HIGHLIGHTS OF PRESCRIBING INFORMATION

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1 HIGHLIGHTS OF PRESCRIBIG IFORMATIO These highlights d nt include all the infrmatin needed t use SPRYCEL safely and effectively. See full prescribing infrmatin fr SPRYCEL. Tablet fr Oral Use Initial U.S. Apprval: 2006 RECET MAJOR CHAGES Indicatins and Usage (1) 10/2010 Dsage and Administratin, Dsage Adjustment fr Adverse Reactins (2.3) 10/2010 Warnings and Precautins, Bleeding Related Events (5.2) 10/2010 Cngestive Heart Failure, Left Ventricular Dysfunctin, and Mycardial Infarctin (5.5) 10/2010 Pulmnary Arterial Hypertensin (5.6) 10/2011 IDICATIOS AD USAGE SPRYCEL is a kinase inhibitr indicated fr the treatment f newly diagnsed adults with Philadelphia chrmsme-psitive (Ph+) chrnic myelid leukemia (CML) in chrnic phase. The trial is nging and further data will be required t determine lng-term utcme. (1, 14) adults with chrnic, accelerated, r myelid r lymphid blast phase Ph+ CML with resistance r intlerance t prir therapy including imatinib. (1, 14) adults with Philadelphia chrmsme-psitive acute lymphblastic leukemia (Ph+ ALL) with resistance r intlerance t prir therapy. (1, 14) DOSAGE AD ADMIISTRATIO Chrnic phase CML: 100 mg nce daily. (2) Accelerated phase CML, myelid r lymphid blast phase CML, r Ph+ ALL: 140 mg nce daily. (2) Administered rally, with r withut a meal. Tablets shuld nt be crushed r cut. (2) DOSAGE FORMS AD STREGTHS Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg. (3, 16) COTRAIDICATIOS ne. (4) WARIGS AD PRECAUTIOS Myelsuppressin: Severe thrmbcytpenia, neutrpenia, and anemia may ccur and require dse interruptin r reductin. Mnitr cmplete bld cunts regularly. (2.3, 5.1, 6.1) Bleeding Related Events (mstly assciated with severe thrmbcytpenia): CS and gastrintestinal hemrrhages, including fatalities, have ccurred. FULL PRESCRIBIG IFORMATIO: COTETS* 1 IDICATIOS AD USAGE 2 DOSAGE AD ADMIISTRATIO 2.1 Dse Mdificatin 2.2 Dse Escalatin 2.3 Dse Adjustment fr Adverse Reactins 3 DOSAGE FORMS AD STREGTHS 4 COTRAIDICATIOS 5 WARIGS AD PRECAUTIOS 5.1 Myelsuppressin 5.2 Bleeding Related Events 5.3 Fluid Retentin 5.4 QT Prlngatin 5.5 Cngestive Heart Failure, Left Ventricular Dysfunctin, and Mycardial Infarctin 5.6 Pulmnary Arterial Hypertensin 5.7 Use in Pregnancy 6 ADVERSE REACTIOS 6.1 Chrnic Myelid Leukemia (CML) 6.2 Philadelphia Chrmsme-Psitive Acute Lymphblastic Leukemia (Ph+ ALL) 6.3 Additinal Data Frm Clinical Trials 6.4 Pstmarketing Experience 7 DRUG ITERACTIOS 7.1 Drugs That May Increase Dasatinib Plasma Cncentratins 7.2 Drugs That May Decrease Dasatinib Plasma Cncentratins 7.3 Drugs That May Have Their Plasma Cncentratin Altered By Dasatinib 8 USE I SPECIFIC POPULATIOS 8.1 Pregnancy 8.3 ursing Mthers 8.4 Pediatric Use 8.5 Geriatric Use Severe hemrrhage may require treatment interruptins and transfusins. Use SPRYCEL (dasatinib) with cautin in patients requiring medicatins that inhibit platelet functin r anticagulants. (5.2, 6.1) Fluid Retentin: SPRYCEL is assciated with fluid retentin, smetimes severe, including ascites, edema, and pleural and pericardial effusins. Manage with apprpriate supprtive care measures. (5.3, 6.1) QT Prlngatin: Use SPRYCEL with cautin in patients wh have r may develp prlngatin f the QT interval. (5.4) Cngestive Heart Failure, Left Ventricular Dysfunctin and Mycardial Infarctin: Mnitr patients fr signs r symptms cnsistent with cardiac dysfunctin and treat apprpriately. (5.5, 6.1) Pulmnary Arterial Hypertensin (PAH): SPRYCEL may increase the risk f develping PAH which may be reversible n discntinuatin. Evaluate patients fr signs and symptms f underlying cardipulmnary disease prir t initiating SPRYCEL and during treatment. (5.6) Use in Pregnancy: Fetal harm may ccur when administered t a pregnant wman. Wmen shuld be advised f the ptential hazard t the fetus and t avid becming pregnant. (5.7, 8.1) ADVERSE REACTIOS Mst cmmn adverse reactins ( 10%) in patients with newly diagnsed chrnic phase CML included myelsuppressin, fluid retentin, diarrhea, headache, musculskeletal pain, and rash. Mst cmmn adverse reactins ( 20%) in patients with resistance r intlerance t prir imatinib therapy included myelsuppressin, fluid retentin events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemrrhage. (6.1) T reprt SUSPECTED ADVERSE REACTIOS, cntact Bristl-Myers Squibb at r FDA at FDA-1088 r DRUG ITERACTIOS CYP3A4 Inhibitrs: May increase dasatinib drug levels and shuld be avided. If cadministratin cannt be avided, mnitr clsely and cnsider reducing SPRYCEL dse. (2.1, 7.1) CYP3A4 Inducers: May decrease dasatinib drug levels. If cadministratin cannt be avided, cnsider increasing SPRYCEL dse. (2.1, 7.2) Antacids: May decrease dasatinib drug levels. Avid simultaneus administratin. If needed, administer the antacid at least 2 hurs prir t r 2 hurs after the dse f SPRYCEL. (7.2) H 2 Antagnists/Prtn Pump Inhibitrs: May decrease dasatinib drug levels. Cnsider antacids in place f H 2 antagnists r prtn pump inhibitrs. (7.2) USE I SPECIFIC POPULATIOS Hepatic Impairment: Use SPRYCEL with cautin in patients with hepatic impairment. (8.6) See 17 fr PATIET COUSELIG IFORMATIO and FDA-apprved patient labeling Revised: 10/ Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTIO 12 CLIICAL PHARMACOLOGY 12.1 Mechanism f Actin 12.3 Pharmackinetics 13 OCLIICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility 14 CLIICAL STUDIES 14.1 ewly Diagnsed Chrnic Phase CML 14.2 Imatinib Resistant r Intlerant CML r Ph+ ALL 15 REFERECES 16 HOW SUPPLIED/STORAGE AD HADLIG 16.1 Hw Supplied 16.2 Strage 16.3 Handling and Dispsal 17 PATIET COUSELIG IFORMATIO 17.1 Bleeding 17.2 Myelsuppressin 17.3 Fluid Retentin 17.4 Pregnancy 17.5 Gastrintestinal Cmplaints 17.6 Pain 17.7 Fatigue 17.8 Rash 17.9 Lactse Missed Dse FDA-Apprved Patient Labeling * Sectins r subsectins mitted frm the full prescribing infrmatin are nt listed

2 FULL PRESCRIBIG IFORMATIO 1 IDICATIOS AD USAGE is indicated fr the treatment f adults with newly diagnsed Philadelphia chrmsme-psitive (Ph+) chrnic myelid leukemia (CML) in chrnic phase. The effectiveness f SPRYCEL is based n cytgenetic respnse and majr mlecular respnse rates [see Clinical Studies (14.1)]. The trial is nging and further data will be required t determine lng-term utcme. chrnic, accelerated, r myelid r lymphid blast phase Ph+ CML with resistance r intlerance t prir therapy including imatinib. Philadelphia chrmsme-psitive acute lymphblastic leukemia (Ph+ ALL) with resistance r intlerance t prir therapy. 2 DOSAGE AD ADMIISTRATIO The recmmended starting dsage f SPRYCEL fr chrnic phase CML is 100 mg administered rally nce daily. The recmmended starting dsage f SPRYCEL fr accelerated phase CML, myelid r lymphid blast phase CML, r Ph+ ALL is 140 mg administered rally nce daily. Tablets shuld nt be crushed r cut; they shuld be swallwed whle. SPRYCEL can be taken with r withut a meal, either in the mrning r in the evening. In clinical studies, treatment with SPRYCEL was cntinued until disease prgressin r until n lnger tlerated by the patient. The effect f stpping treatment after the achievement f a cmplete cytgenetic respnse (CCyR) has nt been investigated. 