Sprycel
(dasatinib)Dosage & Administration
Get Your Patient on Sprycel
Sprycel Prescribing Information
SPRYCEL (dasatinib) is indicated for the treatment of adult patients with
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- newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
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- chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.
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- Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
SPRYCEL (dasatinib) is indicated for the treatment of pediatric patients 1 year of age and older with
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- Ph+ CML in chronic phase.
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- newly diagnosed Ph+ ALL in combination with chemotherapy.
Duration of Treatment
In clinical studies, treatment with SPRYCEL in adults and in pediatric patients with chronic phase CML was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response (including complete cytogenetic response [CCyR]) or major molecular response (MMR and MR4.5) has not been established.
In clinical studies, treatment with SPRYCEL in pediatric patients with Ph+ ALL was administered for a maximum duration of 2 years [see Dosage and Administration (2.2) and Clinical Studies (14.4)].
SPRYCEL is a hazardous product. Follow applicable special handling and disposal procedures.1
SPRYCEL (dasatinib) Tablets are available as 20-mg, 50-mg, 70-mg, 80-mg, 100-mg, and 140-mg white to off-white, biconvex, film-coated tablets.
Pregnancy
Risk Summary
Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Animal reproduction studies in rats have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates. Skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses. These findings occurred at dasatinib plasma concentrations below those in humans receiving therapeutic doses of dasatinib [see Data]. Advise a pregnant woman of the potential risk to a fetus.
The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Transplacental transfer of dasatinib has been reported. Dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. Hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib. These adverse pharmacologic effects on the fetus are similar to adverse reactions observed in adult patients and may result in fetal harm or neonatal death [see Warnings and Precautions (5.1, 5.3)].
Data
Human Data
Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy.
Animal Data
In nonclinical studies at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were 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•h/mL and 44 ng•h/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, and clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. In a pre- and postnatal development study in rats, administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at maternal exposures that were below the exposures in patients treated with dasatinib at the recommended labeling dose.
Lactation
Risk Summary
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 lactating rats. 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 last dose.
Females and Males of Reproductive Potential
SPRYCEL can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Contraception
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 last dose.
Infertility
Based on animal data, dasatinib may result in damage to female and male reproductive tissues [see Nonclinical Toxicology (13.1)].
Pediatric Use
Ph+ CML in Chronic Phase
The safety and effectiveness of SPRYCEL monotherapy have been demonstrated in pediatric patients with newly diagnosed chronic phase CML [see Clinical Studies (14.3)]. There are no data in children under 1 year of age. Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of patients [see Warnings and Precautions (5.10)].
Ph+ ALL
The safety and effectiveness of SPRYCEL in combination with chemotherapy have been demonstrated in pediatric patients one year and over with newly diagnosed Ph+ ALL. Use of SPRYCEL in pediatric patients is supported by evidence from one pediatric study. There are no data in children under 1 year of age. One case of grade 1 osteopenia was reported.
The safety profile of SPRYCEL in pediatric subjects was comparable to that reported in studies in adult subjects [see Adverse Reactions (6.1) and Clinical Studies (14.3, 14.4)].
Monitor bone growth and development in pediatric patients [see Warnings and Precautions (5.10)].
Pediatric Patients with Difficulty Swallowing Tablets
Five patients with Ph+ ALL 2 to 10 years of age received at least one dose of SPRYCEL tablet dispersed in juice on Study CA180372. The exposure for dispersed tablets was 36% lower as compared to intact tablets in pediatric patients [see Clinical Pharmacology (12.3)]. Due to the limited available clinical data, it is unclear whether dispersing SPRYCEL tablets significantly alters the safety and/or efficacy of SPRYCEL.
Geriatric Use
Of the 2712 patients in clinical studies of SPRYCEL, 617 (23%) were 65 years of age and older, and 123 (5%) were 75 years of age and older. No differences in confirmed Complete Cytogenetic Response (cCCyR) and MMR were observed between older and younger patients. 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 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 monitored closely.
