DASATINIB — 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, 140 mg film‑coated tablets

Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) that targets multiple kinases, including BCR-ABL (the causative oncoprotein in Philadelphia chromosome-positive leukemias) and SRC family kinases. It was first approved by the U.S. FDA in 2006 for the treatment of adults with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib. It is also indicated for adults with Ph+ acute lymphoblastic leukemia (ALL) and for pediatric patients 1 year and older with Ph+ CML in chronic phase or newly diagnosed Ph+ ALL in combination with chemotherapy.

Mechanism of action: Dasatinib potently inhibits BCR-ABL kinase activity at nanomolar concentrations, approximately 325 times more potent than imatinib. It binds to both the active and inactive conformations of the ABL kinase domain, allowing it to overcome many imatinib-resistant mutations (except T315I). In addition to BCR-ABL, dasatinib inhibits SRC family kinases (SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN, FRK), c-KIT, PDGFR-α and -β, and ephrin receptor kinase. This broad inhibitory profile contributes to its efficacy but also to some of its unique adverse effects, particularly pleural effusions.

Clinical efficacy: In the pivotal phase 3 DASISION trial, dasatinib 100 mg once daily resulted in deeper and faster cytogenetic and molecular responses compared to imatinib 400 mg once daily in patients with newly diagnosed chronic-phase CML. The 5-year follow-up confirmed durable responses, with cumulative complete cytogenetic response (CCyR) rates of 89% and major molecular response (MMR) rates of 76% for dasatinib. While progression-free survival (PFS) and overall survival (OS) were not significantly different between the two groups, dasatinib demonstrated superior efficacy in achieving early and deep molecular responses.

Pharmacokinetics: Dasatinib is rapidly absorbed, reaching peak plasma concentrations 0.5‑3 hours after oral administration. Its solubility is pH-dependent. It is extensively metabolized in the liver, primarily by CYP3A4, with an elimination half-life of approximately 3‑5 hours. This short half-life allows for once-daily dosing, which improves adherence compared to twice-daily regimens. However, it also means that drug interactions with CYP3A4 inhibitors or inducers can significantly alter dasatinib exposure and require dose adjustments.

• None. Dasatinib has no absolute contraindications listed in the prescribing information. However, use is not recommended in patients with hypersensitivity to dasatinib or any component of the formulation.

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin, grapefruit juice): May increase dasatinib concentrations. Dose reduction may be necessary. Avoid concomitant use if possible; if unavoidable, consider reducing dasatinib dose and monitor for toxicity.
• Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John’s wort): May decrease dasatinib concentrations, potentially reducing efficacy. Dose increase may be necessary. Avoid concomitant use if possible.
• Antacids (aluminum/magnesium hydroxide, calcium carbonate): May decrease dasatinib absorption. Avoid simultaneous administration; separate dosing by at least 2 hours.
• H2 antagonists (famotidine, ranitidine) and proton pump inhibitors (omeprazole, esomeprazole): May decrease dasatinib absorption due to increased gastric pH. Avoid coadministration. Consider using antacids with temporal separation if acid suppression is needed.
• Anticoagulants/antiplatelet agents (warfarin, heparin, aspirin, clopidogrel): Increased bleeding risk due to dasatinib-induced thrombocytopenia and platelet dysfunction. Use with caution and monitor closely.

• Pregnancy: FDA Category D. Can cause fetal harm based on animal studies. Women of reproductive potential should use effective contraception during treatment and for 30 days after the final dose.
• Lactation: It is not known whether dasatinib is excreted in human milk. Advise women not to breastfeed during treatment and for 2 weeks after the final dose due to potential risk of serious adverse reactions in nursing infants.
• Pediatric use: Approved for pediatric patients 1 year and older with Ph+ CML in chronic phase and for newly diagnosed Ph+ ALL in combination with chemotherapy. Dose based on body weight. Monitor bone growth and development.
• Geriatric use: No overall differences in safety or efficacy observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Fluid retention (pleural effusion) may be more common.
• Hepatic impairment: Dasatinib is extensively metabolized in the liver. Use with caution in patients with hepatic impairment. Monitor liver function tests before initiation and monthly thereafter.
• Renal impairment: No dedicated studies; use with caution in severe renal impairment.

• Chronic phase CML (adults): 100 mg orally once daily.
• Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL (adults): 140 mg orally once daily.
• Pediatric patients (1 year and older): Starting dose based on body weight (exact weight‑based dosing table available in prescribing information). Administered orally once daily with or without food. Recalculate dose every 3 months based on changes in body weight.
• Dose modification: Dose adjustments (interruption, reduction, or discontinuation) may be required for hematologic and non-hematologic adverse reactions.
• Administration: Swallow tablets whole. Do not crush, cut, or chew. Can be taken with or without a meal, either in the morning or evening.

• Symptoms: Overdose experience is limited. Expected symptoms include severe myelosuppression, bleeding, and fluid retention.
• Management: Hospitalization, supportive care, monitoring of vital signs, CBCs, and fluid status. No specific antidote. Discontinue dasatinib and provide supportive measures including transfusions and antibiotics as needed.