2.1 Dse Mdificatin Cncmitant Strng CYP3A4 inducers: The use f cncmitant strng CYP3A4 inducers may decrease dasatinib plasma cncentratins and shuld be avided (eg, dexamethasne, phenytin, carbamazepine, rifampin, rifabutin, phenbarbital). St. Jhn s Wrt may decrease dasatinib plasma cncentratins unpredictably and shuld be avided. If patients must be cadministered a strng CYP3A4 inducer, based n pharmackinetic studies, a SPRYCEL dse increase shuld be cnsidered. If the dse f SPRYCEL is increased, the patient shuld be mnitred carefully fr txicity [see Drug Interactins (7.2)]. Cncmitant Strng CYP3A4 inhibitrs: CYP3A4 inhibitrs (eg, ketcnazle, itracnazle, clarithrmycin, atazanavir, indinavir, nefazdne, nelfinavir, ritnavir, saquinavir, telithrmycin, and vricnazle) may increase dasatinib plasma cncentratins. Grapefruit juice may als increase plasma cncentratins f dasatinib and shuld be avided. Selectin f an alternate cncmitant medicatin with n r minimal enzyme inhibitin ptential, if pssible, is recmmended. If SPRYCEL must be administered with a strng CYP3A4 inhibitr, a dse decrease shuld be cnsidered. Based n pharmackinetic studies, a dse decrease t 20 mg daily shuld be cnsidered fr patients taking SPRYCEL 100 mg daily. Fr patients taking SPRYCEL 140 mg daily, a dse decrease t 40 mg daily shuld be cnsidered. These reduced dses f SPRYCEL are predicted t adjust the area under the curve (AUC) t the range bserved withut CYP3A4 inhibitrs. Hwever, there are n clinical data with these dse adjustments in patients receiving strng CYP3A4 inhibitrs. If SPRYCEL is nt tlerated after dse reductin, either the strng CYP3A4 inhibitr must be discntinued, r SPRYCEL shuld be stpped until treatment with the inhibitr has ceased. When the strng inhibitr is discntinued, a washut perid f apprximately 1 week shuld be allwed befre the SPRYCEL dse is increased. [See Drug Interactins (7.1).] 2.2 Dse Escalatin In clinical studies f adult CML and Ph+ ALL patients, dse escalatin t 140 mg nce daily (chrnic phase CML) r 180 mg nce daily (advanced phase CML and Ph+ ALL) was allwed in patients wh did nt achieve a hematlgic r cytgenetic respnse at the recmmended starting dsage. 2.3 Dse Adjustment fr Adverse Reactins Myelsuppressin In clinical studies, myelsuppressin was managed by dse interruptin, dse reductin, r discntinuatin f study therapy. Hematpietic grwth factr has been used in patients with resistant myelsuppressin. Guidelines fr dse mdificatins are summarized in Table 1. Table 1: Dse Adjustments fr eutrpenia and Thrmbcytpenia Chrnic Phase CML (starting dse 100 mg nce daily) AC* < /L r Platelets < /L *AC: abslute neutrphil cunt 1. Stp SPRYCEL until AC /L and platelets /L. 2. Resume treatment with SPRYCEL at the riginal starting dse if recvery ccurs in 7 days. 3. If platelets < /L r recurrence f AC < /L fr >7 days, repeat Step 1 and resume SPRYCEL at a reduced dse f 80 mg nce daily fr secnd episde. Fr third episde, further reduce dse t 50 mg nce daily (fr newly diagnsed patients) r discntinue SPRYCEL (fr patients resistant r intlerant t prir therapy including imatinib). (Cntinued) Table 1: Accelerated Phase CML, Blast Phase CML and Ph+ ALL (starting dse 140 mg nce daily) Dse Adjustments fr eutrpenia and Thrmbcytpenia (Cntinued) AC* < /L r Platelets < /L *AC: abslute neutrphil cunt 1. Check if cytpenia is related t leukemia (marrw aspirate r bipsy). 2. If cytpenia is unrelated t leukemia, stp SPRYCEL until AC /L and platelets /L and resume at the riginal starting dse. 3. If recurrence f cytpenia, repeat Step 1 and resume SPRYCEL at a reduced dse f 100 mg nce daily (secnd episde) r 80 mg nce daily (third episde). 4. If cytpenia is related t leukemia, cnsider dse escalatin t 180 mg nce daily. n-hematlgical adverse reactins If a severe nn-hematlgical adverse reactin develps with SPRYCEL use, treatment must be withheld until the event has reslved r imprved. Thereafter, treatment can be resumed as apprpriate at a reduced dse depending n the initial severity f the event. 3 DOSAGE FORMS AD STREGTHS SPRYCEL (dasatinib) Tablets are available as 20-mg, 50-mg, 70-mg, 80-mg, 100-mg, and 140-mg white t ff-white, bicnvex, film-cated tablets. [See Hw Supplied (16.1).] 4 COTRAIDICATIOS ne. 5 WARIGS AD PRECAUTIOS 5.1 Myelsuppressin Treatment with SPRYCEL is assciated with severe (CI CTC Grade 3 r 4) thrmbcytpenia, neutrpenia, and anemia. Their ccurrence is mre frequent in patients with advanced phase CML r Ph+ ALL than in chrnic phase CML. In a dseptimizatin study in patients with resistance r intlerance t prir imatinib therapy and chrnic phase CML, Grade 3 r 4 myelsuppressin was reprted less frequently in patients treated with 100 mg nce daily than in patients treated with ther dsing regimens. Perfrm cmplete bld cunts weekly fr the first 2 mnths and then mnthly thereafter, r as clinically indicated. Myelsuppressin was generally reversible and usually managed by withhlding SPRYCEL temprarily r dse reductin [see Dsage and Administratin (2.3) and Adverse Reactins (6.1)]. 5.2 Bleeding Related Events In additin t causing thrmbcytpenia in human subjects, dasatinib caused platelet dysfunctin in vitr. In all clinical studies, severe central nervus system (CS) hemrrhages, including fatalities, ccurred in 1% f patients receiving SPRYCEL. Severe gastrintestinal hemrrhage, including fatalities, ccurred in 4% f patients and generally required treatment interruptins and transfusins. Other cases f severe hemrrhage ccurred in 2% f patients. Mst bleeding events were assciated with severe thrmbcytpenia. Patients were excluded frm participatin in initial SPRYCEL clinical studies if they tk medicatins that inhibit platelet functin r anticagulants. In subsequent trials, the use f anticagulants, aspirin, and nn-steridal anti-inflammatry drugs (SAIDs) was allwed cncurrently with SPRYCEL if the platelet cunt was >50,000 75,000 per micrliter. Exercise cautin if patients are required t take medicatins that inhibit platelet functin r anticagulants. 5.3 Fluid Retentin SPRYCEL is assciated with fluid retentin. In clinical trials, severe fluid retentin was reprted in up t 10% f patients. Ascites and generalized edema were each reprted in <1% f patients. Severe pulmnary edema was reprted in 1% f patients. Patients wh develp symptms suggestive f pleural effusin, such as dyspnea r dry cugh, shuld be evaluated by chest X-ray. Severe pleural effusin may require thracentesis and xygen therapy. Fluid retentin events were typically managed by supprtive care measures that include diuretics r shrt curses f sterids. In dse-ptimizatin studies, fluid retentin events were reprted less frequently with nce daily dsing than with ther dsing regimens. 5.4 QT Prlngatin In vitr data suggest that dasatinib has the ptential t prlng cardiac ventricular replarizatin (QT interval). Of the 2440 patients with CML treated with SPRYCEL in clinical studies, 15 patients (<1%) had QTc prlngatin reprted as an adverse reactin. Twenty-tw patients (1%) experienced a QTcF >500 ms. In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bund CI) frm baseline ranged frm 7.0 ms t 13.4 ms. Administer SPRYCEL with cautin t patients wh have r may develp prlngatin f QTc. These include patients with hypkalemia r hypmagnesemia, patients with cngenital lng QT syndrme, patients taking anti-arrhythmic medicines r ther medicinal prducts that lead t QT prlngatin, and cumulative high-dse anthracycline therapy. Crrect hypkalemia r hypmagnesemia prir t SPRYCEL administratin.