None.
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 [see Adverse Reactions (6.1) and Use in Specific Populations (8.4)]. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.
Monitor bone growth and development in pediatric patients.
Laboratory Abnormalities
Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 12 and 13). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.
In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of adult patients with newly diagnosed chronic phase CML and 5% of adult patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions (5.1)].
Grade 3 or 4 elevations of transaminases or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, 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. Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during SPRYCEL therapy often had recovery with oral calcium supplementation.
Laboratory abnormalities reported in adult patients with newly diagnosed chronic phase CML are shown in Table 12. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters.
SPRYCEL (n=258) | Imatinib (n=258) | |
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Percent (%) of Patients | ||
CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). | ||
Hematology Parameters |
|
|
Neutropenia | 29 | 24 |
Thrombocytopenia | 22 | 14 |
Anemia | 13 | 9 |
Biochemistry Parameters |
|
|
Hypophosphatemia | 7 | 31 |
Hypokalemia | 0 | 3 |
Hypocalcemia | 4 | 3 |
Elevated SGPT (ALT) | <1 | 2 |
Elevated SGOT (AST) | <1 | 1 |
Elevated Bilirubin | 1 | 0 |
Elevated Creatinine | 1 | 1 |
Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of SPRYCEL are shown by disease phase in Table 13.
CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). * Hematology parameters for 100 mg once-daily dosing in chronic phase CML reflects 60-month minimum follow-up. | ||||
Chronic Phase CML | Advanced Phase CML | |||
Accelerated | Myeloid Blast | Lymphoid Blast | ||
(n=165) | (n=157) | (n=74) | (n=33) | |
| Percent (%) of Patients | |||
Hematology Parameters* |
|
|
|
|
Neutropenia | 36 | 58 | 77 | 79 |
Thrombocytopenia | 24 | 63 | 78 | 85 |
Anemia | 13 | 47 | 74 | 52 |
Biochemistry Parameters |
|
|
|
|
Hypophosphatemia | 10 | 13 | 12 | 18 |
Hypokalemia | 2 | 7 | 11 | 15 |
Hypocalcemia | <1 | 4 | 9 | 12 |
Elevated SGPT (ALT) | 0 | 2 | 5 | 3 |
Elevated SGOT (AST) | <1 | 0 | 4 | 3 |
Elevated Bilirubin | <1 | 1 | 3 | 6 |
Elevated Creatinine | 0 | 2 | 8 | 0 |
Among adult patients with chronic phase CML with resistance or intolerance to prior imatinib therapy, cumulative Grade 3 or 4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%).
In the pediatric studies in CML, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults.
Effect of Other Drugs on Dasatinib
Strong CYP3A4 Inhibitors
The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations [see Clinical Pharmacology (12.3)]. 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 dose reduction [see Dosage and Administration (2.5)].
Strong CYP3A4 Inducers
The coadministration of SPRYCEL with strong CYP3A inducers may decrease dasatinib concentrations [see Clinical Pharmacology (12.3)]. 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 dose increase.
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 with antacids.
SPRYCEL (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure:

Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol.
SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.
Mechanism of Action
Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.
In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate-sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib could overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.
Pharmacodynamics
Cardiac Electrophysiology
Of 2440 patients treated with SPRYCEL at all doses tested in clinical trials, 16 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF > 500 ms. In 865 patients with leukemia treated with SPRYCEL 70 mg BID in five Phase 2 studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7 ms to 13.4 ms.
An analysis of the data from five Phase 2 studies in patients (70 mg BID) and a Phase 1 study in healthy subjects (100 mg single dose) suggests that there is a maximum increase of 3 to 6 milliseconds in Fridericia corrected QTc interval from baseline for subjects receiving therapeutic doses of dasatinib, with associated upper 95% confidence intervals <10 msec.
Pharmacokinetics
The pharmacokinetics of dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg/day (0.15 times the lowest approved recommended dose) to 240 mg/day (1.7 times the highest approved recommended dose).
