SPRYCEL(tm) (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. Dasatinib has the following chemical structure:

Dasatinib is a white to off-white powder and has a melting point of 280deg-286deg C. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. SPRYCEL tablets are white to off- white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.

CLINICAL PHARMACOLOGY

Mechanism of Action

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRb. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.

, 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 multi-drug resistance gene overexpression.

Pharmacokinetics

The pharmacokinetics of dasatinib have been evaluated in 229 healthy subjects and in 137 patients with leukemia.

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 study 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.

In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug 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.

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. In human liver microsomes, dasatinib was a weak time-dependent inhibitor of CYP3A4. 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 the drug. Dasatinib also had several other inactive oxidative metabolites.

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.

Special Populations

Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of SPRYCEL. The pharmacokinetics of SPRYCEL have not been evaluated in pediatric patients.

No clinical studies were conducted with SPRYCEL in patients with impaired hepatic function. (See

No clinical studies were conducted with SPRYCEL in patients with decreased renal function. Less than 4% of SPRYCEL and its metabolites are excreted via the kidney. (See PRECAUTIONS.)

Drug-Drug Interactions

SPRYCEL is not an inducer of human CYP enzymes. SPRYCEL is a time-dependent inhibitor of CYP3A4 and may decrease the metabolic clearance of drugs that are primarily metabolized by CYP3A4. (See PRECAUTIONS.) At clinically relevant concentrations, dasatinib does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.

CYP3A4 Inhibitors: In a study of 18 patents with solid tumors, 20-mg dasatinib QD coadministered with 200 mg of ketoconazole BID increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Substances that inhibit CYP3A4 activity (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) may decrease metabolism and increase concentrations of dasatinib (see PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION: Dose Modification.

CYP3A4 Inducers: Data from a study of 20 healthy subjects indicate that when a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampicin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively (see PRECAUTIONS: Drug Interactions). Antacids: Nonclinical data indicate that dasatinib has pH dependent solubility. In a study 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. (See PRECAUTIONS: Drug Interactions.) Famotidine: In a study 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. (See PRECAUTIONS: Drug Interactions.)

CYP3A4 Substrates: Single dose data from a study 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. (See PRECAUTIONS: Drug Interactions.)

CLINICAL STUDIES

Four single-arm multicenter studies were conducted to determine the efficacy and safety of SPRYCEL in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant to or intolerant of treatment with imatinib. Resistance to imatinib included failure to achieve a complete hematologic response (within 3-6 months) or major cytogenetic response (by month 12) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance included inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity. The chronic phase CML study enrolled 186 patients, the accelerated phase CML study 107 patients, the myeloid blast phase study 74 patients, and the lymphoid blast phase CML/Ph+ ALL study 78 patients. The studies are ongoing. The results are based on a minimum of 6 months follow-up after the start of dasatinib therapy. Across all studies, 49% of patients were women, 89% were white, 10% were black or Asian, 23% were over the age of 65 years, and 3% were over the age of 75 years. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant (Table 1). The maximum imatinib dose had been 400-600 mg/day in about one-half of the patients and >600 mg/day in the other half.

All patients were treated with dasatinib 70 mg BID on a continuous basis. The median durations of treatment are shown in Table 2.

The primary efficacy endpoint in chronic phase CML was major cytogenetic response (MCyR), defined as elimination (complete cytogenetic response, CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary endpoint in accelerated phase, myeloid blast phase, and lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a complete hematologic response or no evidence of leukemia (defined in Table 3). Dasatinib treatment resulted in cytogenetic and hematologic responses in patients with all phases of CML and with Ph+ ALL. The response rates for the single-arm studies are reported in Table 3. In chronic phase CML patients, the MCyR rate was 45% with a complete response (0% Ph+ cells) rate of 33%. The MaHR rate was 59% in accelerated phase patients, 32% in myeloid phase patients, 31% in lymphoid blast phase patients, and 42% in Ph+ ALL patients. Most cytogenetic responses occurred after 12 weeks of treatment, when the first cytogenetic analyses were performed. Hematologic and cytogenetic responses were stable during the 6-month follow-up of patients with chronic phase, accelerated phase, and myeloid blast phase CML. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph+ ALL. There were no age- or gender-related response differences.

Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL).

CHR (chronic CML): WBC <= institutional ULN, platelets <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <= institutional ULN, and no extramedullary involvement.

CHR (advanced CML/Ph+ ALL): WBC <= institutional ULN, ANC >=1000/mm3, platelets >=100,000/mm3, no blasts or promyelocytes in

peripheral blood, bone marrow blasts <=5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <=

NEL: same criteria as for CHR but ANC >=500/mm3 and <1000/mm3, and/or platelets >=20,000/mm3 and <=100,000/mm3.

Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (>0%-35%). MCyR (0%-35%) combines both complete and partial

CONTRAINDICATIONS

WARNINGS

Pregnancy (Category D)

Dasatinib may cause fetal harm when administered to a pregnant woman. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of SPRYCEL, fetal toxicity was 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 the recommended dose of 70 mg BID) 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. SPRYCEL is not recommended for use in women who are pregnant or contemplating pregnancy. 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. The potential effects of SPRYCEL on sperm counts, function, and fertility have not been studied (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility: Impairment of Fertility). Sexually active male or female patients taking SPRYCEL should use adequate contraception.

PRECAUTIONS

General

Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced CML or Ph+ ALL than in chronic phase CML. Complete blood counts should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS: Laboratory Abnormalities).

In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. Severe CNS hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage occurred in 7% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 4% of patients. Most bleeding events were associated with severe thrombocytopenia. Patients were excluded from participation in SPRYCEL (dasatinib) clinical studies if they took medications that inhibit platelet function or anticoagulants. Caution should be exercised if patients are required to take medications that inhibit platelet function or anticoagulants.

SPRYCEL is associated with fluid retention, which was severe in 9% of patients, including pleural and pericardial effusion reported in 5% and 1% of patients, respectively. Severe ascites and generalized edema were each reported in 1%. Severe pulmonary edema was reported in 1% of patients. Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids.

data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). In single-arm clinical studies in patients with leukemia treated with SPRYCEL, the mean QTc interval changes from baseline using Fridericia's method (QTcF) were 3-6 msec; the upper 95% confidence intervals for all mean changes from baseline were <8 msec. Nine patients had QTc prolongation reported as an adverse event. Three patients (<1%) experienced a QTcF >500 msec.

SPRYCEL (dasatinib) 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.

Information for Patients (see Patient Information Leaflet)

Drug Interactions

CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin) may increase exposure to dasatinib and should be avoided. 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 CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Drugs that induce CYP3A4 activity may decrease dasatinib plasma concentrations. In patients in whom CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital) are indicated, alternative agents with less enzyme induction potential should be used. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered.

St. John's wort (Hypericum perforatum) may decrease SPRYCEL plasma concentrations unpredictably. Patients receiving SPRYCEL should not take St. John's wort. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. 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. (See CLINICAL PHARMACOLOGY.) H2 Blockers/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 blockers or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. The concomitant use of H2 blockers or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving SPRYCEL therapy. (See CLINICAL PHARMACOLOGY.)

: Dasatinib is a time-dependent inhibitor of CYP3A4. 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. (See CLINICAL PHARMACOLOGY.)

Hepatic Impairment

There are currently no clinical studies with SPRYCEL in patients with impaired liver function (clinical studies have excluded patients with ALT and/or AST >2.5 times the upper limit of the normal range and/or total bilirubin >2 times the upper limit of the normal range). Metabolism of dasatinib is mainly hepatic. Caution is recommended in patients with hepatic impairment.