3 5.5 Cngestive Heart Failure, Left Ventricular Dysfunctin, and Mycardial Infarctin Cardiac adverse reactins were reprted in 5.8% f 258 patients taking SPRYCEL, including 1.6% f patients with cardimypathy, heart failure cngestive, diastlic dysfunctin, fatal mycardial infarctin, and left ventricular dysfunctin. Mnitr patients fr signs r symptms cnsistent with cardiac dysfunctin and treat apprpriately. 5.6 Pulmnary Arterial Hypertensin SPRYCEL may increase the risk f develping pulmnary arterial hypertensin (PAH) which may ccur anytime after initiatin, including after mre than ne year f treatment. Manifestatins include dyspnea, fatigue, hypxia, and fluid retentin. PAH may be reversible n discntinuatin f SPRYCEL. Evaluate patients fr signs and symptms f underlying cardipulmnary disease prir t initiating SPRYCEL and during treatment. If PAH is cnfirmed, SPRYCEL shuld be permanently discntinued. 5.7 Use in Pregnancy SPRYCEL may cause fetal harm when administered t a pregnant wman. In nnclinical studies, at plasma cncentratins belw thse bserved in humans receiving therapeutic dses f dasatinib, embry-fetal txicities, including skeletal malfrmatins, were bserved in rats and rabbits. There are n adequate and well-cntrlled studies f SPRYCEL in pregnant wmen. Wmen f childbearing ptential shuld be advised t avid becming pregnant while receiving treatment with SPRYCEL [see Use in Specific Ppulatins (8.1)]. 6 ADVERSE REACTIOS The fllwing adverse reactins are discussed in greater detail in ther sectins f the labeling: Myelsuppressin [see Dsage and Administratin (2.3) and Warnings and Precautins (5.1)]. Bleeding related events [see Warnings and Precautins (5.2)]. Fluid retentin [see Warnings and Precautins (5.3)]. QT prlngatin [see Warnings and Precautins (5.4)]. Cngestive heart failure, left ventricular dysfunctin, and mycardial infarctin [see Warnings and Precautins (5.5)]. Pulmnary Arterial Hypertensin [see Warnings and Precautins (5.6)]. Because clinical trials are cnducted under widely varying cnditins, adverse reactin rates bserved in the clinical trials f a drug cannt be directly cmpared t rates in the clinical trials f anther drug and may nt reflect the rates bserved in practice. The data described belw reflect expsure t SPRYCEL in clinical studies including 258 patients with newly diagnsed chrnic phase CML and in 2182 patients with imatinib resistant r intlerant CML r Ph+ ALL. In the newly diagnsed chrnic phase CML trial, the median duratin f therapy was 18 mnths; the median average daily dse was 99 mg. In the imatinib resistant r intlerant CML r Ph+ ALL clinical trials, patients had a minimum f 2 years fllw-up (starting dsage 100 mg nce daily, 140 mg nce daily, 50 mg twice daily, r 70 mg twice daily). Amng patients with chrnic phase CML and resistance r intlerance t prir imatinib therapy, the median duratin f treatment with SPRYCEL 100 mg nce daily was 24 mnths (range 1 33 mnths). The median duratin f treatment with SPRYCEL 140 mg nce daily was 15 mnths (range mnths) fr accelerated phase CML, 3 mnths (range mnths) fr myelid blast phase CML, and 3 mnths (range mnths) fr lymphid blast CML. The majrity f SPRYCEL-treated patients experienced adverse reactins at sme time. In the newly diagnsed chrnic phase CML trial, drug was discntinued fr adverse reactins in 6% f SPRYCEL-treated patients. Amng patients with resistance r intlerance t prir imatinib therapy, the rates f discntinuatin fr adverse reactin were 15% in chrnic phase CML, 16% in accelerated phase CML, 15% in myelid blast phase CML, 8% in lymphid blast phase CML, and 8% in Ph+ ALL. In a dse-ptimizatin study in patients with resistance r intlerance t prir imatinib therapy and chrnic phase CML, the rate f discntinuatin fr adverse reactin was lwer in patients treated with 100 mg nce daily than in patients treated with ther dsing regimens (10% and 16%, respectively). The mst frequently reprted adverse reactins reprted in 10% f patients in newly diagnsed chrnic phase CML included myelsuppressin, fluid retentin events (pleural effusin, superficial lcalized edema, generalized edema), diarrhea, headache, musculskeletal pain, and rash. Pleural effusins were reprted in 31 patients (see Table 2). The mst frequently reprted adverse reactins reprted in 20% f patients with resistance r intlerance t prir imatinib therapy included myelsuppressin, fluid retentin events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemrrhage. The mst frequently reprted serius adverse reactins in patients with newly diagnsed chrnic phase CML included pleural effusin (2%), hemrrhage (2%), cngestive heart failure (1%), and pyrexia (1%). The mst frequently reprted serius adverse reactins in patients with resistance r intlerance t prir imatinib therapy included pleural effusin (11%), gastrintestinal bleeding (4%), febrile neutrpenia (4%), dyspnea (3%), pneumnia (3%), pyrexia (3%), diarrhea (3%), infectin (2%), cngestive heart failure/cardiac dysfunctin (2%), pericardial effusin (1%), and CS hemrrhage (1%). 6.1 Chrnic Myelid Leukemia (CML) Adverse reactins (excluding labratry abnrmalities) that were reprted in at least 10% f patients are shwn in Table 2 fr newly diagnsed patients with chrnic phase CML and Table 3 fr CML patients with resistance r intlerance t prir imatinib therapy. Table 2: Adverse Reactins Reprted in 10% f Patients with ewly Diagnsed Chrnic Phase CML All Grades Grade 3/4 SPRYCEL Imatinib SPRYCEL Imatinib Preferred Term Fluid retentin Pleural effusin 12 0 <1 0 Superficial lcalized edema <1 Generalized edema Cngestive heart failure/ cardiac dysfunctin a 2 1 <1 <1 Pericardial effusin 2 <1 <1 0 Pulmnary hypertensin Pulmnary edema < Diarrhea <1 1 Headache Musculskeletal pain <1 Rash b ausea Fatigue 8 11 <1 0 Myalgia Hemrrhage c Gastrintestinal bleeding 2 <1 1 0 Other bleeding d CS bleeding 0 <1 0 <1 Vmiting Muscle inflammatin <1 a Includes cardiac failure acute, cardiac failure cngestive, cardimypathy, diastlic dysfunctin, ejectin fractin decreased, and left ventricular dysfunctin. b Includes erythema, erythema multifrme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfliatin, and rash vesicular. c Adverse reactin f special interest with <10% frequency. d Includes cnjunctival hemrrhage, ear hemrrhage, ecchymsis, epistaxis, eye hemrrhage, gingival bleeding, hematma, hematuria, hemptysis, intra-abdminal hematma, petechiae, scleral hemrrhage, uterine hemrrhage, and vaginal hemrrhage. Table 3: Adverse Reactins Reprted in 10% f Patients with CML Resistant r Intlerant t Prir Imatinib Therapy 100 mg Once Daily 140 mg Once Daily Myelid Lymphid Chrnic Accelerated Blast Blast (n=165) (n=157) (n=74) (n=33) Preferred Term All Grade All Grade All Grade All Grade Grades 3/4 Grades 3/4 Grades 3/4 Grades 3/4 Fluid Retentin Superficial lcalized edema Pleural effusin Generalized edema Pericardial effusin Cngestive heart failure/ cardiac dysfunctin a Pulmnary edema Headache Diarrhea a Includes ventricular dysfunctin, cardiac failure, cardiac failure cngestive, cardimypathy, cngestive cardimypathy, diastlic dysfunctin, ejectin fractin decreased, and ventricular failure. (Cntinued)

