Sprycel

Sprycel

dasatinib

Manufacturer:

Bristol-Myers Squibb

Distributor:

DKSH
Full Prescribing Info
Contents
Dasatinib.
Description
Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol.
SPRYCEL (dasatinib) is an inhibitor of multiple tyrosine kinases.
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.
Excipients/Inactive Ingredients: Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose and magnesium stearate. Tablet Coat: Hypromellose, titanium dioxide, and polyethylene glycol.
Action
Pharmacology: Pharmacodynamics: 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 was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK) and multidrug resistance gene overexpression.
In the phase 3 trial of newly diagnosed chronic phase CML, BCR-ABL sequencing was performed on blood samples from patients who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L, and V299L.
Dasatinib, imatinib, and nilotinib do not appear to be active against the T315I mutation, based on in vitro data.
Pharmacokinetics: Absorption: Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean terminal half-life of dasatinib is 3-5 hours.
Data from a trial of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically relevant.
Distribution: In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that dasatinib is extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100-500 ng/mL.
Metabolism: Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was 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 dasatinib AUC. This indicates that the active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of Sprycel. Dasatinib also had several other inactive oxidative metabolites.
Dasatinib is a weak time-dependent inhibitor of CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of human CYP enzymes.
Elimination: Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled dasatinib, approximately 4% and 85% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.
Effects of Age and Gender: Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of dasatinib.
Hepatic Impairment: Dasatinib doses of 50 mg and 20 mg were evaluated in eight patients with moderate (Child-Pugh class B) and seven patients with severe (Child-Pugh class C) hepatic impairment, respectively. Matched controls with normal hepatic function (n=15) were also evaluated and received a dasatinib dose of 70 mg. Compared to subjects with normal liver function, patients with moderate hepatic impairment had decreases in dose normalized Cmax and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had dose normalized Cmax decreased by 43% and AUC decreased by 28% compared to the normal controls.
These differences in Cmax and AUC are not clinically relevant. Dose adjustment is not necessary in patients with hepatic impairment.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility, and reproductive toxicity: In a two-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 generally equivalent to the human exposure at the recommended range of starting doses from 100 mg to 140 mg daily. A statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females and of prostate adenoma in low-dose males was noted. The relevance of the findings from the rat carcinogenicity study for humans is not known.
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 male or female fertility in a conventional rat fertility and early embryonic development study, but induced embryolethality at dose levels approximating human clinical exposures. In embryofetal development studies, dasatinib likewise induced embryolethality with associated decreases in litter size in rats as well as fetal skeletal alterations in both rats and rabbits. These effects occurred at doses that did not produce maternal toxicity, indicating that dasatinib is a selective reproductive toxicant from implantation through the completion of organogenesis. In an exploratory peri- and post-natal development study, indirect exposure of rat pups to dasatinib (in utero or through lactation) initiating from the end of organogenesis through early lactation was incompatible with pup survival, even at maternal exposures that are subtherapeutic.
Indications/Uses
SPRYCEL (dasatinib) is indicated for the treatment of adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase; chronic, accelerated, or myeloid or lymphoid blast phase CML with resistance or intolerance to prior therapy including imatinib; Philadelphia chromosome-positive acute lymphobastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy including imatinib.
Dosage/Direction for Use
The recommended starting dosage of SPRYCEL (dasatinib) for chronic phase CML is 100 mg administered orally once daily. The recommended starting dosage of SPRYCEL for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily. Tablets should not be crushed or cut; they should be swallowed whole. SPRYCEL can be taken with or without a meal, either in the morning or in the evening.
In clinical studies, treatment with SPRYCEL 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 investigated.
Dose Modification: Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers may decrease dasatinib plasma concentrations and should be avoided (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital). St. John's Wort may decrease dasatinib plasma concentrations unpredictably and should be avoided. If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, a SPRYCEL dose increase should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity (see Interactions).
Concomitant Strong CYP3A4 inhibitors: CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) may increase dasatinib plasma concentrations. Grapefruit juice may also increase plasma concentrations of dasatinib and should be avoided.
Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible, is recommended. If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered. Based on pharmacokinetic studies, a dose decrease to 20 mg daily should be considered for patients taking SPRYCEL 100 mg daily. For patients taking SPRYCEL 140 mg daily, a dose decrease to 40 mg daily should be considered. These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors. However, there are no clinical data with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dose reduction, either the strong CYP3A4 inhibitor must be discontinued, or SPRYCEL should be stopped until treatment with the inhibitor has ceased. When the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the SPRYCEL dose is increased. (See Interactions.)
Dose Escalation: In clinical studies of adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a hematologic or cytogenetic response at the recommended starting dosage.
Dose Adjustment for Adverse Reactions: Myelosuppression: 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 resistant myelosuppression. Guidelines for dose modifications are summarized in Table 1. (See Table 1.)

