PRODUCT INFORMATION SPRYCEL(r)

NAME OF THE MEDICINE

SPRYCEL(r) (Dasatinib) SPRYCEL(r) (Dasatinib) is a potent inhibitor of multiple oncogenic kinases, cellular enzymes involved in the transmission of growth signals from the cell membrane to the nucleus. 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 C22H26C1N7O2S * H2O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib drug substance has the following chemical structure: The CAS number for dasatinib monohydrate is 863127-77-9.

DESCRIPTION

Dasatinib is a white to off-white powder. The drug substance is insoluble in water (0.008 mg/mL) at 24 +- 4 oC. The pH of a saturated solution of dasatinib in water is about 6.0. Two basic ionization constants (pKa) were determined to be 6.8 and 3.1, and one weakly acidic pKa was determined to be 10.8. The solubilities of dasatinib in various solvents at 24 +- 4 oC are as follows: slightly soluble in ethanol (USP), methanol, polyethylene glycol 400, and propylene glycol; very slightly soluble in acetone and acetonitrile; and practically insoluble in corn oil. SPRYCEL(r) film coated tablets contain the following inactive ingredients: lactose, microcrystalline cellulose, croscarmellose sodium, hydroxpropyl cellulose and magnesium stearate. The tablet coating contains: hypromellose, titanium dioxide and polyethylene glycol.

PHARMACOLOGY

Mechanism of Action

Dasatinib inhibits the activity of the BCR-ABL kinase and SRC-family kinases at low nanomolar or subnanomolar concentrations. Dasatinib also inhibits a number of other kinases including c-KIT, the EPHA2 receptor and the PDGFb receptor. Unlike imatinib, it binds not only to the inactive but also to the active conformation of the BCR-ABL kinase. This suggests a reduced propensity for acquired drug resistance due to the emergence of mutations that promote the adoption of kinase's active conformation. Dasatinib has been demonstrated to inhibit the survival/proliferation of human leukaemic cell lines in vitro, and to inhibit the growth of human CML (chronic myeloid leukaemia) xenografts in SCID mice, in both imatinib-sensitive and resistant models of the disease. Antileukaemic activity was seen in dasatinib-treated mice in a model of CML with CNS involvement. Non-clinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL independence, most BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving SRC-family kinases (LYN and FYN) and P-glycoprotein (multi-drug resistance protein 1) overexpression.

PHARMACOKINETICS

The pharmacokinetics of SPRYCEL(r) (dasatinib) were evaluated in 229 healthy subjects and in 84 patients with leukaemia.

Absorption

Dasatinib is rapidly absorbed in patients following oral administration. The absolute bioavailability of dasatinib has not been determined. Peak concentrations were observed between 0.5-3 hours. Following oral administration, the increase in the mean exposure (AUCt) is approximately proportional to the dose increment across doses ranging from 25 mg to 120 mg twice daily (BID). 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 indicated a 14% increase in the mean AUC of dasatinib. Consumption of a low-fat meal 30 minutes prior to dasatinib resulted in a 21% increase in the mean AUC of dasatinib. The observed food effects are unlikely to be clinically significant.

Distribution

In patients, SPRYCEL(r) has a large apparent volume of distribution (2505 L) suggesting that the drug is extensively distributed in the extravascular space.

Metabolism

Dasatinib is extensively metabolized in humans. In a study of 8 healthy subjects administered 100 mg of [14C]-labelled dasatinib, unchanged dasatinib represented 29% of circulating radioactivity in plasma. Plasma concentration and measured in vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observed pharmacology of the drug. The overall mean terminal half-life of dasatinib is approximately 5-6 hours. CYP3A4 is a major enzyme responsible for the metabolism of dasatinib.

