic phase CML, complete blood counts (CBCs) should be performed every 2 weeks for the first 12 weeks, then every 3 months or as clinically required. In advanced phase CML or Ph+ ALL, CBCs should be monitored weekly for the first 2 months, then monthly or as needed. Myelosuppression is usually reversible and can be managed by temporarily stopping dasatinib and/or reducing the dose.

Bleeding-Related Events:
Serious and potentially fatal bleeding can occur with dasatinib. The risk is increased when used with anticoagulants or drugs that impair platelet function.

Fluid Retention:
Dasatinib may lead to fluid retention. These events are generally managed with supportive care such as diuretics or short courses of corticosteroids. Severe pleural effusion may require thoracentesis and oxygen therapy. Dose interruption or reduction may be necessary.

Cardiovascular Events:
Cardiac dysfunction may occur during dasatinib therapy. Patients should be closely monitored for signs and symptoms of heart-related complications and managed appropriately.

Pulmonary Arterial Hypertension (PAH):
Dasatinib may increase the risk of PAH in both adult and pediatric patients, which can develop at any time during treatment, even after more than one year. Symptoms include shortness of breath, fatigue, low oxygen levels, and fluid retention. PAH may improve after discontinuation of dasatinib. Patients should be evaluated for cardiopulmonary disease before starting and during treatment. If PAH is confirmed, dasatinib should be permanently discontinued.

QT Prolongation:
Dasatinib may prolong the QTc interval, especially in patients with electrolyte imbalances (hypokalemia, hypomagnesemia), congenital long QT syndrome, or those taking antiarrhythmic drugs or other QT-prolonging medications. Electrolyte abnormalities should be corrected before and during treatment.

Severe Dermatologic Reactions:
Severe skin and mucocutaneous reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported. If a severe reaction occurs and no other cause is identified, dasatinib should be permanently discontinued.

Tumor Lysis Syndrome:
Tumor lysis syndrome has been observed mainly in patients with advanced disease or resistance to prior imatinib therapy. Preventive measures include adequate hydration, correction of uric acid levels before starting treatment, and monitoring of electrolytes. Patients with high tumor burden or advanced disease require closer monitoring.

Clinical experience with dasatinib overdose is limited to a few isolated cases. The highest reported overdose was 280 mg per day for one week in two patients, both of whom developed severe myelosuppression and bleeding complications. Because dasatinib is associated with significant myelosuppression, patients who take more than the recommended dose should be closely monitored for signs of bone marrow suppression and bleeding, and should receive appropriate supportive care.

Targeted Cancer Therapy

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