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Non-hematological adverse reactions: If a severe non-hematological adverse reaction develops with SPRYCEL use, treatment must be withheld until the event has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence of the event (see Precautions).
Overdosage
Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. The highest overdosage of 280 mg per day for 1 week was reported in two patients and both developed a significant decrease in platelet count. Since SPRYCEL is associated with severe myelosuppression (see Precautions and Adverse Reactions), patients who ingest more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment.
Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2).
Contraindications
SPRYCEL is contraindicated in patients with hypersensitivity to dasatinib or to any other component of SPRYCEL.
Special Precautions
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.
Use In Pregnancy & Lactation
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 preganacy. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential 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.
Sexually active male or female patients of child bearing potential taking SPRYCEL should use adequate contraception.
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•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.
Use in Lactation: It is unknown whether SPRYCEL 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.
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling.
Myelosuppression (see Dosage & Administration and Precautions).
Bleeding related events (see Precautions).
Fluid retention (see Precautions).
QT prolongation (see Precautions).
Cardiac Adverse Reactions (see Precautions).
Pulmonary Arterial Hypertension (see Precautions).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in the following text reflect exposure to SPRYCEL at all doses studies in clinical studies including 324 patients with newly diagnosed chronic phase CML and in 2388 patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ALL. The median duration of therapy in 2712 SPRYCEL treated patients was 19.2 months (range 0-93.2 months).
In the Phase III newly diagnosed chronic phase CML study, the median duration of therapy was approximately 60 months for both SPRYCEL (range 0.03-72.7 months) and imatinib (range 0.3-74.6 months). In these 1618 patients with chronic phase CML the median duration of therapy was 29 months (range 0-92.9 months). In 1094 patients with advanced phase CML or Ph+ ALL, the median duration of treatment for patients was 6.2 months (range 0-93.2 months).
The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the overall population of 2712 SPRYCEL-treated subjects, 520 (19%) experienced adverse reactions leading to treatment discontinuation.
In the Phase III newly diagnosed chronic phase CML study, drug was discontinued for adverse reactions in 14% of SPRYCEL-treated patients and 7% of imatinib-treated patients with a minimum of 60 months follow up. Among the 1,618 SPRYCEL-treated subjects with chronic phase CML, adverse reactions leading to discontinuation were reported in 329 (20.3%) subjects, and among the 1,094 SPRYCEL-treated subjects with advanced phase disease, adverse reactions leading to discontinuation were reported in 191 (17.5%) subjects.
Adverse reactions reported in ≥ 10 % of patients, and other adverse reactions of interest, in a Phase III trial of newly diagnosed chronic phase CML at a median follow-up of approximately 60 months are presented in Table 2. In this study, pleural effusion was reported in 73 patients (28%) receiving SPRYCEL. The median time to onset for Grade 1 or 2 pleural effusion events was 114 weeks (range 4-299 weeks). Fewer than 3% of pleural effusion events were Grade 3 or 4. With appropriate medical care, 58 patients (80% of those with pleural effusion) were able to continue on SPRYCEL (see Precautions).
Adverse reactions reported in ≥10% of patients treated at the recommended dose of 100 mg once daily (n=165), and other adverse reactions of interest, in a Phase III trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy at a median follow-up of approximately 84 months are presented in Table 4. (See Table 4.)
Drug-related serious adverse events (SAEs) were reported for 16.7% of SPRYCEL-treated patients in a Phase III trial of patients with newly diagnosed chronic phase CML. The only serious adverse reaction reported in ≥5% of patients was pleural effusion (5%).
Drug-related SAEs were reported for 26.1% of patients treated at the recommended dose of 100 mg once daily in a Phase III trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. The only serious adverse reaction reported in ≥5% of patients was pleural effusion (10%).
Chronic Myeloid Leukemia (CML): Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of the patients are shown in Table 2 for newly diagnosed patients with chronic phase CML and Tables 4 and 6 for CML patients with resistance or intolerance to prior imatinib therapy. (See Tables 2, 4 and 6.)

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A comparison of cumulative rates of selected adverse reactions in the Phase III study of newly diagnosed patients with chronic phase CML with minimum follow-up of one and five years are shown in Table 3. (See Table 3.)

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Cumulative rates of selected adverse reactions that were reported over time in patients treated with the 100 mg once daily recommended starting dose in a Phase III trial of imatinib-resistant or -intolerant patients with chronic phase CML are shown in Table 5. (See Table 5.)