4 Table 3: Adverse Reactins Reprted in 10% f Patients with CML Resistant r Intlerant t Prir Imatinib Therapy (Cntinued) 100 mg Once Daily 140 mg Once Daily Myelid Lymphid Chrnic Accelerated Blast Blast (n=165) (n=157) (n=74) (n=33) Preferred Term All Grade All Grade All Grade All Grade Grades 3/4 Grades 3/4 Grades 3/4 Grades 3/4 Fatigue Dyspnea Musculskeletal pain ausea Skin rash b Myalgia Arthralgia Infectin (including bacterial, viral, fungal, and nn-specified) Abdminal pain Hemrrhage Gastrintestinal bleeding CS bleeding Vmiting Pyrexia Febrile neutrpenia a Includes ventricular dysfunctin, cardiac failure, cardiac failure cngestive, cardimypathy, cngestive cardimypathy, diastlic dysfunctin, ejectin fractin decreased, and ventricular failure. b Includes drug eruptin, erythema, erythema multifrme, erythrsis, exfliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematus, rash fllicular, rash generalized, rash macular, rash maculpapular, rash papular, rash pruritic, rash pustular, skin exfliatin, skin irritatin, urticaria vesiculsa, and rash vesicular. Labratry Abnrmalities Myelsuppressin was cmmnly reprted in all patient ppulatins. The frequency f Grade 3 r 4 neutrpenia, thrmbcytpenia, and anemia was higher in patients with advanced phase CML than in chrnic phase CML (Tables 4 and 5). Myelsuppressin was reprted in patients with nrmal baseline labratry values as well as in patients with pre-existing labratry abnrmalities. In patients wh experienced severe myelsuppressin, recvery generally ccurred fllwing dse interruptin r reductin; permanent discntinuatin f treatment ccurred in 2% f patients with newly diagnsed chrnic phase CML and 5% f patients with resistance r intlerance t prir imatinib therapy [see Warnings and Precautins (5.1)]. Grade 3 r 4 elevatins f transaminase r bilirubin and Grade 3 r 4 hypcalcemia, hypkalemia, and hypphsphatemia were reprted in patients with all phases f CML but were reprted with an increased frequency in patients with myelid r lymphid blast phase CML. Elevatins in transaminase r bilirubin were usually managed with dse reductin r interruptin. Patients develping Grade 3 r 4 hypcalcemia during the curse f SPRYCEL therapy ften had recvery with ral calcium supplementatin. Labratry abnrmalities reprted in patients with newly diagnsed chrnic phase CML are shwn in Table 4. There were n discntinuatins f SPRYCEL therapy in this patient ppulatin due t bichemical labratry parameters. Table 4: CTC Grade 3/4 Labratry Abnrmalities in Patients with ewly Diagnsed Chrnic Phase CML SPRYCEL Imatinib Hematlgy Parameters eutrpenia Thrmbcytpenia Anemia 11 7 Bichemistry Parameters Hypphsphatemia 5 24 Hypkalemia 0 2 Hypcalcemia 3 2 Elevated SGPT (ALT) <1 1 Elevated SGOT (AST) <1 1 Elevated Bilirubin 1 0 Elevated Creatinine <1 1 CTC grades: neutrpenia (Grade < /L, Grade 4 < /L); thrmbcytpenia (Grade 3 25 < /L, Grade 4 < /L); anemia (hemglbin Grade 3 65 <80 g/l, Grade 4 <65 g/l); elevated creatinine (Grade 3 >3 6 upper limit f nrmal range (UL), Grade 4 >6 UL); elevated bilirubin (Grade 3 >3 10 UL, Grade 4 >10 UL); elevated SGOT r SGPT (Grade 3 >5 20 UL, Grade 4 >20 UL); hypcalcemia (Grade 3 < mg/dl, Grade 4 <6.0 mg/dl); hypphsphatemia (Grade 3 < mg/dl, Grade 4 <1.0 mg/dl); hypkalemia (Grade 3 < mml/l, Grade 4 <2.5 mml/l). Labratry abnrmalities reprted in patients with CML resistant r intlerant t imatinib wh received the recmmended starting dses f SPRYCEL are shwn by disease phase in Table 5. Table 5: CTC Grade 3/4 Labratry Abnrmalities in Clinical Studies f CML: Resistance r Intlerance t Prir Imatinib Therapy Chrnic Phase CML Advanced Phase CML 140 mg Once Daily 100 mg Accelerated Myelid Lymphid Once Daily Phase Blast Phase Blast Phase (n=165) (n=157) (n=74) (n=33) Hematlgy Parameters eutrpenia Thrmbcytpenia Anemia Bichemistry Parameters Hypphsphatemia Hypkalemia Hypcalcemia < Elevated SGPT (ALT) Elevated SGOT (AST) < Elevated Bilirubin < Elevated Creatinine CTC grades: neutrpenia (Grade < /L, Grade 4 < /L); thrmbcytpenia (Grade 3 25 < /L, Grade 4 < /L); anemia (hemglbin Grade 3 65 <80 g/l, Grade 4 <65 g/l); elevated creatinine (Grade 3 >3 6 upper limit f nrmal range (UL), Grade 4 >6 UL); elevated bilirubin (Grade 3 >3 10 UL, Grade 4 >10 UL); elevated SGOT r SGPT (Grade 3 >5 20 UL, Grade 4 >20 UL); hypcalcemia (Grade 3 < mg/dl, Grade 4 <6.0 mg/dl); hypphsphatemia (Grade 3 < mg/dl, Grade 4 <1.0 mg/dl); hypkalemia (Grade 3 < mml/l, Grade 4 <2.5 mml/l). 6.2 Philadelphia Chrmsme-Psitive Acute Lymphblastic Leukemia (Ph+ ALL) A ttal f 135 patients with Ph+ ALL were treated with SPRYCEL in clinical studies. The median duratin f treatment was 3 mnths (range mnths). The safety prfile f patients with Ph+ ALL was similar t thse with lymphid blast phase CML. The mst frequently reprted adverse reactins included fluid retentin events, such as pleural effusin (24%) and superficial edema (19%), and gastrintestinal disrders, such as diarrhea (31%), nausea (24%), and vmiting (16%). Hemrrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were als frequently reprted. The mst frequently reprted serius adverse reactins included pleural effusin (11%), gastrintestinal bleeding (7%), febrile neutrpenia (6%), infectin (5%), pyrexia (4%), pneumnia (3%), diarrhea (3%), nausea (2%), vmiting (2%), and clitis (2%). 6.3 Additinal Data Frm Clinical Trials The fllwing adverse reactins were reprted in patients in the SPRYCEL clinical studies at a frequency f 1% <10%, 0.1% <1%, r <0.1%. These events are included n the basis f clinical relevance. Gastrintestinal Disrders: 1% <10% mucsal inflammatin (including mucsitis/ stmatitis), dyspepsia, abdminal distensin, cnstipatin, gastritis, clitis (including neutrpenic clitis), ral sft tissue disrder; 0.1% <1% ascites, dysphagia, anal fissure, upper gastrintestinal ulcer, esphagitis, pancreatitis; <0.1% prtein lsing gastrenterpathy. General Disrders and Administratin Site Cnditins: 1% <10% asthenia, pain, chest pain, chills; 0.1% <1% malaise, temperature intlerance. Skin and Subcutaneus Tissue Disrders: 1% <10% pruritus, alpecia, acne, dry skin, hyperhidrsis, urticaria, dermatitis (including eczema); 0.1% <1% pigmentatin disrder, skin ulcer, bullus cnditins, phtsensitivity, nail disrder, acute febrile neutrphilic dermatsis, panniculitis, palmar-plantar erythrdysesthesia syndrme. Respiratry, Thracic, and Mediastinal Disrders: 1% <10% cugh, lung infiltratin, pneumnitis, pulmnary hypertensin; 0.1% <1% asthma, brnchspasm; <0.1% acute respiratry distress syndrme. ervus System Disrders: 1% <10% neurpathy (including peripheral neurpathy), dizziness, dysgeusia, smnlence; 0.1% <1% amnesia, tremr, syncpe; <0.1% cnvulsin, cerebrvascular accident, transient ischemic attack, ptic neuritis. Bld and Lymphatic System Disrders: 1% <10% pancytpenia; <0.1% aplasia pure red cell. Musculskeletal and Cnnective Tissue Disrders: 1% <10% muscular weakness; 0.1% <1% musculskeletal stiffness, rhabdmylysis; <0.1% tendnitis. Investigatins: 1% <10% weight increased, weight decreased; 0.1% <1% bld creatine phsphkinase increased. Infectins and Infestatins: 1% <10% pneumnia (including bacterial, viral, and fungal), upper respiratry tract infectin/inflammatin, herpes virus infectin, enterclitis infectin; 0.1% <1% sepsis (including fatal utcmes).