Elimination

Elimination is predominantly in the faeces, mostly as metabolites. Following a single oral dose of [14C]-labelled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 85% of the administered radioactivity recovered in the urine and faeces, respectively. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and faeces, 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(r). The pharmacokinetics of SPRYCEL(r) have not been evaluated in paediatric patients. The effect of hepatic impairment on the single-dose pharmacokinetics of dasatinib was assessed in 8 moderately hepatic-impaired subjects who received a 50 mg dose and 5 severely hepatic-impaired subjects who received a 20 mg dose compared to matched healthy subjects who received a 70 mg dose of dasatinib. The mean Cmax and AUC of dasatinib adjusted for the 70 mg dose was decreased by 47% and 8%, respectively, in subjects with moderate hepatic impairment compared to subjects with normal hepatic function. In severely hepatic- impaired subjects, the mean Cmax and AUC adjusted for the 70 mg dose was decreased by 43% and 28% respectively, compared to subjects with normal hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

CLINICAL TRIALS

In the Phase I study, haematologic and cytogenetic responses were observed in all phases of CML and in Ph+ ALL in the first 84 patients treated and followed for up to 27 months. Responses were durable across all phases of CML and Ph+ ALL. Four single-arm, uncontrolled, open-label Phase II clinical trials were conducted to determine the safety and efficacy of SPRYCEL in patients with CML in chronic, accelerated, or myeloid blast phase, who were either resistant or intolerant to imatinib. One randomized, comparative trial was conducted in chronic phase patients who failed initial treatment with 400 or 600 mg imatinib. The starting dose of SPRYCEL was 70 mg twice daily. Dose modifications were allowed for improving activity or management of toxicity. Two randomised, open-label Phase III trials were conducted to evaluate the efficacy of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. In addition, one open-label, randomised, comparative Phase III study was conducted in adult patients with newly diagnosed chronic phase CML. The efficacy of SPRYCEL is based on haematological and cytogenetic response rates. Durability of response and estimated survival rates provide additional evidence of SPRYCEL clinical benefit. A total of 2,440 patients were evaluated in clinical trials; of these 23% were >= 65 years of age and 5% were >= 75 years of age.

Chronic Phase CML - Newly Diagnosed

An international open-label, multi-centre, randomised, comparative Phase III study was conducted in adult patients with newly diagnosed chronic phase CML. Patients were randomised to receive either SPRYCEL(r) 100 mg once daily or imatinib 400 mg once daily. The primary end-point was the rate of confirmed complete cytogenetic response (cCCyR) within 12 months. Secondary endpoints included time in cCCyR (measure of durability of response), time to cCCyR, major molecular response (MMR) rate, time to MMR, progression free survival (PFS) and overall survival (OS). Other relevant efficacy results included CCyR and complete molecular response (CMR) rates. A total of 519 patients were randomised to a treatment group: 259 to SPRYCEL(r) and 260 to imatinib. Baseline characteristics were well balanced between the two treatment groups with respect to age (median age was 46 years for the SPRYCEL(r) group and 49 years for the imatinib group with 10% and 11% of patients 65 years of age or older, respectively), gender (women 44% and 37%, respectively), and race (Caucasian 51% and 55%; Asian 42% and 37%, respectively). At baseline, the distribution of Hasford Scores was similar in the SPRYCEL(r) and imatinib treatment groups (low risk: 33% and 34%; intermediate risk 48% and 47%; high risk: 19% and 19%, respectively). With a minimum of 12 months follow-up, 85% of patients randomised to the SPRYCEL(r) group and 81% of patients randomised to the imatinib group were still receiving first-line treatment. Discontinuation due to disease progression occurred in 3% of SPRYCEL(r)-treated patients and 5% of imatinib-treated patients. With a minimum of 36 months follow-up, 71% of patients randomised to the SPRYCEL(r) group and 69% of patients randomised to the imatinib group were still receiving first-line treatment. Discontinuation due to disease progression occurred in 7% of SPRYCEL(r)-treated patients and 7% of imatinib-treated patients. Efficacy results are presented in Table 1. A statistically significantly greater proportion of patients in the SPRYCEL(r) group achieved a cCCyR compared with patients in the imatinib group within the first 12 months of treatment. Efficacy of SPRYCEL(r) was consistently demonstrated across different subgroups, including age, gender, and baseline Hasford score.