At 100 mg QD, the maximum concentration at steady state (Cmax) is 82.2 ng/mL (CV% 69%), area under the plasma drug concentration time curve (AUC) is 397 ng/mL*hr (CV% 55%). The clearance of dasatinib is found to be time-invariant. When administered to adult healthy subjects as dispersed tablets in juice, the adjusted geometric mean ratio was 0.97 (90% CI: 0.85, 1.10) for Cmax and 0.84 (90% CI: 0.78, 0.91) for AUC as compared to intact tablets.
Absorption
The maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 hours and 6 hours (Tmax) following oral administration.
Food Effect
A high-fat meal increased the mean AUC of dasatinib following a single dose of 100 mg by 14%. The total calorie content of the high-fat meal was 985 kcal. The calories derived from fat, carbohydrates, and protein were 52%, 34%, and 14% for the high-fat meal.
Distribution
The apparent volume of distribution is 2505 L (CV% 93%).
Binding of dasatinib to human plasma proteins in vitro was approximately 96% and of its active metabolite was 93%, with no concentration dependence over the range of 100 ng/mL to 500 ng/mL.
Dasatinib is a P-gp substrate in vitro.
Elimination
The mean terminal half-life of dasatinib is 3 hours to 5 hours. The mean apparent oral clearance is 363.8 L/hr (CV% 81.3%).
Metabolism
Dasatinib is metabolized in humans, primarily by CYP3A4. CYP3A4 is the primary enzyme responsible for the formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites.
The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% of the AUC of dasatinib. The active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also has several other inactive oxidative metabolites.
Excretion
Elimination is primarily via the feces. Following a single radiolabeled dose of oral dasatinib, 4% of the administered radioactivity was recovered in the urine and 85% in the feces within 10 days. Unchanged dasatinib accounted for 0.1% of the administered dose in the urine and 19% of the administered dose in the feces with the remainder of the dose being metabolites.
Specific Populations
Age (15 to 86 years old), sex, and renal impairment (creatinine clearance 21.6 mL/min to 342.3 mL/min as estimated by Cockcroft Gault) have no clinically relevant effect on the pharmacokinetics of dasatinib.
Pediatric Patients
The pharmacokinetics of dasatinib were evaluated in 43 pediatric patients with leukemia or solid tumors at oral doses ranging from 60 mg/m2 to 120 mg/m2 once daily, taken with or without food. The pharmacokinetics showed dose proportionality with a dose-related increase in exposure. The mean Tmax was observed between 0.5 hours and 6 hours and the mean half-life was 2 hours to 5 hours. The geometric mean (CV%) of body weight normalized clearance in these 43 pediatric patients is 5.98 (41.5%) L/h/kg. In pediatric patients with a dosing regimen of 60 mg/m2, the model simulated geometric mean (CV%) steady-state plasma average concentrations of dasatinib were 14.7 (64.6%) ng/mL (for 2 to <6 years old), 16.3 (97.5%) ng/mL (for 6 to <12 years old), and 18.2 (67.7%) ng/mL (for 12 years and older) [see Dosage and Administration (2.2)]. Dasatinib clearance and volume of distribution change with body weight in pediatric patients. Dasatinib has not been studied in patients < 1 year old.
The bioavailability of dispersed tablets in pediatric patients was estimated to be 36% lower than that of intact tablets.
Patients with Hepatic Impairment
Compared to subjects with normal liver function, patients with moderate hepatic impairment (Child Pugh B) had decreases in mean Cmax by 47% and mean AUC by 8%. Patients with severe hepatic impairment (Child Pugh C) had decreases in mean Cmax by 43% and in mean AUC by 28% compared to the subjects with normal liver function.
Drug Interaction Studies
Cytochrome P450 Enzymes
The coadministration of ketoconazole (strong CYP3A4 inhibitor) twice daily increased the mean Cmax of dasatinib by 4-fold and the mean AUC of dasatinib by 5-fold following a single oral dose of 20 mg.