5 Metablism and utritin Disrders: 1% <10% anrexia, appetite disturbances; 0.1% <1% hyperuricemia, hypalbuminemia. Cardiac Disrders: 1% <10% arrhythmia (including tachycardia), palpitatins; 0.1% <1% angina pectris, cardimegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia); <0.1% cr pulmnale, mycarditis, acute crnary syndrme. Eye Disrders: 1% <10% visual disrder (including visual disturbance, visin blurred, and visual acuity reduced), dry eye; 0.1% <1% cnjunctivitis. Vascular Disrders: 1% <10% flushing, hypertensin; 0.1% <1% hyptensin, thrmbphlebitis; <0.1% lived reticularis. Psychiatric Disrders: 1% <10% insmnia, depressin; 0.1% <1% anxiety, affect lability, cnfusinal state, libid decreased. Reprductive System and Breast Disrders: 0.1% <1% gynecmastia, menstruatin irregular. Injury, Pisning, and Prcedural Cmplicatins: 1% <10% cntusin. Ear and Labyrinth Disrders: 1% <10% tinnitus; 0.1% <1% vertig. Hepatbiliary Disrders: 0.1% <1% chlestasis, chlecystitis, hepatitis. Renal and Urinary Disrders: 0.1% <1% urinary frequency, renal failure, prteinuria. eplasms Benign, Malignant, and Unspecified: 0.1% <1% tumr lysis syndrme. Immune System Disrders: 0.1% <1% hypersensitivity (including erythema ndsum). 6.4 Pstmarketing Experience The fllwing additinal adverse reactins have been identified during pst apprval use f SPRYCEL. Because these reactins are reprted vluntarily frm a ppulatin f uncertain size, it is nt always pssible t reliably estimate their frequency r establish a causal relatinship t drug expsure. Cardiac disrders: atrial fibrillatin/atrial flutter Vascular disrders: thrmbsis/emblism (including pulmnary emblism, deep vein thrmbsis) Respiratry, thracic, and mediastinal disrders: interstitial lung disease, pulmnary arterial hypertensin 7 DRUG ITERACTIOS 7.1 Drugs That May Increase Dasatinib Plasma Cncentratins CYP3A4 Inhibitrs: Dasatinib is a CYP3A4 substrate. In a study f 18 patients with slid tumrs, 20-mg SPRYCEL nce daily cadministered with 200 mg f ketcnazle twice daily increased the dasatinib C max and AUC by fur- and five-fld, respectively. Cncmitant use f SPRYCEL and drugs that inhibit CYP3A4 may increase expsure t dasatinib and shuld be avided. In patients receiving treatment with SPRYCEL, clse mnitring fr txicity and a SPRYCEL dse reductin shuld be cnsidered if systemic administratin f a ptent CYP3A4 inhibitr cannt be avided [see Dsage and Administratin (2.1)]. 7.2 Drugs That May Decrease Dasatinib Plasma Cncentratins CYP3A4 Inducers: When a single mrning dse f SPRYCEL was administered fllwing 8 days f cntinuus evening administratin f 600 mg f rifampin, a ptent CYP3A4 inducer, the mean C max and AUC f dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme inductin ptential shuld be cnsidered. If SPRYCEL must be administered with a CYP3A4 inducer, a dse increase in SPRYCEL shuld be cnsidered [see Dsage and Administratin (2.1)]. Antacids: nclinical data demnstrate that the slubility f dasatinib is ph dependent. In a study f 24 healthy subjects, administratin f 30 ml f aluminum hydrxide/ magnesium hydrxide 2 hurs prir t a single 50-mg dse f SPRYCEL was assciated with n relevant change in dasatinib AUC; hwever, the dasatinib C max increased 26%. When 30 ml f aluminum hydrxide/magnesium hydrxide was administered t the same subjects cncmitantly with a 50-mg dse f SPRYCEL, a 55% reductin in dasatinib AUC and a 58% reductin in C max were bserved. Simultaneus administratin f SPRYCEL with antacids shuld be avided. If antacid therapy is needed, the antacid dse shuld be administered at least 2 hurs prir t r 2 hurs after the dse f SPRYCEL. H 2 Antagnists/Prtn Pump Inhibitrs: Lng-term suppressin f gastric acid secretin by H 2 antagnists r prtn pump inhibitrs (eg, famtidine and meprazle) is likely t reduce dasatinib expsure. In a study f 24 healthy subjects, administratin f a single 50-mg dse f SPRYCEL 10 hurs fllwing famtidine reduced the AUC and C max f dasatinib by 61% and 63%, respectively. In a study f 14 healthy subjects, administratin f a single 100-mg dse f SPRYCEL 22 hurs fllwing a 40-mg meprazle dse at steady state reduced the AUC and C max f dasatinib by 43% and 42%, respectively. The cncmitant use f H 2 antagnists r prtn pump inhibitrs with SPRYCEL is nt recmmended. The use f antacids (at least 2 hurs prir t r 2 hurs after the dse f SPRYCEL) shuld be cnsidered in place f H 2 antagnists r prtn pump inhibitrs in patients receiving SPRYCEL therapy. 7.3 Drugs That May Have Their Plasma Cncentratin Altered By Dasatinib CYP3A4 Substrates: Single-dse data frm a study f 54 healthy subjects indicate that the mean C max and AUC f simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in cmbinatin with a single 100-mg dse f SPRYCEL. Therefre, CYP3A4 substrates knwn t have a narrw therapeutic index such as alfentanil, astemizle, terfenadine, cisapride, cyclsprine, fentanyl, pimzide, quinidine, sirlimus, tacrlimus, r ergt alkalids (ergtamine, dihydrergtamine) shuld be administered with cautin in patients receiving SPRYCEL. 8 USE I SPECIFIC POPULATIOS 8.1 Pregnancy Pregnancy Categry D SPRYCEL may cause fetal harm when administered t a pregnant wman. There are n adequate and well-cntrlled studies f SPRYCEL in pregnant wmen. Wmen f childbearing ptential shuld be advised f the ptential hazard t the fetus and t avid becming pregnant. If SPRYCEL is used during pregnancy, r if the patient becmes pregnant while taking SPRYCEL, the patient shuld be apprised f the ptential hazard t the fetus. In nnclinical studies, at plasma cncentratins belw thse bserved in humans receiving therapeutic dses f dasatinib, embry-fetal txicities were bserved in rats and rabbits. Fetal death was bserved in rats. In bth rats and rabbits, the lwest dses f dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m 2 /day] and rabbit: 0.5 mg/kg/day [6 mg/m 2 /day]) resulted in embry-fetal txicities. These dses prduced maternal AUCs f 105 ng hr/ml (0.3-fld the human AUC in females at a dse f 70 mg twice daily) and 44 ng hr/ml (0.1-fld the human AUC) in rats and rabbits, respectively. Embry-fetal txicities included skeletal malfrmatins at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ssificatin (sternum; thracic, lumbar, and sacral vertebrae; frepaw phalanges; pelvis; and hyid bdy), edema, and micrhepatia. 