a

Confirmed complete cytogenetic response (cCCyR) is defined as a response noted on two consecutive occasions (at least 28 days apart).

b

Cytogenetic response (CCyR) is based on a single bone marrow cytogenetic evaluation. The CCyR results refer to best unconfirmed cytogenic response within 12 months for any number of metaphases.

c

Major molecular response (at any time) was defined as BCR-ABL ratios <= 0.1% by RQ-PCR in peripheral blood samples standardized on the International scale. These are cumulative rates representing minimum follow-up for the timeframe specified.

d

Formal statistical comparison of cCCyR and MMR rates was only performed at the time of the primary endpoint (cCCyR within 12 months)

*Adjusted for Hasford Score and indicated statistical significance at a pre-defined nominal level of significance.

* *Not significant.

CI = confidence interval

For time-to cCCyR, a hazard ratio of 1.55 indicates that a patient treated with SPRYCEL is 55% more likely to achieve a cCCyR at any time compared to a patient treated with imatinib. Similarly, for time-to MMR, a hazard ratio of 2.01 indicates a patient treated with SPRYCEL is more than two times more likely to achieve a MMR at any time compared to a patient treated with imatinib. For durability of cCCyR (time-in response), a hazard ratio of 0.7 indicates a patient treated with SPRYCEL is 30% less likely to have disease progression after achieving a cCCyR (or never achieving a cCCyR) compared to a patient treated with imatinib. After 36 months follow-up, median time to cCCyR was 3.1 months in the 214 SPRYCEL(r) group responders and 5.8 months in the 201 imatinib group responders.. Median time to MMR after 36 months follow-up was 8.9 months in the 179 SPRYCEL(r) group responders and 13.4 months in the 146 imatinib group responders. The rates of cCCyR in the SPRYCEL(r) and imatinib treatment groups, respectively, within 3 months (54% and 30%), 6 months (70% and 56%), 9 months (75% and 63%), 24 months (80% and 74%) and 36 months (83% and 77%) were consistent with the primary endpoint. The rates of MMR in the SPRYCEL(r) and imatinib treatment groups, respectively, within 3 months (8% and 0.4%), 6 months (27% and 8%), 9 months (39% and 18%), 12 months (46% and 28%), 24 months (64% and 46%) and 36 months (67% and 55%) were also consistent with the primary endpoint. The rate of CMR (i.e. at least 4.5-log reduction from a standardised baseline value BCR-ABL ratio <= 0.0032%) at any time was 25.9% versus 14.2% in the SPRYCEL(r) and imatinib treatment groups, respectively. Progression was defined as increasing white blood cells despite appropriate therapeutic management, loss of CHR (complete haematologic response), partial CyR or CCyR, progression to accelerated phase or blast phase, or death. The estimated 36-month PFS rate was 91.0% (CI: 87.4% - 94.7%) and 90.9% (CI: 87.1% - 94.6%) for the SPRYCEL(r) and imatinib treatment groups, respectively. Transformation to accelerated or blast phase occurred less frequently with SPRYCEL(r) (n = 8; 3.1%) than with imatinib-treated patients (n = 13; 5%). The estimated 36-month survival rates for SPRYCEL(r) and imatinib-treated patients were 93.7% (CI: 90.6% - 96.7%) and 93.2% (CI: 90.1% - 96.4%) respectively. In a phase III trial of newly diagnosed chronic phase CML, BCR-ABL sequencing was performed on blood samples from patients who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L and V299L. Dasatinib does not appear to be active against the T315I mutation, based on in vitro data. Data described below are from studies using a starting dosage of 70 mg twice daily. See DOSAGE AND ADMINISTRATION for the recommended starting dosages for chronic phase CML, accelerated phase CML, myeloid and lymphoid blast phase CML, and Ph+ALL.