The coadministration of rifampin (strong CYP3A4 inducer) once daily decreased the mean Cmax of dasatinib by 81% and the mean AUC of dasatinib by 82%.
Dasatinib is a time-dependent inhibitor of CYP3A4. Dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib does not induce CYP enzymes.
Gastric Acid Reducing Agents
The administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single dose of SPRYCEL was associated with no relevant change in the mean AUC of dasatinib; however, the mean Cmax of dasatinib was increased by 26%.
The simultaneous administration of 30 mL of aluminum hydroxide/magnesium hydroxide with a single dose of SPRYCEL was associated with a 55% reduction in the mean AUC of dasatinib and a 58% reduction in the mean Cmax of dasatinib.
The administration of a single dose of SPRYCEL 10 hours following famotidine (H2 antagonist) reduced the mean AUC of dasatinib by 61% and the mean Cmax of dasatinib by 63%.
The administration of a single 100 mg dose of SPRYCEL 22 hours following a 40 mg dose of omeprazole (proton pump inhibitor) at steady state reduced the mean AUC of dasatinib by 43% and the mean Cmax of dasatinib by 42%.
Transporters
Dasatinib is not an inhibitor of P-gp in vitro.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level approximately 60% of the human exposure at 100 mg once daily. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females and prostate adenoma in low-dose males.
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 vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study.
Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) similar to the human exposure at 100 mg daily. In repeat dose studies, administration of dasatinib resulted in 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.
Newly Diagnosed Chronic Phase CML in Adults
DASISION (Dasatinib vs Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients) (NCT00481247) was an open-label, multicenter, international, randomized trial conducted in adult patients with newly diagnosed chronic phase CML. A total of 519 patients were randomized to receive either SPRYCEL 100 mg once daily or imatinib 400 mg once daily. Patients with a history of cardiac disease were included in this trial except those who had a myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation. The primary endpoint was the rate of confirmed complete cytogenetic response (CCyR) within 12 months. Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least 28 days apart).
Median age was 46 years in the SPRYCEL group and 49 years in the imatinib groups, with 10% and 11% of patients ≥65 years of age, respectively. There were slightly more male than female patients in both groups (59% vs 41%). Fifty-three percent of all patients were Caucasian and 39% were Asian. At baseline, the distribution of Hasford scores was similar in the SPRYCEL and imatinib treatment groups (low risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively). With a minimum of 12 months follow-up, 85% of patients randomized to SPRYCEL and 81% of patients randomized to imatinib were still on study.
With a minimum of 24 months follow-up, 77% of patients randomized to SPRYCEL and 75% of patients randomized to imatinib were still on study and with a minimum of 60 months follow-up, 61% and 62% of patients, respectively, were still on treatment at the time of study closure.
Efficacy results are summarized in Table 16.
SPRYCEL (n=259) | Imatinib (n=260) | |
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a Confirmed CCyR is defined as a CCyR noted on two consecutive occasions at least 28 days apart. b Major molecular response (at any time) was defined as BCR-ABL ratios ≤0.1% by RQ-PCR in peripheral blood samples standardized on the International scale. These are cumulative rates representing minimum follow up for the time frame specified. * Adjusted for Hasford score and indicated statistical significance at a pre-defined nominal level of significance. CI = confidence interval. | ||
Confirmed CCyRa | ||
Within 12 months (95% CI) | 76.8% (71.2–81.8) | 66.2% (60.1–71.9) |
P-value | 0.007* | |
Major Molecular Responseb | ||
12 months (95% CI) | 52.1% (45.9–58.3) | 33.8% (28.1–39.9) |
P-value | <0.0001 | |
60 months (95% CI) | 76.4% (70.8–81.5) | 64.2% (58.1–70.1) |
The confirmed CCyR within 24, 36, and 60 months for SPRYCEL versus imatinib arms were 80% versus 74%, 83% versus 77%, and 83% versus 79%, respectively. The MMR at 24 and 36 months for SPRYCEL versus imatinib arms were 65% versus 50% and 69% versus 56%, respectively.
