Included as part of the PRECAUTIONS section.

Myelosuppression

Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombo-cytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. Complete blood counts should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. In a Phase 3 dose-optimization study in patients with chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with 70 mg twice daily [see Table 6, ADVERSE REACTIONS].

Bleeding Related Events

In addition to causing thrombocytopenia in human subjects,dasatinib caused platelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in < 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage occurred in 4% of patients and generally required treatment interruptions and transfusions.Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe thrombo-cytopenia [see ADVERSE REACTIONS)].

Patients were excluded from participation in SPRYCEL clinical studies if they took medications that inhibit platelet function or anticoagulants. In some trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was > 50,000.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.In all clinical studies,severe fluid retention was reported in 8% of patients,including pleural and pericardial effusion reported in 5% and 1% of patients, respectively. Severe ascites and generalized edema were each reported in < 1% of patients. Severe pulmonary edema was reported in 1% of patients [see ADVERSE REACTIONS].Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids.

In the Phase 3 dose-optimization study in patients with chronic phase CML,fluid retention events were reported less frequently in patients treated with 100 mg once daily than in patients treated with 70 mg twice daily [see Table 4, ADVERSE REACTIONS].

QT Prolongation

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). In single-arm clinical studies in patients with leukemia treated with SPRYCEL,the mean QTc interval changes from baseline using Fridericia's method (QTcF) were 3-6 msec; the upper 95% confidence intervals for all mean changes from baseline were < 8 msec. Nine patients had QTc prolongation reported as an adverse event.Three patients ( < 1%) experienced a QTcF > 500 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.

Pregnancy

Pregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, fetal toxicity was observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits,the lowest doses of dasatinib tested (rat:2.5 mg/kg/day [15 mg/m²/day] and rabbit:0.5 mg/kg/day [6 mg/m²/day]) resulted in embryo-fetal toxicities.These doses produced maternal AUCs of 105 ng•hr/mL (0.3-fold the human AUC in females at a dose of 70 mg twice daily) and 44 ng•hr/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body),edema,and microhepatia.

Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant.If SPRYCEL is used during pregnancy,or if the patient becomes pregnant while taking SPRYCEL,the patient should be apprised of the potential hazard to the fetus.

Patient Counseling Information

See FDA-Approved Patient Labeling

Bleeding

Patients should be informed of the possibility of serious bleeding and to report immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding or easy bruising).

Myelosuppression

Patients should be informed of the possibility of developing low blood cell counts; they should be instructed to report immediately should fever develop, particularly in association with any suggestion of infection.

Fluid Retention

Patients should be informed of the possibility of developing fluid retention (swelling,weight gain,or shortness of breath) and to seek medical attention if those symptoms arise.

Pregnancy

Patients should be informed that dasatinib may cause fetal harm when administered to a pregnant woman.Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant. If SPRYCEL is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus [see WARNINGS and PRECAUTIONS].

Gastrointestinal Complaints

Patients should be informed that they may experience nausea, vomiting, or diarrhea with SPRYCEL.If these symptoms are significant,they should seek medical attention.

Pain

Patients should be informed that they may experience headache or musculoskeletal pain with SPRYCEL.If these symptoms are significant,they should seek medical attention.

Fatigue

Patients should be informed that they may experience fatigue with SPRYCEL. If this symptom is significant,they should seek medical attention.

Rash

Patients should be informed that they may experience skin rash with SPRYCEL.If this symptom is significant,they should seek medical attention.

Lactose

Patients should be informed that SPRYCEL contains 135 mg of lactose monohydrate in a 100-mg daily dose and 189 mg of lactose monohydrate in a 140-mg daily dose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were not performed with dasatinib.

Dasatinib was clastogenic when tested in vitro in Chinese hamster ovary cells, with and without metabolic activation. Dasatinib was not mutagenic when tested in an in vitrobacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study.

The effects of dasatinib on male and female fertility have not been studied.However, results of repeat-dose toxicity studies in multiple species indicate the potential for dasatinib to impair reproductive function and fertility.Effects evident in male animals included reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents.

Use In Specific Populations

Pregnancy

Pregnancy Category D [see WARNINGS and PRECAUTIONS].

Nursing Mothers

It is unknown whether SPRYCEL (dasatinib) is excreted in human milk.Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SPRYCEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of SPRYCEL in patients < 18 years of age have not been established.

Geriatric Use

Of the 2182 patients in clinical studies of SPRYCEL,547 (25%) were 65 years of age and over, and 105 (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 fluid retention events and should be monitored closely. No differences in efficacy were observed between older and younger patients. However, in the two randomized studies in patients with chronic phase CML, the rates of major cytogenetic response (MCyR) were lower among patients aged 65 years and over.

Hepatic Impairment

There are currently no clinical studies with SPRYCEL in patients with impaired liver function (clinical studies excluded patients with ALT or AST > 2.5 times the upper limit of the normal range or total bilirubin > 2 times the upper limit of the normal range). Metabolism of dasatinib is mainly hepatic. Caution is recommended in 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.

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