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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 7 and 8). In newly diagnosed chronic phase CML, myelosuppression was less frequently reported than in chronic phase CML patients with resistance or intolerance to prior imatinib therapy (Tables 7 and 8). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. (See Tables 7 and 8.)
In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase CML patients in the Phase III study and 5 % of patients with resistance or intolerance to prior imatinib therapy in the Phase III study (see Precautions).
Grade 3 or 4 elevations of transaminase 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 transaminase or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation.
Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 7. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters. (See Table 7.)

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Laboratory abnormalities received at 24 months of follow-up reported in CML patients with imatinib resistance or intolerance who received the recommended starting doses of SPRYCEL are shown by disease phase in Table 8. (See Table 8.)

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Among chronic phase CML patients 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%).
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): A total of 135 patients with Ph+ ALL were treated with SPRYCEL in clinical studies. The median duration of treatment was 3 months (range 0.03-31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders such as diarrhea (31%), nausea (24%) and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. Serious adverse reactions reported in ≥5% of patients included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), and infection (5%).
Additional Data From Multiple Clinical Trials: The following additional adverse reactions were reported in SPRYCEL CML and Ph+ ALL clinical studies at a frequency of ≥10%, 1%-<10%, 0.1%-<1%, or <0.1%. These events are included on the basis of clinical relevance.
Gastrointestinal Disorders: ≥10% - diarrhea, nausea, vomiting, abdominal pain; 1%-<10% - gastrointestinal bleeding, mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%-<1% - ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis, gastro-esophageal reflux disease; <0.1% - protein-losing gastroenteropathy, ileus, pancreatitis acute, anal fistula.
General Disorders and Administration Site Conditions: ≥10% - peripheral edemaf, fatigue, pyrexia, face edemag; 1%-<10% - asthenia, pain, chest pain, generalized edemah, chills; 0.1%-<1% - malaise, other superficial edemai; <0.1% - gait disturbance.
Skin and Subcutaneous Tissue Disorders: ≥10% - skin rashe; 1%-<10% - pruritus, acne, alopecia, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%-<1% - pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, neutrophilic dermatosis, palmar-plantar erythrodysesthesia syndrome, panniculitis, hair disorder; <0.1% - leukocytoclastic vasculitis, skin fibrosis.
Respiratory, Thoracic, and Mediastinal Disorders: ≥10% - pleural effusion, dyspnea; 1%-<10% -pulmonary edema, lung infiltration, pneumonitis, pulmonary hypertension, cough; 0.1%-<1% -pulmonary arterial hypertension, asthma, bronchospasm, dysphonia; <0.1% - pulmonary embolism, acute respiratory distress syndrome.
Nervous System Disorders: ≥10% - headache; 1%-<10% - neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%-<1% - CNS bleedingb, amnesia, tremor, syncope, balance disorder; <0.1% - convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis, VIIth nerve paralysis, dementia, ataxia.
Blood and Lymphatic System Disorders: ≥10% - myelosuppression (including anemia, neutropenia, thrombocytopenia); 1%-<10% - febrile neutropenia; 0.1%-<1% - lymphadenopathy, lymphopenia; <0.1% - aplasia pure red cell.
Musculoskeletal and Connective Tissue Disorders: ≥10% - musculoskeletal pain; 1%-<10% - arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm; 0.1%-<1% - rhabdomyolysis, oteonecrosis, tendonitis, muscle inflammation, arthritis.
Investigations: 1%-<10% - weight decreased, weight increased; 0.1%-<1% - blood creatine phosphokinase increased, Gamma-glutamyltransferase increased.
Infections and Infestations: ≥10% - infection (including bacterial, viral, fungal, non-specified); 1%-<10% - pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including uncommon reports of fatal outcomes).
Metabolism and Nutrition Disorders: 1%-<10% - appetite disturbances, hyperuricemia; 0.1%-<1%- tumor lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia; <0.1% - diabetes mellitus.
Cardiac Disorders: 1%- <10% - pericardial effusion, arrhythmia (including tachycardia), congestive heart failure/cardiac dysfunctionc, palpitations; 0.1%-<1% - electrocardiogram QT prolonged, angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia), myocardial infarction (including fatal outcomes), electrocardiogram T-wave abnormal, troponin increased; <0.1% - myocarditis, acute coronary syndrome, cor pulmonale, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis.
Eye Disorders: 1%-<10% - visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1% -<1% - visual impairment, conjunctivitis, photophobia, lacrimation increased.
Vascular Disorders: ≥10% - hemorrhaged ; 1%-<10% - flushing, hypertension; 0.1%-<1% - hypotension, thrombophlebitis; <0.1% - deep vein thrombosis, embolism, livedo reticularis.
Psychiatric Disorders: 1%-<10% - insomnia, depression; 0.1%-<1% - anxiety, affect lability, confusional state, libido decreased.
Pregnancy, puerperium and perinatal conditions: <0.1%- Abortion.
Reproductive System and Breast Disorders: 0.1%-<1% - gynecomastia, menstrual disorder.
Injury, Poisoning, and Procedural Complications: 1%-<10% - contusion.
Ear and Labyrinth Disorders: 1%-<10% - tinnitus, 0.1%-<1% - hearing loss, vertigo.
Hepatobiliary Disorders: 0.1%-<1% - cholestasis, cholecystitis, hepatitis.
Renal and Urinary Disorders: 0.1%-<1% - urinary frequency, renal failure, proteinuria; <0.1%-renal impairment.
Immune System Disorders: 0.1%-<1%- hypersensitivity (including erythema nodosum).
Endocrine Disorders: 0.1%-<1%- hypothyroidism; <0.1%- hyperthyroidism, thyroiditis.
a Includes decreased appetite, early satiety, increased appetite.
b Includes central nervous system hemorrhage, cerebral hematoma, cerebral hemorrhage, extradural hematoma, hemorrhage intracranial, hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma, and subdural hemorrhage.
c Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular dysfunction, right ventricular dysfunction, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, ventricular failure, left ventricular failure, right ventricular failure, and ventricular hypokinesis.
d Excludes gastrointestinal bleeding and CNS bleeding; these ADRs are reported under the gastrointestinal disorders system organ class and the nervous system disorders system organ class, respectively.
e Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, miliaria, pustular psoriasis, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, toxic skin eruption, urticaria vesiculosa, and vasculitic rash.
f Includes gravitational edema, localized edema, edema peripheral.
g Includes conjunctival edema, eye edema, eye swelling, eyelid edema, face edema, lip edema, macular edema, edema mouth, orbital edema, periorbital edema, swelling face.
h Includes fluid overload, fluid retention, gastrointestinal edema, generalized edema, edema, edema due to cardiac disease, perinephric effusion, post procedural edema, visceral edema.
Postmarketing Experience: The following additional adverse reactions have been identified during post approval use of SPRYCEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. (See Table 9.)