8.3 ursing Mthers It is unknwn whether SPRYCEL is excreted in human milk. Because many drugs are excreted in human milk and because f the ptential fr serius adverse reactins in nursing infants frm SPRYCEL, a decisin shuld be made whether t discntinue nursing r t discntinue the drug, taking int accunt the imprtance f the drug t the mther. 8.4 Pediatric Use The safety and efficacy f SPRYCEL in patients less than 18 years f age have nt been established. 8.5 Geriatric Use In the newly diagnsed chrnic phase CML study, 25 patients (10%) were 65 years f age and ver and 7 patients (3%) were 75 years f age and ver. Of the 2182 patients in clinical studies f SPRYCEL with resistance r intlerance t imatinib therapy, 547 (25%) were 65 years f age and ver and 105 (5%) were 75 years f age and ver. differences in efficacy were bserved between lder and yunger patients. Cmpared t patients under age 65 years, patients aged 65 years and lder are mre likely t experience txicity. 8.6 Hepatic Impairment The effect f hepatic impairment n the pharmackinetics f dasatinib was evaluated in healthy vlunteers with nrmal liver functin and patients with mderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Cmpared t the healthy vlunteers with nrmal hepatic functin, the dse nrmalized pharmackinetic parameters were decreased in the patients with hepatic impairment. dsage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmaclgy (12.3)]. Cautin is recmmended when administering SPRYCEL t patients with hepatic impairment. 8.7 Renal Impairment There are currently n clinical studies with SPRYCEL in patients with impaired renal functin. Less than 4% f dasatinib and its metablites are excreted via the kidney. 10 OVERDOSAGE Experience with verdse f SPRYCEL in clinical studies is limited t islated cases. Overdsage f 280 mg per day fr 1 week was reprted in tw patients and bth develped severe myelsuppressin and bleeding. Since SPRYCEL is assciated with severe myelsuppressin [see Warnings and Precautins (5.1) and Adverse Reactins (6.1)], patients wh ingested mre than the recmmended dsage shuld be clsely mnitred fr myelsuppressin and given apprpriate supprtive treatment. Acute verdse in animals was assciated with carditxicity. Evidence f carditxicity included ventricular necrsis and valvular/ventricular/atrial hemrrhage at single dses 100 mg/kg (600 mg/m 2 ) in rdents. There was a tendency fr increased systlic and diastlic bld pressure in mnkeys at single dses 10 mg/kg (120 mg/m 2 ). 11 DESCRIPTIO SPRYCEL (dasatinib) is a kinase inhibitr. The chemical name fr dasatinib is -(2-chlr-6-methylphenyl)-2-[[6-[4-(2-hydrxyethyl)-1-piperazinyl]-2-methyl-4- pyrimidinyl]amin]-5-thiazlecarbxamide, mnhydrate. The mlecular frmula is C 22 H 26 Cl 7 O 2 S H 2 O, which crrespnds t a frmula weight f (mnhydrate). The anhydrus free base has a mlecular weight f Dasatinib has the fllwing chemical structure: HO CH 3 H S O H Cl H 3C H 2 O

6 Dasatinib is a white t ff-white pwder. The drug substance is insluble in water and slightly sluble in ethanl and methanl. SPRYCEL tablets are white t ff-white, bicnvex, film-cated tablets cntaining dasatinib, with the fllwing inactive ingredients: lactse mnhydrate, micrcrystalline cellulse, crscarmellse sdium, hydrxyprpyl cellulse, and magnesium stearate. The tablet cating cnsists f hyprmellse, titanium dixide, and plyethylene glycl. 12 CLIICAL PHARMACOLOGY 12.1 Mechanism f Actin Dasatinib, at nanmlar cncentratins, inhibits the fllwing kinases: BCR-ABL, SRC family (SRC, LCK, YES, FY), c-kit, EPHA2, and PDGFR. Based n mdeling studies, dasatinib is predicted t bind t multiple cnfrmatins f the ABL kinase. In vitr, dasatinib was active in leukemic cell lines representing variants f imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the grwth f chrnic myelid leukemia (CML) and acute lymphblastic leukemia (ALL) cell lines verexpressing BCR-ABL. Under the cnditins f the assays, dasatinib was able t vercme imatinib resistance resulting frm BCR-ABL kinase dmain mutatins, activatin f alternate signaling pathways invlving the SRC family kinases (LY, HCK), and multi-drug resistance gene verexpressin Pharmackinetics Absrptin Maximum plasma cncentratins (C max ) f dasatinib are bserved between 0.5 and 6 hurs (T max ) fllwing ral administratin. Dasatinib exhibits dse prprtinal increases in AUC and linear eliminatin characteristics ver the dse range f 15 mg t 240 mg/day. The verall mean terminal half-life f dasatinib is 3 5 hurs. Data frm a study f 54 healthy subjects administered a single, 100-mg dse f dasatinib 30 minutes fllwing cnsumptin f a high-fat meal resulted in a 14% increase in the mean AUC f dasatinib. The bserved fd effects were nt clinically relevant. Distributin In patients, dasatinib has an apparent vlume f distributin f 2505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding f dasatinib and its active metablite t human plasma prteins in vitr was apprximately 96% and 93%, respectively, with n cncentratin dependence ver the range f ng/ml. Metablism Dasatinib is extensively metablized in humans, primarily by the cytchrme P450 enzyme 3A4. CYP3A4 was the primary enzyme respnsible fr the frmatin f the active metablite. Flavin-cntaining mnxygenase 3 (FMO-3) and uridine diphsphate-glucurnsyltransferase (UGT) enzymes are als invlved in the frmatin f dasatinib metablites. The expsure f the active metablite, which is equiptent t dasatinib, represents apprximately 5% f the dasatinib AUC. This indicates that the active metablite f dasatinib is unlikely t play a majr rle in the bserved pharmaclgy f the drug. Dasatinib als had several ther inactive xidative metablites. Dasatinib is a weak time-dependent inhibitr f CYP3A4. At clinically relevant cncentratins, dasatinib des nt inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, r 2E1. Dasatinib is nt an inducer f human CYP enzymes. Eliminatin Eliminatin is primarily via the feces. Fllwing a single ral dse f [ 14 C]-labeled dasatinib, apprximately 4% and 85% f the administered radiactivity was recvered in the urine and feces, respectively, within 10 days. Unchanged dasatinib accunted fr 0.1% and 19% f the administered dse in urine and feces, respectively, with the remainder f the dse being metablites. Effects f Age and Gender Pharmackinetic analyses f demgraphic data indicate that there are n clinically relevant effects f age and gender n the pharmackinetics f dasatinib. Hepatic Impairment Dasatinib dses f 50 mg and 20 mg were evaluated in eight patients with mderate (Child-Pugh class B) and seven patients with severe (Child-Pugh class C) hepatic impairment, respectively. Matched cntrls with nrmal hepatic functin (n=15) were als evaluated and received a dasatinib dse f 70 mg. Cmpared t subjects with nrmal liver functin, patients with mderate hepatic impairment had decreases in dse nrmalized C max and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had dse nrmalized C max decreased by 43% and AUC decreased by 28% cmpared t the nrmal cntrls. These differences in C max and AUC are nt clinically relevant. Dse adjustment is nt necessary in patients with hepatic impairment. 