SPRYCEL® (dasatinib) is indicated for the treatment of adult patients with:
- Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase
- Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
- Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy
SPRYCEL® is indicated for the treatment of pediatric patients 1 year of age and olderwith:
- Newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in combination withchemotherapy
- Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronicphase
SUMMARY OF WARNINGS AND PRECAUTIONS
SPRYCEL is associated with the following warnings and precautions: myelosuppression, bleeding-related events, fluid retention, cardiovascular toxicity, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, tumor lysis syndrome, embryo-fetal toxicity, and hepatotoxicity.
IMPORTANT SAFETY INFORMATION
Treatment with SPRYCEL is associated with severe (NCI CTCAE Grade 3/4) 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. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.
- In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated
- In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated
- In pediatric patients with Ph+ ALL treated with SPRYCEL in combination with chemotherapy, perform CBCs prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery
- Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily and/or dose reduction
- In clinical studies, myelosuppression may have also been managed by discontinuation of study therapy
- Hematopoietic growth factor has been used in patients with resistant myelosuppression
SPRYCEL can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. The incidence of Grade 3/4 hemorrhage occurred in 5.8% of patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal.
- Most bleeding events in clinical studies were associated with severe thrombocytopenia
- In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro
- Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage
SPRYCEL may cause fluid retention. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML study (n=258), grade 3/4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3/4 pleural effusion. In adult patients with newly diagnosed or imatinib-resistant or -intolerant chronic phase CML, grade 3/4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548).
In patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade 3/4 fluid retention was reported in 8% of patients, including grade 3/4 pleural effusion reported in 7% of patients.
In pediatric patients with chronic phase CML, cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients.
- Patients who develop symptoms 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 a 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
- Consider dose reduction or treatmentinterruption
SPRYCEL can cause cardiac dysfunction. After 5 years of follow-up in the randomized, newly diagnosed chronic phase CML trial (n=258), the following cardiac adverse reactions occurred:
- Cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac-related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib
Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.
Pulmonary Arterial Hypertension(PAH):
SPRYCEL may increase the risk of developing PAH, which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation ofSPRYCEL.
- Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued
SPRYCEL may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracyclinetherapy.
- Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL administration
Severe Dermatologic Reactions:
Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated withSPRYCEL.
- Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can beidentified
Tumor Lysis Syndrome(TLS):
TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease.
- Due to potential for TLS, maintain adequate hydration, correct uric acid levels prior to initiating therapy with SPRYCEL, and monitor electrolyte levels
- Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently
Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternalplasma.
- Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with SPRYCEL and for 30 days after the lastdose
Effects on Growth and Development in Pediatric Patients:
In pediatric trials of SPRYCEL in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved duringtreatment.
Monitor bone growth and development in pediatricpatients.
SPRYCEL may result in hepatotoxicity as measured by elevation in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Monitor transaminases at baseline and monthly or as clinically indicated during treatment. Reduce dose, withhold, or permanently discontinue SPRYCEL based on severity. When combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Monitoring of hepatic function is recommended.
No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. However, dasatinib is present in the milk of lactatingrats.
- Because of the potential for serious adverse reactions in nursing children from SPRYCEL, breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the lastdose
Effect of Other Drugs onDasatinib
- Strong CYP3A4 inhibitors: The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations. Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a SPRYCEL dosereduction
- Grapefruit juice may increase plasma concentrations of SPRYCEL and should beavoided
- Strong CYP3A4 inducers: The coadministration of SPRYCEL with strong CYP3A inducers may decrease dasatinib concentrations. Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a SPRYCEL doseincrease
- St. John’s wort may decrease plasma concentrations of SPRYCEL and should beavoided
- Gastric Acid Reducing Agents: The coadministration of SPRYCEL with a gastric acid reducing agent may decrease the concentrations of dasatinib. Decreased dasatinib concentrations may reduce efficacy
Do not administer H2 antagonists or proton pump inhibitors with SPRYCEL. Consider the use of antacids in place of H2 antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of SPRYCEL. Avoid simultaneous administration of SPRYCEL withantacids.