Renal Impairment

There are currently no clinical studies with SPRYCEL in patients with impaired renal function (clinical studies have excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range). Dasatinib and its metabolites are minimally excreted via the kidney. Since the renal excretion of unchanged dasatinib and its metabolites is <4%, a decrease in total body clearance is not expected in patients with renal insufficiency.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

The effects of dasatinib on male and female fertility have not been studied. However, results of repeat- dose toxicity studies in multiple species indicate the potential for dasatinib to impair reproductive function and fertility. Effects evident in male animals included reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents.

Pregnancy

Nursing Mothers

It is unknown whether SPRYCEL is excreted in human milk. Women who are taking SPRYCEL should not breast-feed.

Pediatric Use

The safety and efficacy of SPRYCEL in patients <18 years of age have not been established.

Geriatric Use

Of the 511 patients in clinical studies of SPRYCEL (dasatinib), 119 (23%) were over 65 years of age, while 13 (3%) were over 75 years of age. No overall differences in safety or efficacy were observed between these patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS

The data described below reflect exposure to SPRYCEL in 911 patients with leukemia from 1 Phase I and 5 Phase II clinical studies. The median duration of therapy was 6 months (range 0 - 19 months). The majority of SPRYCEL-treated patients experienced adverse drug reactions at some time. Drug was discontinued for adverse drug reactions in 6% of patients in chronic phase CML, 5% in accelerated phase CML, 11% in myeloid blast phase CML, and 6% in lymphoid blast phase CML or Ph+ ALL. The most frequently reported adverse events included fluid retention events such as pleural effusion; gastrointestinal events including diarrhea, nausea, abdominal pain and vomiting; and bleeding events. The most frequently reported serious adverse events (SAEs) included pyrexia (9%), pleural effusion (8%) febrile neutropenia (7%), gastrointestinal bleeding (6%), pneumonia (6%), thrombocytopenia (5%), dyspnea (4%), anemia (3%), cardiac failure (3%), and diarrhea (2%). All treatment-emergent adverse events (excluding laboratory abnormalities), regardless of relationship to study drug, that were reported in at least 10% of the patients in SPRYCEL clinical studies are shown in Table 4.

Table 4: Adverse Events Reported >=10% in Clinical Studies
	All Patients		Chronic Phase	Accelerated Phase	Myeloid Blast Phase	Lymphoid Blast Phase and Ph+ ALL
	(n=911)		(n=488)	(n=186)	(n=132)	(n=105)
	All Grades Grades 3/4		Grades 3/4	Grades 3/4	Grades 3/4	Grades 3/4
Preferred Term Percent (%) of Patients
Fluid Retention	50	9	6	6	23	9
Superficial Edema	36	1	0	2	3	2
Pleural Effusion	22	5	3	3	14	8
Other Fluid Retention	14	5	4	4	12	3
Generalized Edema	5	1	<1	0	2	1
Congestive Heart
Failure/Cardiac	4	2	3	1	5	1
a Dysfunction
Pericardial Effusion	4	1	<1	1	3	0
Pulmonary Edema	4	1	1	2	0	1
Ascites	1	1	0	1	2	2
Pulmonary
Hypertension	1	0	<1	1	2	0
Diarrhea	49	5	3	10	8	6
Headache	40	2	2	2	4	6
Hemorrhage	40	10	3	18	23	17
Gastrointestinal Bleeding	14	7	2	12	14	10
CNS Bleeding	2	1	0	1	2	2
Musculoskeletal Pain	39	4	2	3	6	13
Pyrexia	39	5	1	5	13	9
Fatigue	39	3	2	4	4	8
b Skin Rash	35	1	1	1	1	4
Nausea	34	1	<1	0	5	2
Dyspnea	32	6	5	7	11	9
Cough	28	<1	<1	1	1	0
Infection (including bacterial, viral, fungal,	34	7	4	8	15	13
non-specified)
Infection/Inflammation	26	1	1	1	5	1
Abdominal Pain	25	2	1	2	4	6
Pain	26	2	<1	1	5	4
Vomiting	22	1	1	2	2	2
Anorexia	19	1	<1	2	2	3
Asthenia	19	3	1	4	6	5
Arthralgia	19	1	1	0	3	2