Chronic Phase CML - Resistance or Intolerance to Prior Imatinib Therapy Two clinical trials were conducted in patients resistant or intolerant to imatinib; the primary efficacy endpoint in these trials was Major Cytogenetic Response (MCyR):

1. An open-label, randomised, comparative multi-centre study was conducted in patients who failed initial treatment with 400 or 600 mg imatinib. They were randomised (2:1) to either SPRYCEL(r) (70 mg twice daily) or imatinib (400 mg twice daily). Crossover to the

alternative treatment arm was allowed if patients showed evidence of disease progression or intolerance that could not be managed by dose modification. The primary endpoint was MCyR at 12 weeks. Results are available for 150 patients: 101 were randomised to SPRYCEL and 49 to imatinib (all imatinib-resistant). The median time from diagnosis to randomisation was 64 months in the SPRYCEL(r) group and 52 months in the imatinib group. All subjects were extensively pretreated. Prior complete haematologic response (CHR) to imatinib was achieved in 93% of the overall patient population. A prior MCyR to imatinib was achieved in 28% and 29% of the patients in the dasatinib and imatinib arms, respectively. Median duration of treatment was 23 months for dasatinib (with 44% of patients treated for > 24 months to date) and 3 months for imatinib (with 10% of patients treated for >24 months to date). Ninety-three percent (93%) of patients in the SPRYCEL(r) arm and 82% of the patients in the imatinib arm achieved a CHR prior to cross-over. At 3 months, a MCyR occurred more often in the SPRYCEL(r) arm (36%) than in the imatinib arm (29%). Notably, 22% of patients reported a complete cytogenetic response (CCyR) in the SPRYCEL(r) arm while only 8% achieved a CCyR in the imatinib arm. With longer treatment and follow-up (median of 24 months), MCyR was achieved in 53% of the SPRYCEL-treated patients (CCyR in 44%) and 33% of the imatinib-treated patients (CCyR in 18%) prior to crossover. Among patients who had received imatinib 400 mg prior to study entry, MCyR was achieved in 61% of patients in the SPRYCEL arm and 50% in the imatinib arm. Based on the Kaplan-Meier estimates, the proportion of patients who maintained MCyR for 1 year was 92% (95% CI: [85%-100%]) for SPRYCEL (CCyR 97%, 95% CI: [92%-100%]) and 74% (95% CI: [49%-100%]) for imatinib (CCyR 100%). The proportion of patients who maintained MCyR for 18 months was 90% (95% CI: [82%-98%]) for SPRYCEL (CCyR 94%, 95% CI: [87%-100%]) and 74% (95% CI: [49%-100%]) for imatinib (CCyR 100%). Based on the Kaplan-Meier estimates, the proportion of patients who had progression-free survival (PFS) for 1 year was 91% (95% CI: [85%-97%]) for SPRYCEL and 73% (95% CI: [54%-91%]) for imatinib. The proportion of patients who had PFS at 2 years was 86% (95% CI: [78%-93%]) for SPRYCEL and 65% (95% CI: [43%-87%]) for imatinib. A total of 43% of the patients in the dasatinib arm, and 82% in the imatinib arm had treatment failure, defined as disease progression or cross-over to the other treatment (lack of response, study drug intolerance, etc. ). The rate of major molecular response (defined as BCR-ABL/control transcripts <= 0.1% by RQ-PCR in peripheral blood samples) prior to crossover was 29% for SPRYCEL and 12% for imatinib. An open-label, single-arm, multi-centre study was conducted in patients resistant or intolerant to imatinib (i.e. patients who experienced significant toxicity during treatment with imatinib that precluded further treatment). A total of 387 patients received dasatinib 70 mg twice daily (288 resistant and 99 intolerant). The median time from diagnosis to start of treatment was 61 months. The majority of the patients (53%) had received prior imatinib treatment for more than 3 years. Most resistant patients (72%) had received > 600 mg imatinib. In addition to imatinib, 35% of patients had received prior cytotoxic chemotherapy, 65% had received prior interferon, and 10% had received a prior stem cell transplant. Thirty-eight percent of patients had baseline mutations known to confer imatinib resistance. Median duration of treatment on SPRYCEL was 24 months with 51% of patients treated for > 24 months to date. Efficacy results are reported in Table 2. MCyR was achieved in 55% of imatinib-resistant patients and 82% of imatinib- intolerant patients. With a minimum of 24 months follow-up, 21 of the 240 patients who had achieved a MCyR had progressed and the median duration of MCyR had not been reached. Based on the Kaplan-Meier estimates, 95% (95% CI: [92%-98%]) of the patients maintained MCyR for 1 year and 88% (95% CI: [83%-93%]) maintained MCyR for 2 years. The proportion of patients who maintained CCyR for 1 year was 97% (95% CI: [94%-99%]) and for 2 years was 90% (95% CI: [86%-95%]). Fifty-two percent (52%) of the imatinib-resistant patients with no prior MCyR to imatinib (n = 188) achieved a MCyR with SPRYCEL(r). There were 45 different BCR-ABL mutations in 38% of patients enrolled in this trial. Complete haematologic response or MCyR was achieved in patients harbouring a variety of BCR-ABL mutations associated with imatinib resistance except T315I. The rates of MCyR at 2 years were similar whether patients had any baseline BCR-ABL mutation, P-loop mutation, or no mutation (63%, 61% and 62%, respectively). Among imatinib-resistant patients, the estimated rate of PFS was 88% (95% CI: [84%-92%]) at 1 year and 75% (95% CI: [69%-81%]) at 2 years. Among imatinib-intolerant patients, the estimated rate of PFS was 98% (95% CI: [95%-100%]) at 1 year and 94% (95% CI: [88%- 99%]) at 2 years. The rate of major molecular response at 24 months was 45% (35% for imatinib-resistant patients and 74% for imatinib-intolerant patients).

