Myelosuppression: Treatment with SPRYCEL is associated with severe (NCI CTC 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 patients with chronic phase CML.
In patients with chronic phase CML, complete blood counts (CBCs) should be performed every two weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, CBCs should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction (see Dosage & Administration and Adverse Reactions).
Bleeding Related Events: In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. In patients with chronic phase CML, 5 patients (1%) receiving SPRYCEL at the recommended dose (n=548) had severe hemorrhage. In patients with advanced phase CML or Ph+ ALL, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL at the recommended dose (n=304). Severe gastrointestinal hemorrhage, including fatalities, occurred in 6% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events in clinical studies were associated with severe thrombocytopenia.
Caution should be exercised if patients are required to take medications that inhibit platelet function or anticoagulants.
Fluid Retention: SPRYCEL is associated with fluid retention. After 5 years of follow-up in the Phase III newly diagnosed chronic phase CML study (n=258), severe fluid retention was reported in 13 patients (5%) receiving SPRYCEL compared to 2 patients (1%) receiving imatinib (n=258) (see Adverse Reactions). In all patients with newly diagnosed or imatinib resistant or intolerant patients with chronic phase CML (n=548), severe fluid retention occurred in 32 (6%) patients receiving SPRYCEL at the recommended dose. In patients with advanced phase CML or Ph+ ALL receiving SPRYCEL at the approved dose (n=304), severe fluid retention was reported in 8% of patients, including severe pleural and pericardial effusion reported in 7% and 1% of patients, respectively. Also in these patients, severe pulmonary edema and severe pulmonary hypertension were each reported in 1% of patients.
Patients who develop symptoms suggestive of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with 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. Dose modification should be considered. (See Dosage & Administration and Adverse Reactions.)
Cardiac Adverse Reactions: SPRYCEL was studied in a randomized trial of 519 patients with newly diagnosed CML in chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QT prolongation, and myocardial infarction (including fatal) were reported in patients taking SPRYCEL. Adverse cardiac events were more frequent in patients with risk factors or a previous medical history of cardiac disease. Patients with risk factors or a history of cardiac disease should be monitored carefully for signs or symptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately. (See Adverse Reactions.)
Pulmonary Arterial Hypertension: Pulmonary arterial hypertension (PAH), confirmed by right heart catheterization, has been reported in association with SPRYCEL treatment. In these cases, PAH was reported after initiation
of SPRYCEL therapy, including after more than one year of treatment. Patients with PAH reported during SPRYCEL treatment were often taking concomitant medications or had co-morbidities in addition to the underlying malignancy.
Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL therapy. Patients who develop dyspnea and fatigue after initiation of therapy should be evaluated for more common etiologies including pleural effusion, pulmonary edema, anemia, or lung infiltration. During this evaluation, guidelines for non-hematologic adverse reactions should be followed (see Dosage & Administration). If the adverse reaction is severe, treatment must be withheld until the event has resolved or improved. If no alternative diagnosis is found, the diagnosis of PAH should be considered. If PAH is confirmed, SPRYCEL should be permanently discontinued. Follow up should be performed according to standard practice guidelines. Improvements in hemodynamic and clinical parameters have been observed in SPRYCEL-treated patients with PAH following cessation of SPRYCEL therapy.
QT Prolongation: In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). After 5 years of follow-up in the Phase III clinical study of newly diagnosed chronic phase CML, 1 patient (<1%) in each of the SPRYCEL (n=258) and imatinib (n=258) treatment groups had QTc prolongation reported as an adverse reaction. The median changes in QTcF from baseline were 3.0 msec in SPRYCEL patients compared to 8.2 msec in imatinib patients. One patient (<1%) in each group experienced a QTcF >500 msec. Of the 2182 patients with resistance or intolerance to prior imatinib therapy treated with SPRYCEL in clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one patients (1%) experienced a QTcF >500 msec.
In 865 patients with leukemia treated with SPRYCEL in Phase II clinical studies, the mean changes in QTcF from baseline were 4-6 msec; the upper 95% confidence intervals (CIs) for all mean changes from baseline were <7 msec.
SPRYCEL should be administered with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to SPRYCEL administration.
Hepatitis B virus reactivation: BCR-ABL TKIs have been associated with hepatitis B virus (HBV) reactivation including individual case reports for SPRYCEL. In some instances, HBV reactivation occurring in conjunction with other BCR-ABL TKIs resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.
Screening for HBV should be considered in accordance with published guidelines before starting therapy with SPRYCEL. Consultation with a physician with expertise in the treatment of HBV is recommended for patients who test positive for HBV serology.
Patients who are carriers of HBV and require treatment with BCR-ABL TKIs should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop reactivation of HBV while receiving SPRYCEL, prompt consultation with a physician with expertise in the treatment of HBV is recommended.
Severe dermatologic reactions: Individual cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported with the use of SPRYCEL. SPRYCEL should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the dose normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment. No dosage adjustment is necessary in patients with hepatic impairment (see Pharmacology under Actions). Caution is recommended when administering SPRYCEL to patients with hepatic impairment.
Renal Impairment: There are currently no clinical studies with SPRYCEL in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney.
Use in Pregnancy:Pregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. There have been reports of spontaneous abortion and fetal and infant anomalies from women who have taken SPRYCEL during pregnancy. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SPRYCEL (see Use in Pregnancy & Lactation).
Use in Children: The safety and efficacy of SPRYCEL in patients <18 years of age have not been established.
Use in the Elderly: No differences in cCCyR and MMR were observed between older and younger patients. Of the 2712 patients in clinical studies of SPRYCEL, 617 (23%) were 65 years of age and over, and 123 (5%) were 75 years of age and over. While the safety profile of SPRYCEL in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions fatigue, pleural effusion, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported events abdominal distention, dizziness, pericardial effusion, congestive heart failure, and weight decrease, and should be monitored closely.