The safety data reflects exposure to SPRYCEL at doses tested in clinical studies (n=2712), including 324 adult patients with newly diagnosed chronic phase CML and 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase Ph+ CML orPh+ALL.
The median duration of therapy in a total of 2712SPRYCEL-treated adult patients was 19.2months (range 0–93.2 months). Median duration of therapyin:
- 1618 adult patients with chronic phase CML was 29 months (range0–92.9months)
- 324 patients in the newly diagnosed chronic phase CML trial was approximately 60 months
- 1094 adult patients with advanced phase CML or Ph+ ALL was 6.2months (range 0–93.2 months)
In the overall population of 2712 SPRYCEL-treated adult patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatmentdiscontinuation.
Among the 1618 SPRYCEL-treated patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%)patients.
In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 16% of the adult patients with a minimum of 60 months of follow-up. After a minimum of 60 months of follow-up, the cumulative discontinuation rate was39%.
Among the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191(17.5%)patients.
Patients ≥65 years are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema and weight decrease, and should be monitoredclosely.
- In newly diagnosed chronic phase CMLpatients:
- Drug-related serious adverse reactions (SARs) were reported for 16.7% of SPRYCEL-treated patients. Serious adverse reactions reported in ≥5% of patients included pleural effusion(5%)
- The most common adverse reactions (≥15%) included myelosuppression, fluid retention, anddiarrhea
- Grade 3/4 laboratory abnormalities included neutropenia(29%), thrombocytopenia(22%), anemia(13%), hypophosphatemia(7%), hypocalcemia(4%), elevated bilirubin (1%), and elevated creatinine(1%)
- In adult patients resistant or intolerant to prior imatinibtherapy:
- Drug-related SARs were reported for 26.1% of SPRYCEL-treated patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion(10%)
- The most common adverse reactions (≥15%) included myelosuppression, fluid retention events, headache, diarrhea, fatigue, dyspnea, musculoskeletal pain, nausea, hemorrhage and skin rash
- Grade 3/4 hematologic laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily with a minimum follow up of 60 months included neutropenia(36%), thrombocytopenia (24%), and anemia(13%). Other grade 3/4 laboratory abnormalities included: hypophosphatemia(10%), and hypokalemia(2%)
- Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases ofCML
- Elevations in transaminases 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
In a multicohort study of SPRYCEL administered continuously in combination with multiagent chemotherapy in 81 pediatric patients with newly diagnosed Ph+ ALL, the median duration of therapy was 24 months (range 2 to27months).
- In pediatric subjects with Ph+ ALL who were administered SPRYCEL in combination with multiagentchemotherapy:
- Fatal adverse reactions occurred in 3 patients (4%), all of which were due toinfections
- Eight patients (10%) experienced adverse reactions leading to treatment discontinuation
- The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain, and musculoskeletalpain
- The most common adverse reactions (≥30%) in pediatric patients receiving SPRYCEL in combination with chemotherapy included mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, constipation, arrhythmia, hypertension, edema, infections (bacterial, viral and fungal), hypotension, decreased appetite, hypersensitivity, dyspnea, epistaxis, peripheral neuropathy, and altered state ofconsciousness
- Grade 3/4 laboratory abnormalities (≥10%) included neutropenia (96%), thrombocytopenia (88%), anemia (82%), elevated SGPT (ALT) (47%), hypokalemia (40%), elevated SGOT (AST) (26%), hypocalcemia (19%), hyponatremia (19%), elevated bilirubin(11%), and hypophosphatemia(11%)
In two non-randomized trials in 97 pediatric patients with chronic phase CML (51 patients newly diagnosed and 46 patients resistant or intolerant to previous treatment with imatinib), the median duration of therapy was 51.1 months (range 1.9 to99.6months).
- Among the 97 CML pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient(1%)
- Drug-related serious adverse reactions were reported for 14.4% of pediatricpatients
- Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of pediatric patients with chronic phaseCML
- The most common adverse reactions (≥15%) in pediatric patients included myelosuppression, headache, nausea, diarrhea, skin rash, pain in extremity, and abdominalpain.
Please see full PrescribingInformation.