Accelerated Phase CML

An open-label, single-arm, multi-centre study was conducted in patients intolerant or resistant to imatinib. A total of 174 patients received SPRYCEL(r) 70 mg twice daily (161 resistant and 13 intolerant to imatinib). The median time from diagnosis to start of treatment was 82 months. Median duration of treatment on SPRYCEL was 14 months with 31% of patients treated for >24 months to date. The rate of major molecular response (assessed in 41 patients with a CCyR) was 46% at 24 months. Efficacy results are reported in Table 2.

Myeloid Blast Phase CML

An open-label, single-arm, multi-centre study was conducted in patients intolerant or resistant to imatinib. A total of 109 patients received SPRYCEL(r) 70 mg twice daily (99 resistant and 10 intolerant to imatinib). The median time from diagnosis to start of treatment was 48 months. Median duration of treatment on SPRYCEL was 3.5 months with 12% of patients treated for >24 months to date. The rate of major molecular response (assessed in 19 patients with a CCyR) was 68% at 24 months. Efficacy results are reported in Table 2.

Lymphoid Blast Phase CML and Ph+ ALL

An open-label, single-arm, multi-centre study was conducted in patients with lymphoid blast phase CML or Ph+ ALL who were resistant or intolerant to prior imatinib therapy. A total of 48 patients with lymphoid blast CML received SPRYCEL(r) 70 mg twice daily (42 resistant and 6 intolerant to imatinib). The median time from diagnosis to start of treatment was 28 months. Median duration of treatment on SPRYCEL was 3 months with 2% treated for >24 months to date. The rate of major molecular response (all 22 treated patients with a CCyR) was 50% at 24 months. In addition, 46 patients with Ph+ ALL received SPRYCEL(r) 70 mg twice daily (44 resistant and 2 intolerant to imatinib). The median time from diagnosis to start of treatment was 18 months. Median duration of treatment on SPRYCEL was 3.0 months with 7% of patients treated for >24 months to date. The rate of major molecular response (all 25 treated patients with a CCyR) was 52% at 24 months. Efficacy results are reported in Table 2. Of note, major haematologic responses (MaHR) were achieved quickly (most within 35 days of first SPRYCEL(r) administration for patients with lymphoid blast CML, and within 55 days for patients with Ph+ ALL).