13 OCLIICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility In a tw-year carcingenicity study, rats were administered ral dses f dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dse resulted in a plasma drug expsure (AUC) level equivalent t human expsure at 70 mg twice daily. Dasatinib induced a statistically significant increase in the cmbined incidence f squamus cell carcinmas and papillmas in the uterus and cervix f high-dse females and prstate adenma in lw-dse males. Dasatinib was clastgenic when tested in vitr in Chinese hamster vary cells, with and withut metablic activatin. Dasatinib was nt mutagenic when tested in an in vitr bacterial cell assay (Ames test) and was nt gentxic in an in viv rat micrnucleus study. The effects f dasatinib n male and female fertility have nt been studied. Hwever, results f repeat-dse txicity studies in multiple species indicate the ptential fr dasatinib t impair reprductive functin and fertility. Effects evident in male animals included reduced size and secretin f seminal vesicles, and immature prstate, seminal vesicle, and testis. The administratin f dasatinib resulted in uterine inflammatin and mineralizatin in mnkeys, and cystic varies and varian hypertrphy in rdents. 14 CLIICAL STUDIES 14.1 ewly Diagnsed Chrnic Phase CML An pen-label, multicenter, internatinal, randmized trial was cnducted in adult patients with newly diagnsed chrnic phase CML. A ttal f 519 patients were randmized t receive either SPRYCEL 100 mg nce daily r imatinib 400 mg nce daily. The primary endpint was the rate f cnfirmed cmplete cytgenetic respnse (CCyR) within 12 mnths. Cnfirmed CCyR was defined as a CCyR nted n tw cnsecutive ccasins (at least 28 days apart). Median age was 46 years in the SPRYCEL grup and 49 years in the imatinib grups, with 10% and 11% f patients 65 years f age. There were slightly mre male than female patients in bth grups (59% vs 41%). Fifty-three percent f all patients were Caucasian, and 39% were Asian. At baseline, the distributin f Hasfrd Scres was similar in the SPRYCEL and imatinib treatment grups (lw risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively). The median duratin f treatment was 14 mnths fr SPRYCEL and 14 mnths fr imatinib. With a minimum f 12 mnths fllw-up, 85% f patients randmized t SPRYCEL and 81% f patients randmized t imatinib were still n study. Efficacy results are summarized in Table 6. Table 6: Efficacy Results in ewly Diagnsed Patients with Chrnic Phase CML SPRYCEL Imatinib p-value (n=259) (n=260) Respnse rate (95% CI) Cnfirmed CCyR within 12 mnths a 76.8% ( ) 66.2% ( ) p=0.007* Majr Mlecular Respnse b 52.1% ( ) 33.8% ( ) p<0.0001* a Cnfirmed CCyR is defined as a CCyR nted n tw cnsecutive ccasins at least 28 days apart. b Majr mlecular respnse (at any time) was defined as BCR-ABL ratis 0.1% by RQ-PCR in peripheral bld samples standardized n the Internatinal scale. *Adjusted fr Hasfrd Scre and indicated statistical significance at a pre-defined nminal level f significance. CI = cnfidence interval. Median time t cnfirmed CCyR was 3.1 mnths in 199 SPRYCEL respnders and 5.6 mnths in 177 imatinib respnders. Median time t MMR was 6.3 mnths in 135 SPRYCEL respnders and 9.2 mnths in 88 imatinib respnders. Five patients n the dasatinib arm prgressed t either accelerated phase r blast crisis while nine patients n the imatinib arm prgressed t either accelerated phase r blast crisis Imatinib Resistant r Intlerant CML r Ph+ ALL The efficacy and safety f SPRYCEL were investigated in adult patients with CML r Ph+ ALL whse disease was resistant t r wh were intlerant t imatinib: 1158 patients had chrnic phase CML, 858 patients had accelerated phase, myelid blast phase, r lymphid blast phase CML, and 130 patients had Ph+ ALL. In a clinical study in chrnic phase CML, resistance t imatinib was defined as failure t achieve a cmplete hematlgic respnse (CHR; after 3 mnths), majr cytgenetic respnse (MCyR; after 6 mnths), r cmplete cytgenetic respnse (CCyR; after 12 mnths); r lss f a previus mlecular respnse (with cncurrent 10% increase in Ph+ metaphases), cytgenetic respnse, r hematlgic respnse. Imatinib intlerance was defined as inability t tlerate 400 mg r mre f imatinib per day r discntinuatin f imatinib because f txicity. Results described belw are based n a minimum f 2 years fllw-up after the start f SPRYCEL therapy in patients with a median time frm initial diagnsis f apprximately 5 years. Acrss all studies, 48% f patients were wmen, 81% were white, 15% were black r Asian, 25% were 65 years f age r lder, and 5% were 75 years f age r lder. Mst patients had lng disease histries with extensive prir treatment, including imatinib, cyttxic chemtherapy, interfern, and stem cell transplant. Overall, 80% f patients had imatinib-resistant disease and 20% f patients were intlerant t imatinib. The maximum imatinib dse had been mg/day in abut 60% f the patients and >600 mg/day in 40% f the patients. The primary efficacy endpint in chrnic phase CML was MCyR, defined as eliminatin (CCyR) r substantial diminutin (by at least 65%, partial cytgenetic respnse) f Ph+ hematpietic cells. The primary efficacy endpint in accelerated phase, myelid blast phase, lymphid blast phase CML, and Ph+ ALL was majr hematlgic respnse (MaHR), defined as either a CHR r n evidence f leukemia (EL). Chrnic Phase CML Dse-Optimizatin Study: A randmized, pen-label study was cnducted in patients with chrnic phase CML t evaluate the efficacy and safety f SPRYCEL administered