Upper Respiratory Tract

Table 4: Adverse Events Reported >=10% in Clinical Studies
			Chronic	Accelerated	Myeloid	Lymphoid Blast Phase and
	All Patients		Phase	Phase	Blast Phase	Ph+ ALL
	(n=911)		(n=488)	(n=186)	(n=132)	(n=105)
	All Grades Grades 3/4		Grades 3/4	Grades 3/4	Grades 3/4	Grades 3/4
Preferred Term Percent (%) of Patients Mucosal Inflammation
(including	16	1	<1	0	4	1
mucositis/stomatitis)
Dizziness	14	<1	<1	0	0	0
Weight Decreased	14	1	<1	1	1	0
Constipation	14	<1	<1	0	1	0
Chest Pain	13	1	<1	0	4	3
Neuropathy (including
peripheral neuropathy)	13	1	1	1	0	0
Myalgia	12	1	0	1	2	2
Abdominal Distention	11	0	0	0	0	0
Weight Increased	11	1	<1	1	1	1
Arrhythmia	11	2	2	1	2	3
Chills	11	<1	0	1	0	0
Pruritus	11	0	0	0	0	0
Pneumonia (including
bacterial, viral, and	11	6	3	8	11	10
fungal)
Febrile Neutropenia	9	8	2	11	17	20

Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive

cardiomyopathy, ejection fraction decreased, and left ventricular failure.

Includes erythema, exfoliative rash, generalized erythema, milia, rash, rash erythematous, rash follicular,

rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, systemic lupus erythematosus rash, urticaria vesiculosa, drug eruption, and rash vesicular.

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 CML or Ph+ ALL than in chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption and/or reduction; permanent discontinuation of treatment occurred in 1% of patients. Grade 3 or 4 elevations of transaminases or bilirubin and Grade 3 or 4 hypocalcemia and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast CML and Ph+ ALL. Elevations in transaminases 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.

Table 5: CTC Grades 3/4 Laboratory Abnormalities in Clinical

Studies

Chronic Phase (n=488)

Accelerated Phase (n=186)

Myeloid Blast Phase (n=132)

Lymphoid Blast Phase and Ph+ ALL (n=105)

Hematology Parameters

Percent (%) of Patients
Neutropenia	49		74	83	81
Thrombocytopenia	48		83	82	83
Anemia	18		70	70	51
Biochemistry Parameters Hypophosphatemia	11		13	23	21
Hypocalcemia	2		9	20	15
Elevated SGPT (ALT)	1		4	7	11
Elevated SGOT (AST)	1		2	5	8
Elevated Bilirubin	<1		1	5	8
Elevated Creatinine	0		2	1	1
CTC grades: neutropenia (Grade 3	>=0.5-1.0 x 1	9 9/ 0 /L, Grade 4 <0.5 x 10 L)		; thrombocyt	openia

9 9

(Grade 3 >=10-50 x 10 /L, Grade 4 <10 x 10 /L); anemia (hemoglobin >=65-80 g/L, Grade 4 <65 g/L);

elevated creatinine (Grade 3 >3-6 x upper limit normal range (ULN), Grade 4 >6 x ULN); elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN); elevated SGOT or SGPT (Grade 3 >5-20 x

ULN, Grade 4 >20 x ULN); hypocalcemia (Grade 3 <7.0-6.0 mg/dL, Grade 4 <6.0 mg/dL);

hypophosphatemia (Grade 3 <2.0-1.0 mg/dL, Grade 4 <1.0 mg/dL).

Additional Data From Clinical Trials

The following treatment-emergent adverse events, regardless of relationship to study drug, were reported in patients in the SPRYCEL clinical studies at a frequency of <10%. These events are presented by frequency category. Frequent adverse events are those occurring in 1%-<10% of patients and infrequent adverse events are those occurring in 0.1%-<1% of patients. Infrequent events are included on the basis of clinical relevance.