After 60 months follow-up, median time to confirmed CCyR was 3.1 months in 215 SPRYCEL responders and 5.8 months in 204 imatinib responders. Median time to MMR after 60 months follow-up was 9.3 months in 198 SPRYCEL responders and 15.0 months in 167 imatinib responders.
At 60 months, 8 patients (3%) on the dasatinib arm progressed to either accelerated phase or blast crisis while 15 patients (6%) on the imatinib arm progressed to either accelerated phase or blast crisis.
The estimated 60-month survival rates for SPRYCEL- and imatinib-treated patients were 90.9% (CI: 86.6%–93.8%) and 89.6% (CI: 85.2%–92.8%), respectively. Based on data 5 years after the last patient was enrolled in the trial, 83% and 77% of patients were known to be alive in the dasatinib and imatinib treatment groups, respectively, 10% were known to have died in both treatment groups, and 7% and 13% had unknown survival status in the dasatinib and imatinib treatment groups, respectively.
At 60 months follow-up in the SPRYCEL arm, the rate of MMR at any time in each risk group determined by Hasford score was 90% (low risk), 71% (intermediate risk) and 67% (high risk). In the imatinib arm, the rate of MMR at any time in each risk group determined by Hasford score was 69% (low risk), 65% (intermediate risk), and 54% (high risk).
BCR-ABL sequencing was performed on blood samples from patients in the newly diagnosed trial who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L, and V299L.
Dasatinib does not appear to be active against the T315I mutation, based on in vitro data.
Imatinib-Resistant or -Intolerant CML or Ph+ ALL in Adults
The efficacy and safety of SPRYCEL were investigated in adult patients with CML or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL. In a clinical trial in chronic phase CML, resistance to imatinib was defined as failure to achieve a complete hematologic response (CHR; after 3 months), major cytogenetic response (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or loss of a previous molecular response (with concurrent ≥10% increase in Ph+ metaphases), cytogenetic response, or hematologic response. Imatinib intolerance was defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity.
Results described below are based on a minimum of 2 years follow-up after the start of SPRYCEL therapy in patients with a median time from initial diagnosis of approximately 5 years. Across all studies, 48% of patients were women, 81% were white, 15% were black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or older. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant. Overall, 80% of patients had imatinib-resistant disease and 20% of patients were intolerant to imatinib. The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients and >600 mg/day in 40% of the patients.
The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary efficacy endpoint in accelerated phase, myeloid blast phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL).
Chronic Phase CML
Dose-Optimization Trial: A randomized, open-label trial (NCT00123474) was conducted in adult patients with chronic phase CML to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. Patients with significant cardiac diseases, including myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation were excluded from the trial. The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML. A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized to the SPRYCEL 100 mg once-daily, 140 mg once-daily, 50 mg twice-daily, or 70 mg twice-daily group. Median duration of treatment was 22 months.
Efficacy was achieved across all SPRYCEL treatment groups with the once-daily schedule demonstrating comparable efficacy (non-inferiority) to the twice-daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [−6.8%–10.6%]); however, the 100-mg once-daily regimen demonstrated improved safety and tolerability.
Efficacy results are presented in Tables 17 and 18 for adult patients with chronic phase CML who received the recommended starting dose of 100 mg once daily.
