Dasatinib

Severe dose-related bone marrow suppression (thrombocytopenia, neutropenia, anemia) is associated with dasatinib treatment. Hematologic toxicity is usually reversible with dosage adjustment and/or temporary treatment interruption. The incidence of myelosuppression is higher in patients with advanced chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL). Monitor blood counts every 2 weeks for 12 weeks and then every 3 months thereafter or as clinically indicated (for chronic phase CML) or weekly for the first 2 months, then monthly thereafter or as clinically necessary (for accelerated or blast phase CML or for ALL).

Dasatinib may cause cardiac dysfunction; cardiac ischemic events, cardiac fluid retention-related events, and conduction abnormalities (arrhythmia and palpitations) have been reported. Monitor for signs and symptoms of cardiac dysfunction. Monitor blood pressure routinely during dasatinib treatment; if indicated, initiate appropriate antihypertensive treatment to reduce the risk for cardiotoxicity (Armenian 2017).

Cases of severe mucocutaneous dermatologic reactions (including Stevens-Johnson syndrome and erythema multiforme) have been reported with dasatinib. Discontinue dasatinib if severe mucocutaneous reaction occurs and other etiologies have been ruled out.

Dasatinib may cause fluid retention, including pleural and pericardial effusions, pulmonary hypertension, and generalized or superficial edema. A prompt chest x-ray (or other appropriate diagnostic imaging) is recommended for symptoms suggestive of effusion (new or worsening dyspnea on exertion or at rest, pleuritic chest pain, or dry cough). Fluid retention may be managed with supportive care (diuretics or corticosteroids); thoracentesis and oxygen therapy may be necessary for severe fluid retention; consider dose reduction or treatment interruption. Utilizing once-daily dosing is associated with a decreased frequency of fluid retention. The risk for pleural effusion is increased in patients with hypertension, prior cardiac history and a twice a day administration schedule; interrupt treatment for grade ≥2 effusion; may consider reinitiating at a reduced dose after resolution (Quintás-Cardama 2007). Grade 3 or 4 fluid retention/pleural effusion was observed in adults and grade 1 or 2 fluid retention was observed in pediatric patients. Use with caution in patients where fluid accumulation may be poorly tolerated, such as in cardiovascular disease (HF or hypertension) and pulmonary disease.

Dasatinib may cause serious and fatal bleeding, including grades 3 and higher CNS hemorrhage. The most frequent hemorrhage site was gastrointestinal. Grades 3 or 4 hemorrhage usually required treatment interruptions and transfusions. Most bleeding events in clinical studies were associated with severe thrombocytopenia, although dasatinib may also cause platelet dysfunction. Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of bleeding.

Dasatinib may increase the risk for pulmonary arterial hypertension (PAH) in both adult and pediatric patients. PAH may occur at any time after starting treatment, including after >12 months of therapy. Evaluate for underlying cardiopulmonary disease prior to therapy initiation and during therapy; evaluate and rule out alternative etiologies in patients with symptoms suggestive of PAH (eg, dyspnea, fatigue, hypoxia, fluid retention) and interrupt therapy if symptoms are severe. Discontinue permanently with confirmed PAH diagnosis (may be reversible upon discontinuation).

Dasatinib may increase the risk for QT interval prolongation; there are reports of patients with QTcF >500 msec. Use caution in patients at risk for QT prolongation, including patients with long QT syndrome, patients taking antiarrhythmic medications or other medications that lead to QT prolongation or potassium-wasting diuretics, patients with cumulative high-dose anthracycline therapy, and conditions which cause hypokalemia or hypomagnesemia. Correct hypokalemia and hypomagnesemia prior to and during dasatinib therapy.

Tumor lysis syndrome (TLS) has been reported in patients with resistance to imatinib therapy, usually in patients with advanced phase disease. Risk for TLS is higher in patients with advanced stage disease and/or a high tumor burden; monitor patients at risk more frequently. Maintain adequate hydration and correct uric acid levels prior to treatment; monitor electrolyte levels. Disease-related concerns:

Use with caution in patients with hepatic impairment due to extensive hepatic metabolism. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Use with caution in patients taking anticoagulants or medications interfering with platelet function; not studied in clinical trials. Avoid concomitant use with CYP3A4 inducers and inhibitors; if concomitant use cannot be avoided, consider dasatinib dosage adjustments.

Elevated gastric pH may reduce dasatinib bioavailability; do not administer proton pump inhibitors and H2 blockers concomitantly with dasatinib. If needed, may consider antacid administration separated by at least 2 hours before or 2 hours after the dasatinib dose. Special populations:

Patients 65 years of age and older are more likely to experience toxicity (compared with younger patients).

Adverse reactions associated with bone growth and development have been reported in pediatric studies of chronic phase CML (including a report of severe [grade 3] growth retardation). Cases have included epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia; some cases resolved during treatment. Monitor bone growth/development in pediatric patients.