Gastrointestinal Disorders: Frequent - dyspepsia, oral soft tissue disorder, gastritis, colitis, anal fissure, dysphagia; Infrequent - esophagitis, upper gastrointestinal ulcer, ileus, pancreatitis.

General Disorders and Administration Site Conditions: Frequent - malaise; Infrequent - temperature intolerance.

Skin and Subcutaneous Tissue Disorders: Frequent - hyperhidrosis, alopecia, dry skin, acne, urticaria, dermatitis (including eczema), photosensitivity reaction, nail disorder, pigmentation disorder; Infrequent - skin ulcer, acute febrile neutrophilic dermatosis, bullous conditions, palmar-plantar erythrodysesthesia syndrome.

Respiratory, Thoracic, and Mediastinal Disorders:

Frequent -

lung infiltration, pneumonitis, asthma;

Infrequent -

bronchospasm, acute respiratory distress syndrome.

Nervous System Disorders: Frequent - dysgeusia, somnolence, syncope, tremor, convulsion; Infrequent - amnesia, cerebrovascular accident, transient ischemic attack, reversible posterior leukoencephalopathy syndrome.

Blood and Lymphatic System Disorders: Frequent - pancytopenia; Infrequent - coagulopathy, aplasia pure red cell.

Musculoskeletal and Connective Tissue Disorders: Frequent - muscle inflammation, muscular weakness, musculoskeletal stiffness; Infrequent - tendonitis, rhabdomyolysis.

Investigations: Frequent - blood creatine phosphokinase increased, troponin increased; Infrequent - platelet aggregation abnormal.

Infections and Infestations:

Frequent -

herpes virus infection, sepsis (including fatal outcomes), enterocolitis infection.

Metabolism and Nutrition Disorders: Frequent - appetite disturbances, hyperuricemia; Infrequent - hypoalbuminemia.

Cardiac Disorders:

Frequent -

palpitations, angina pectoris, cardiomegaly, myocardial infarction;

Infrequent -

pericarditis, ventricular tachycardia, acute coronary syndrome, myocarditis.

Eye Disorders:

Frequent -

conjunctivitis, dry eye.

Vascular Disorders: Frequent - flushing, hypotension, hypertension; Infrequent - livedo reticularis.

Psychiatric Disorders:

Frequent -

insomnia, depression, anxiety, confusional state, affect lability;

Infrequent -

libido decreased.

Reproductive System and Breast Disorders: Frequent - gynecomastia; Infrequent - menstruation irregular.

Injury, Poisoning, and Procedural Complications:

Frequent

- contusion.

Ear and Labyrinth Disorders:

Frequent

- tinnitus, vertigo.

Hepatobiliary Disorders:

Infrequent

- cholecystitis, hepatitis, cholestasis.

Renal and Urinary Disorders: Frequent - urinary frequency, renal failure; Infrequent - proteinuria.

Neoplasms Benign, Malignant and Unspecified:

Frequent

- tumor lysis syndrome.

Immune System Disorders:

Infrequent

- hypersensitivity.

OVERDOSAGE

A single-dose overdose of SPRYCEL 200 mg in a patient with accelerated phase CML was reported with no associated symptoms or change in laboratory parameters. In the event of overdosage, the patient should be observed and appropriate supportive treatment given. (See PRECAUTIONS.) 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).

DOSAGE AND ADMINISTRATION

The recommended dosage of SPRYCEL (dasatinib) is 140 mg/day administered orally in two divided doses (70 mg twice daily [BID]), one in the morning and one in the evening with or without a meal. Tablets should not be crushed or cut; they should be swallowed whole. In clinical studies, treatment with SPRYCEL was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.