All Patients | 100 mg Once Daily (n=167) |
---|---|
a CHR (response confirmed after 4 weeks): WBC ≤ institutional ULN, platelets <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement. b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses. | |
Hematologic Response Rate % (95% CI) | |
CHRa | 92% (86–95) |
Cytogenetic Response Rate % (95% CI) | |
MCyRb | 63% (56–71) |
CCyR | 50% (42–58) |
Minimum Follow-up Period | |||
---|---|---|---|
2 Years | 5 Years | 7 Years | |
a Results reported in recommended starting dose of 100 mg once daily. b Major molecular response criteria: Defined as BCR-ABL/control transcripts ≤0.1% by RQ-PCR in peripheral blood samples. | |||
Major Molecular Responseb % (n/N) | |||
All Patients Randomized | 34% (57/167) | 43% (71/167) | 44% (73/167) |
Imatinib-Resistant Patients | 33% (41/124) | 40% (50/124) | 41% (51/124) |
Imatinib-Intolerant Patients | 37% (16/43) | 49% (21/43) | 51% (22/43) |
Based on data 7 years after the last patient was enrolled in the trial, 44% were known to be alive, 31% were known to have died, and 25% had an unknown survival status.
By 7 years, transformation to either accelerated or blast phase occurred in nine patients on treatment in the 100 mg once-daily treatment group.
Advanced Phase CML and Ph+ ALL
Dose-Optimization Trial: One randomized open-label trial (NCT00123487) was conducted in patients with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. The primary efficacy endpoint was MaHR. A total of 611 patients were randomized to either the SPRYCEL 140 mg once-daily or 70 mg twice-daily group. Median duration of treatment was approximately 6 months for both treatment groups. The once-daily schedule demonstrated comparable efficacy (non-inferiority) to the twice-daily schedule on the primary efficacy endpoint; however, the 140-mg once-daily regimen demonstrated improved safety and tolerability.
Response rates for patients in the 140 mg once-daily group are presented in Table 19.
140 mg Once Daily | ||||
---|---|---|---|---|
Accelerated (n=158) | Myeloid Blast (n=75) | Lymphoid Blast (n=33) | Ph+ ALL (n=40) | |
a Hematologic response criteria (all responses confirmed after 4 weeks): Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL). CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement. NEL: same criteria as for CHR but ANC ≥500/mm3 and <1000/mm3, or platelets ≥20,000/mm3 and ≤100,000/mm3. b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses. CI = confidence interval ULN = upper limit of normal range. | ||||
MaHRa | 66% | 28% | 42% | 38% |
(95% CI) | (59–74) | (18–40) | (26–61) | (23–54) |
CHRa | 47% | 17% | 21% | 33% |
(95% CI) | (40–56) | (10–28) | (9–39) | (19–49) |
NELa | 19% | 11% | 21% | 5% |
(95% CI) | (13–26) | (5–20) | (9–39) | (1–17) |
MCyRb | 39% | 28% | 52% | 70% |
(95% CI) | (31–47) | (18–40) | (34–69) | (54–83) |
CCyR | 32% | 17% | 39% | 50% |
(95% CI) | (25–40) | (10–28) | (23–58) | (34–66) |
In the SPRYCEL 140 mg once-daily group, the median time to MaHR was 1.9 months (min-max: 0.7-14.5) for patients with accelerated phase CML, 1.9 months (min-max: 0.9-6.2) for patients with myeloid blast phase CML, and 1.8 months (min-max: 0.9-2.8) for patients with lymphoid blast phase CML.
In patients with myeloid blast phase CML, the median duration of MaHR was 8.1 months (min-max: 2.7-21.1) and 9.0 (min-max: 1.8-23.1) months for the 140 mg once-daily group and the 70 mg twice-daily group, respectively. In patients with lymphoid blast phase CML, the median duration of MaHR was 4.7 months (min-max: 3.0-9.0) and 7.9 months (min-max: 1.6-22.1) for the 140 mg once-daily group and the 70 mg twice-daily group, respectively. In patients with Ph+ ALL who were treated with SPRYCEL 140 mg once-daily, the median duration of MaHR was 4.6 months (min-max: 1.4-10.2). The medians of progression-free survival for patients with Ph+ ALL treated with SPRYCEL 140 mg once-daily and 70 mg twice-daily were 4.0 months (min-max: 0.4-11.1) and 3.1 months (min-max: 0.3-20.8), respectively.
