INDICATIONS AND IMPORTANT SAFETY INFORMATION:
SPRYCEL is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib. The effectiveness of SPRYCEL is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
SPRYCEL is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
IMPORTANT SAFETY INFORMATION
Myelosuppression:
- Treatment with SPRYCEL® (dasatinib) is associated with severe CTC Grade 3/4 thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in advanced phase CML or Ph+ ALL than in chronic-phase CML. Myelosuppression was reported in patients with normal baseline laboratory values, as well as in patients with preexisting laboratory abnormalities
- Complete blood counts (CBCs) should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated
- In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy
- Hematopoietic growth factor has been used in patients with persistent myelosuppression
Bleeding Events:
- Dasatinib caused platelet dysfunction in vitro and thrombocytopenia in humans. Severe CNS hemorrhage, including fatalities, occurred in <1% of patients
- Severe GI 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 thrombocytopenia
- Caution is advised in patients required to take medications that inhibit platelet function or anticoagulants
Fluid Retention:
- Fluid retention was severe in 8% of patients, including pleural and pericardial effusions reported in 5% and 1%, respectively. Severe ascites and generalized edema were reported in <1% of patients. Severe pulmonary edema was reported in 1% of patients
- Patients who develop symptoms suggestive of pleural effusion (dyspnea or dry cough) should be evaluated by chest X-ray
- Severe pleural effusion may require oxygen therapy and thoracentesis
- Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids
- Patients over the age of 65 years are more likely to experience fluid retention events, and should be monitored closely
QT Prolongation:
- In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval)
- Nine patients had QTc prolongation 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, including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, or cumulative high-dose anthracycline therapy
- Hypokalemia or hypomagnesemia should be corrected prior to SPRYCEL administration
Pregnancy:
SPRYCEL 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.
Drug Interactions:
Dasatinib is a CYP3A4 substrate.
- Drugs that may increase dasatinib concentrations are:
- Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)
- Concomitant use of dasatinib and drugs that inhibit CYP3A4 should be avoided
- If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered
- Grapefruit juice may also increase plasma concentrations of dasatinib and should be avoided
- Drugs that may decrease dasatinib concentrations are:
- Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital), which should be avoided. If SPRYCEL must be administered with a CYP3A4 inducer, alternative agents with less enzyme induction potential should be used or a dose increase of SPRYCEL should be considered
- St John's Wort may decrease dasatinib plasma concentrations unpredictably and should be avoided
Dasatinib is a time-dependent inhibitor of CYP3A4.
- Drugs that may have their plasma concentration altered by dasatinib are:
- CYP3A4 substrates such as simvastatin. Therefore, CYP3A4 substrates with a narrow therapeutic index (eg, alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids [ergotamine, dihydroergotamine]) should be administered with caution in patients receiving SPRYCEL
Long-term suppression of gastric acid secretion by use of H
2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. Therefore, concomitant use of H
2 antagonists or proton pump inhibitors with SPRYCEL is not recommended.
- The use of antacids should be considered
- Simultaneous administration of SPRYCEL and antacids should be avoided
- If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL
Nursing Mothers:
It is unknown whether SPRYCEL is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue drug.
Adverse Reactions:
The safety data reflect exposure to SPRYCEL in 2182 patients with leukemia in clinical studies (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Drug was discontinued for adverse reactions in 9% of patients in chronic phase, 10% in accelerated phase, 15% in myeloid blast phase CML, and 8% in lymphoid blast phase CML or Ph+ ALL.
- The most frequently reported adverse reactions (reported in >20% of patients) included fluid retention events (37%), diarrhea (31%), headache (24%), skin rash (22%), nausea (22%), hemorrhage (21%), fatigue (21%), and dyspnea (20%)
- The most frequently reported serious adverse reactions included pleural effusion (9%), febrile neutropenia (4%), gastrointestinal bleeding (4%), pyrexia (3%), pneumonia (3%), dyspnea (3%), infection (2%), diarrhea (2%), congestive heart failure (2%), sepsis (1%), and pericardial effusion (1%)
- Grade 3/4 laboratory abnormalities in clinical studies in chronic phase CML included neutropenia (46%), thrombocytopenia (41%), anemia (18%), hypophosphatemia (10%), and hypocalcemia (2%)
- Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia and hypophosphatemia were reported in patients with all phases of CML, but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL
- Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption
- Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation
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