Click on icon to see table/diagram/image
Drug Interactions
Drugs That May Increase Dasatinib Plasma Concentrations: CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a trial of 18 patients with solid tumors, 20-mg SPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. Selection of an alternate concomitant medication with no or minimal CYP3A4 inhibition potential is recommended. In patients receiving treatment with SPRYCEL, close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided. (See Dosage & Administration.)
Drugs That May Decrease Dasatinib Plasma Concentrations: CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should be considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered (see Dosage & Administration).
Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a trial of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of SPRYCEL with 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. Simultaneous administration of SPRYCEL with antacids should be avoided.
H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a trial of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. In a trial of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy.
Drugs That May Have Their Plasma Concentration Altered By Dasatinib: CYP3A4 Substrates: Single-dose data from a trial of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving SPRYCEL.
Caution For Usage
Handling and Disposal: SPRYCEL is an anticancer drug. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. However, for the safety of personnel handling this agent and to prevent environmental contamination, the handling and disposal of anticancer drug must be strictly followed.
SPRYCEL (dasatinib) tablets consist of a core tablet (containing the active drug substance), surrounded by a film coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. However, if tablets are inadvertently crushed or broken, pharmacy and clinical personnel should wear disposable chemotherapy gloves. Personnel who are pregnant should avoid exposure to crushed and/or broken tablets.
Storage
SPRYCEL (dasatinib) tablets should be stored below 30°C.
Patient Counseling Information
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, dry cough, chest pain on respiration, or shortness of breath) and to seek medical attention if those symptoms arise.
Hepatitis B virus reactivation: Patients should be informed that treatment with SPRYCEL and other drugs of this class may cause reactivation of hepatitis B virus (HBV). HBV carriers should be informed that they will be monitored closely during and for several months after treatment with SPRYCEL.
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 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.
ATC Classification
L01EA02 - dasatinib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.
Presentation/Packing
FC tab 20 mg (white to off-white, biconvex, round, with "BMS" debossed on one side and "527" on the other side) x 60's. 50 mg (white to off-white, biconvex, oval, with "BMS" debossed on one side and "528" on the other side) x 60's. 70 mg (white to off-white, biconvex, round, with "BMS" debossed on one side and "524" on the other side) x 60's.
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