CML in Pediatric Patients
The efficacy of SPRYCEL in pediatric patients was evaluated in two pediatric studies of 97 patients with chronic phase CML. Among 97 patients with chronic phase CML treated in two pediatric studies, an open-label, non-randomized dose-ranging trial (NCT00306202) and an open-label, non-randomized, single-arm trial (NCT00777036), 51 patients (exclusively from the single-arm trial) had newly diagnosed chronic phase CML and 46 patients (17 from the dose-ranging trial and 29 from the single-arm trial) were resistant or intolerant to previous treatment with imatinib. Ninety-one of the 97 pediatric patients were treated with SPRYCEL tablets 60 mg/m2 once daily (maximum dose of 100 mg once daily for patients with high BSA). Patients were treated until disease progression or unacceptable toxicity.
Baseline demographic characteristics of the 46 imatinib resistant or intolerant patients were: median age 13.5 years (range 2 to 20 years), 78.3% White, 15.2% Asian, 4.4% Black, 2.2% other, and 52% female. Baseline characteristics of the 51 newly diagnosed patients were: median age 12.8 years (range 1.9 to 17.8 years), 60.8% White, 31.4% Asian, 5.9% Black, 2% Other, and 49% female.
Median duration of follow-up was 5.2 years (range 0.5 to 9.3 years) for the imatinib resistant or intolerant patients and 4.5 years (range 1.3 to 6.4 years) for the newly diagnosed patients, respectively. Efficacy results for the two pediatric studies are summarized in Table 20.
Table 20 shows increasing trend for response for CCyR, MCyR, and MMR across time (3 months to 24 months). The increasing trend in response for all three endpoints is seen in both the newly diagnosed and imatinib resistant or intolerant patients.
Table 20: Efficacy of SPRYCEL in Pediatric Patients with CP-CML Cumulative Response Over Time by Minimum Follow-Up Period
3 months | 6 months | 12 months | 24 months | |
---|---|---|---|---|
a Patients from pediatric study of newly diagnosed CP-CML receiving oral tablet formulation b Patients from pediatric studies of imatinib-resistant or -intolerant CP-CML receiving oral tablet formulation | ||||
CCyR | ||||
Newly diagnosed | 43.1% | 66.7% | 96.1% | 96.1% |
Prior imatinib | 45.7% | 71.7% | 78.3% | 82.6% |
MCyR | ||||
Newly diagnosed | 60.8% | 90.2% | 98.0% | 98.0% |
Prior imatinib | 60.9% | 82.6% | 89.1% | 89.1% |
MMR | ||||
Newly diagnosed | 7.8% | 31.4% | 56.9% | 74.5% |
Prior imatinib | 15.2% | 26.1% | 39.1% | 52.2% |
With a median follow-up of 4.5 years in newly diagnosed patients, the median durations of CCyR, MCyR, MMR could not be estimated as more than half of the responding patients had not progressed at the time of data cut-off. Range of duration of response was (2.5+ to 66.5+ months for CCyR), (1.4 to 66.5+ months for MCyR), and (5.4+ to 72.5+ months for subjects who achieved MMR by month 24 and 0.03+ to 72.5+ months for subjects who achieved MMR at any time), where ‘+’ indicates a censored observation.
With a median follow-up of 5.2 years in imatinib-resistant or - intolerant patients, the median durations of CCyR, MCyR, and MMR could not be estimated as more than half the responding patients had not progressed at the time of data cut-off. Range of duration of response was (2.4 to 86.9+ months for CCyR), (2.4 to 86.9+ months for MCyR), and (2.6+ to 73.6+ months for MMR), where ‘+’ indicates a censored observation.
The median time to response for MCyR was 2.9 months (95% CI: 2.8 months, 3.5 months) in the pooled imatinib-resistant/intolerant CP-CML patients. The median time to response for CCyR was 3.3 months (95% CI: 2.8 months, 4.7 months) in the pooled imatinib-resistant/intolerant CP-CML patients. The median time to response for MMR was 8.3 months (95% CI: 5.0 months, 11.8 months) in the pooled imatinib- resistant/intolerant CP-CML patients.