7 nce daily cmpared with SPRYCEL administered twice daily. Patients with significant cardiac diseases, including mycardial infarctin within 6 mnths, cngestive heart failure within 3 mnths, significant arrhythmias, r QTc prlngatin were excluded frm the study. The primary efficacy endpint was MCyR in patients with imatinib-resistant CML. A ttal f 670 patients, f whm 497 had imatinib-resistant disease, were randmized t the SPRYCEL 100 mg nce daily, 140 mg nce daily, 50 mg twice daily, r 70 mg twice daily grup. Median duratin f treatment was 22 mnths. Efficacy was achieved acrss all SPRYCEL treatment grups with the nce daily schedule demnstrating cmparable efficacy (nn-inferirity) t the twice daily schedule n the primary efficacy endpint (difference in MCyR 1.9%; 95% CI [-6.8% 10.6%]). Efficacy results are presented in Table 7 fr patients with chrnic phase CML wh received the recmmended starting dse f 100 mg nce daily. Additinal efficacy results in this patient ppulatin are described after the table. Results fr all patients with chrnic phase CML, regardless f dsage (a starting dsage f 100 mg nce daily, 140 mg nce daily, 50 mg twice daily, r 70 mg twice daily), were cnsistent with thse fr patients treated with 100 mg nce daily. Table 7: Efficacy f SPRYCEL in Imatinib Resistant r Intlerant Chrnic Phase CML 100 mg Once Daily (n=167) CHR a % (95% CI) 92% (86 95) MCyR b % (95% CI) 63% (56 71) CCyR % (95% CI) 50% (42 58) a CHR (respnse cnfirmed after 4 weeks): WBC institutinal UL, platelets <450,000/mm 3, n blasts r prmyelcytes in peripheral bld, <5% myelcytes plus metamyelcytes in peripheral bld, basphils in peripheral bld <20%, and n extramedullary invlvement. b MCyR cmbines bth cmplete (0% Ph+ metaphases) and partial (>0% 35%) respnses. In the SPRYCEL 100 mg nce daily grup, median time t MCyR was 2.9 mnths (95% CI: [ ]). Based n the Kaplan-Meier estimates, 93% (95% CI: [88% 98%]) f patients wh had achieved an MCyR maintained that respnse fr 18 mnths. The estimated rate f prgressin-free survival and verall survival in all patients treated with 100 mg nce daily was 80% (95% CI: [73% 87%]) and 91% (95% CI: [86% 96%]), respectively, at 2 years. Advanced Phase CML and Ph+ ALL Dse-Optimizatin Study: One randmized pen-label study was cnducted in patients with advanced phase CML (accelerated phase CML, myelid blast phase CML, r lymphid blast phase CML) t evaluate the efficacy and safety f SPRYCEL administered nce daily cmpared with SPRYCEL administered twice daily. The primary efficacy endpint was MaHR. A ttal f 611 patients were randmized t either the SPRYCEL 140 mg nce daily r 70 mg twice daily grup. Median duratin f treatment was apprximately 6 mnths fr bth treatment grups. The nce daily schedule demnstrated cmparable efficacy (nn-inferirity) t the twice daily schedule n the primary efficacy endpint. The efficacy and safety f SPRYCEL were als investigated in patients with Ph+ ALL in ne randmized study (starting dsage 140 mg nce daily r 70 mg twice daily) and ne single-arm study (starting dsage 70 mg twice daily). The primary efficacy endpint was MaHR. A ttal f 130 patients were enrlled in these studies. The median duratin f therapy was 3 mnths. Respnse rates are presented in Table 8. Table 8: Efficacy f SPRYCEL in Imatinib Resistant r Intlerant Advanced Phase CML and Ph+ ALL 140 mg Once Daily Accelerated Myelid Blast Lymphid Blast Ph+ ALL (n=158) (n=75) (n=33) (n=40) MaHR a 66% 28% 42% 38% (95% CI) (59 74) (18 40) (26 61) (23 54) CHR a 47% 17% 21% 33% (95% CI) (40 56) (10 28) (9 39) (19 49) EL a 19% 11% 21% 5% (95% CI) (13 26) (5 20) (9 39) (1 17) MCyR b 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) a Hematlgic respnse criteria (all respnses cnfirmed after 4 weeks): Majr hematlgic respnse: (MaHR) = cmplete hematlgic respnse (CHR) + n evidence f leukemia (EL). CHR: WBC institutinal UL, AC 1000/mm 3, platelets 100,000/mm 3, n blasts r prmyelcytes in peripheral bld, bne marrw blasts 5%, <5% myelcytes plus metamyelcytes in peripheral bld, basphils in peripheral bld <20%, and n extramedullary invlvement. EL: same criteria as fr CHR but AC 500/mm 3 and <1000/mm 3, r platelets 20,000/mm 3 and 100,000/mm 3. b MCyR cmbines bth cmplete (0% Ph+ metaphases) and partial (>0% 35%) respnses. CI = cnfidence interval UL = upper limit f nrmal range. In the SPRYCEL 140 mg nce daily grup, the median time t MaHR was 1.9 mnths fr patients with accelerated phase CML, 1.9 mnths fr patients with myelid blast phase CML, and 1.8 mnths fr patients with lymphid blast phase CML. In patients with myelid blast phase CML, the median duratin f MaHR was 8 mnths and 9 mnths fr the 140 mg nce daily grup and the 70 mg twice daily grup, respectively. In patients with lymphid blast phase CML, the median duratin f MaHR was 5 mnths and 8 mnths fr the 140 mg nce daily grup and the 70 mg twice daily grup, respectively. In patients with Ph+ ALL wh were treated with SPRYCEL 140 mg nce daily, the median duratin f MaHR was 4.6 mnths. The medians f prgressin-free survival fr patients with Ph+ ALL treated with SPRYCEL 140 mg nce daily and 70 mg twice daily were 4.0 mnths and 3.5 mnths, respectively. 15 REFERECES 1. IOSH Alert: Preventing ccupatinal expsures t antineplastic and ther hazardus drugs in healthcare settings U.S. Department f Health and Human Services, Public Health Service, Centers fr Disease Cntrl and Preventin, atinal Institute fr Occupatinal Safety and Health, DHHS (IOSH) Publicatin OSHA Technical Manual, TED A, Sectin VI: Chapter 2. Cntrlling Occupatinal Expsure t Hazardus Drugs. OSHA, 1999, 3. American Sciety f Health-System Pharmacists. ASHP guidelines n handling hazardus drugs. Am J Health-Syst Pharm. (2006) 63: Plvich M, White JM, Kelleher LO (eds) Chemtherapy and bitherapy guidelines and recmmendatins fr practice (2nd ed). Pittsburgh, PA: Onclgy ursing Sciety. 16 HOW SUPPLIED/STORAGE AD HADLIG 16.1 Hw Supplied tablets are available as described in Table 9. Table 9: SPRYCEL Trade Presentatins DC umber Strength Descriptin Tablets per Bttle white t ff-white, bicnvex, rund, film mg cated tablet with BMS debssed n ne 60 side and 527 n the ther side white t ff-white, bicnvex, val, film mg cated tablet with BMS debssed n ne 60 side and 528 n the ther side white t ff-white, bicnvex, rund, film mg cated tablet with BMS debssed n ne 60 side and 524 n the ther side white t ff-white, bicnvex, triangle, film mg cated tablet with BMS and 80 (BMS 30 ver 80) debssed n ne side and 855 n the ther side white t ff-white, bicnvex, val, film mg cated tablet with BMS 100 debssed 30 n ne side and 852 n the ther side white t ff-white, bicnvex, rund mg film-cated tablet with BMS and (BMS ver 140) debssed n ne side and 857 n the ther side 16.2 Strage SPRYCEL tablets shuld be stred at 20 t 25 C (68 t 77 F); excursins permitted between C (59 86 F) [see USP Cntrlled Rm Temperature] Handling and Dispsal Prcedures fr prper handling and dispsal f anticancer drugs shuld be cnsidered. Several guidelines n this subject have been published [see References (15)]. SPRYCEL (dasatinib) tablets cnsist f a cre tablet (cntaining the active drug substance), surrunded by a film cating t prevent expsure f pharmacy and clinical persnnel t the active drug substance. Hwever, if tablets are inadvertently crushed r brken, pharmacy and clinical persnnel shuld wear dispsable chemtherapy glves. Persnnel wh are pregnant shuld avid expsure t crushed r brken tablets. 17 PATIET COUSELIG IFORMATIO See FDA-Apprved Patient Labeling Bleeding Patients shuld be infrmed f the pssibility f serius bleeding and t reprt immediately any signs r symptms suggestive f hemrrhage (unusual bleeding r easy bruising) Myelsuppressin Patients shuld be infrmed f the pssibility f develping lw bld cell cunts; they shuld be instructed t reprt immediately shuld fever develp, particularly in assciatin with any suggestin f infectin.