Dose Modification

Dose increase or reduction of 20-mg increments per dose is recommended based on individual safety and tolerability. CYP3A4 inducers such as rifampin may decrease SPRYCEL plasma concentrations. Coadministration of SPRYCEL with rifampin resulted in a decrease in the mean Cmax and AUC of dasatinib by 81% and 82%, respectively (a 5-fold decrease in SPRYCEL plasma concentrations). Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Drug Interactions). St. John's wort may decrease SPRYCEL plasma concentrations unpredictably. Patients receiving SPRYCEL should not take St. John's wort concomitantly. CYP3A4 inhibitors such as ketoconazole may increase SPRYCEL plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease to 20-40 mg daily should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Drug Interactions).

Dose Escalation

In clinical studies of adult CML and Ph+ ALL patients, dose escalation to 90 mg BID (chronic phase CML) or 100 mg BID (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a hematologic or cytogenetic response at the recommended dosage.

Dose Adjustment for Adverse Reactions

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 6.

and resume SPRYCEL at a reduced dose of 50 mg BID (second episode) or 40 mg BID (third episode).

If recurrence of cytopenia, repeat Step 1 and resume SPRYCEL at a reduced dose of

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 initial severity of the event.

HOW SUPPLIED

Storage

SPRYCEL (dasatinib) tablets should be stored at 25deg C (77deg F); excursions permitted between 15deg- 30deg C (59deg-86deg F) [see USP Controlled Room Temperature].

Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-9 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 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 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.

REFERENCES

AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985; 253:1590-1592. National Study Commission on Cytotoxic Exposure. Recommendations for Handling Cytotoxic Agents. 1987. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426-428. Jones RB, Prank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983; 33:258-263. American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049.

NIOSH Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Publication number 2004-165. September, 2004. Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA US Patent No 6,596,746

Chronic	Accelerated	Myeloid Blast	Lymphoid Blast	Ph+ ALL
(n=186)	(n=107)	(n=74)	(n=42)	(n=36)
64 (4-251)	91 (4-355)	49 (3-216)	28 (2-186)	20 (3-97)

Resistant	68%	93%	92%	88%	94%
Intolerant	32%	7%	8%	12%	6%

>3 years	54%	68%	47%	24%	3%
>1 year	80%	92%	85%	52%	56%
otoxic motherapy 42% 67% 66% 79% 92%
rferon	70%	75%	55%	48%	8%
m cell transplant 9% 18% 12% 33% 42%

Chronic	Accelerated	Myeloid Blast	Lymphoid Blast	Ph+ ALL
(n=186)	(n=107)	(n=74)	(n=42)	(n=36)
5.6 (0.03-8.3)	5.5 (0.2-10.1)	3.5 (0.03-9.2)	2.8 (0.1-6.4)	3.2 (0.2-8.1)

NDC Number	Strength	Description	Tablets per Bottle
0003-0527-11	20 mg	white to off-white, biconvex, round, film coated tablet with "BMS" debossed on one side and "527" on the other side	60
0003-0528-11	50 mg	white to off-white, biconvex, oval, film coated tablet with "BMS" debossed on one side and "528" on the other side	60
0003-0524-11	70 mg	white to off-white, biconvex, round, film coated tablet with "BMS" debossed on one side and "524" on the other side	60

Patient Information Included DESCRIPTION

CLINICAL PHARMACOLOGY

Mechanism of Action

Pharmacokinetics

Special Populations

Drug-Drug Interactions

CLINICAL STUDIES

INDICATIONS AND USAGE

CONTRAINDICATIONS

WARNINGS

Pregnancy (Category D)

PRECAUTIONS

General

Information for Patients (see Patient Information Leaflet)

Drug Interactions

Hepatic Impairment

Renal Impairment

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Nursing Mothers

Pediatric Use

Geriatric Use

ADVERSE REACTIONS

Laboratory Abnormalities

OVERDOSAGE

DOSAGE AND ADMINISTRATION

Dose Modification

Dose Escalation

Dose Adjustment for Adverse Reactions

HOW SUPPLIED

Storage

Handling and Disposal

REFERENCES