The median time to response for MCyR was 3.0 months (95% CI: 2.8 months, 4.3 months) in the newly diagnosed treatment-naïve CP-CML patients. The median time to response for CCyR was 5.5 months (95% CI: 3.0 months, 5.7 months) in the newly diagnosed treatment-naïve CP-CML patients. The median time to response for MMR was 8.9 months (95% CI: 6.2 months, 11.7 months) in the newly diagnosed treatment-naïve CP-CML patients.
In the Phase II pediatric study, 1 newly diagnosed patient and 2 imatinib-resistant or -intolerant patients progressed to blast phase CML.
Ph+ ALL in Pediatric Patients
The efficacy of SPRYCEL in combination with chemotherapy was evaluated in a single cohort (cohort 1) of Study CA180372 (NCT01460160), a multicenter, multiple-cohort study of pediatric patients with newly diagnosed B-cell precursor Ph+ ALL. The 78 patients in cohort 1 received SPRYCEL at a daily dose of 60 mg/m2 for up to 24 months, in combination with chemotherapy. The backbone chemotherapy regimen was the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol.
Patients had a median age of 10.4 years (range 2.6 to 17.9 years) and included 20 patients (25%) 2 to 6 years of age, 37 patients (46%) 7 to 12 years of age, and 24 patients (30%) 13 to 17 years of age. Eighty-two percent of patients were white, and 55% were male. Thirty-two patients (41%) had a white blood cell count (WBC) of ≥50,000 mcl at diagnosis, and 17 patients (22%) had extramedullary disease.
Efficacy was established on the basis of 3-year event-free survival (EFS), defined as the time from the start of SPRYCEL to lack of complete response at the end of the third high risk block, relapse, secondary malignancy, or death from any cause. The 3-year EFS binary rate for patients on Study CA180372 was 64.1% (95% CI: 52.4, 74.7). At the end of induction, 75 patients (96%) had a bone marrow with <5% lymphoblasts, and 76 patients (97%) achieved this by the end of consolidation.
How Supplied
SPRYCEL® (dasatinib) tablets are available as described in Table 21.
NDC Number | Strength | Description | Tablets per Bottle |
0003-0527-11 | 20 mg | white to off-white, biconvex, round, film-coated tablet with “BMS” debossed on one side and “527” on the other side | 60 |
0003-0528-11 | 50 mg | white to off-white, biconvex, oval, film-coated tablet with “BMS” debossed on one side and “528” on the other side | 60 |
0003-0524-11 | 70 mg | white to off-white, biconvex, round, film-coated tablet with “BMS” debossed on one side and “524” on the other side | 60 |
0003-0855-22 | 80 mg | white to off-white, biconvex, triangle, film-coated tablet with “BMS” and “80” (BMS over 80) debossed on one side and “855” on the other side | 30 |
0003-0852-22 | 100 mg | white to off-white, biconvex, oval, film-coated tablet with “BMS 100” debossed on one side and “852” on the other side | 30 |
0003-0857-22 | 140 mg | white to off-white, biconvex, round, film-coated tablet with “BMS” and “140” (BMS over 140) debossed on one side and “857” on the other side | 30 |
Storage
SPRYCEL tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
Handling and Disposal
SPRYCEL is an antineoplastic product. Follow special handling and disposal procedures.1
Personnel who are pregnant should avoid exposure to crushed or broken tablets.
SPRYCEL tablets consist of a core tablet, surrounded by a film coating to prevent exposure of healthcare professionals to the active substance. The use of latex or nitrile gloves for appropriate disposal when handling tablets that are inadvertently crushed or broken is recommended, to minimize the risk of dermal exposure.
Mechanism of Action
Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.
In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate-sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib could overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.
Sprycel Prior Authorization Resources
Most recent state uniform prior authorization forms
Benefits investigation
Reimbursement help (FRM)
Financial Assistance Programs
Sprycel retails for $178 per dose without insurance or financial assistance.
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