Note: Data described in this table are from using a starting dosage of 70 mg twice daily. See DOSAGE AND ADMINISTRATION for the recommended starting dosage.

a

Numbers in bold font are the results of primary endpoints

b

Haematologic response criteria (all responses confirmed after 4 weeks): Major haematologic responses: (MaHR)

= complete haematologic response (CHR) + no evidence of leukaemia (NEL).

CHR (chronic CML): WBC institutional ULN, platelets < 450 x 109/L, no blasts or promyelocytes inperipheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement. CHR (advanced CML/Ph+ ALL): WBC institutional ULN, ANC 1.0 x 109/L , platelets 100 x 109/L , no blasts or promyelocytes in peripheral blood, bone marrow blasts 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.

NEL: same criteria as for CHR but ANC 0.5 x 109/L and < 1.0 x 109/L, or platelets 20 x 109/L and 100 x 109/L.

c

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

n/a = not applicable C1 = confidence interval ULN = upper limit of normal range

The outcome of patients with bone marrow transplantation after SPRYCEL has not been fully evaluated.

Phase III Clinical Trials in patients with CML in chronic, accelerated, or myeloid blast phase, and Ph+ ALL who were resistant or intolerant to imatinib

Two randomised, open-label studies were conducted to evaluate the efficacy of SPRYCEL administered once daily compared with SPRYCEL administered twice daily: The results described in Tables 3 and 4 are based on a minimum of 24 months and 60 months follow-up after the start of dasatinib therapy. In the study in chronic phase CML, the primary endpoint was MCyR (once daily vs. twice daily) in imatinib-resistant patients. The main secondary endpoint was MCyR by total daily dose level in the imatinib-resistant patients. Other secondary endpoints included duration of MCyR, progression-free survival, and overall survival. A total of 670 patients, of whom 497 were imatinib-resistant, were randomised to the SPRYCEL 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. Median duration of treatment was approximately 22 months (range <1 to31 months). In patients with resistant or intolerant chronic phase CML, the median duration of treatment for patients still on therapy (n=205) was 59 months (range 28 to 66 months). Efficacy results are presented in Tables 3 and 4. Efficacy was achieved across all SPRYCEL treatment groups with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy end-point (difference in MCyR 1.9%; 95% confidence interval [-6.8% - 10.6% ]). The main secondary end-point of the study also showed comparable efficacy (non-inferiority) between the 100 mg total daily dose and the 140 mg total daily dose (difference in MCyR -0.2%; 95% confidence interval [-8.9% - 8.5%]).

Table 3: Efficacy of SPRYCEL in Phase III Dose-Optimisation Study: Chronic Phase CML (2 year results)

a Not a recommended starting dosage of SPRYCEL(r) for chronic phase CML

b

Haematologic response criteria

(all responses confirmed after 4 weeks):

Complete haematologic response (CHR) (chronic CML): WBC institutional ULN, platelets < 450 x 109/L, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood

< 20%, and no extramedullary involvement.

c

Cytogenetic response criteria

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

d

Major molecular response criteria: Defined as BCR-ABL/control transcripts <= 0.1% by RQ-PCR in peripheral blood samples.

Molecular response was evaluated in a subset of assessed patients who had a CCyR CI = confidence interval; ULN = upper limit of normal range.

Table 4: Efficacy of SPRYCEL in Phase III Dose-Optimisation Study: Chronic Phase CML (5 year results)

a Not a recommended starting dosage of SPRYCEL(r) for chronic phase CML

b

Progression was defined as increasing WBC count, loss of CHR or MCyR, >30% increase in Ph+ metaphases, confirmed AP/BP disease or death. PFS was analysed on an intent-to-treat principle and patients were followed to events including subsequent therapy.

Based on the Kaplan-Meier estimates, the proportion of patients treated with SPRYCEL(r) 100 mg once daily who maintained MCyR for 24 months was 87% (95% CI: [78%-97%]) and 88% (95% CI: [81% - 95%]) for patients treated with 70 mg of SPRYCEL(r) twice daily. In all patients resistant to imatinib who received 100 mg once daily, major molecular response (MMR) in all patients assessed for MMR was achieved in 35% within 2 years and 42% within 5 years. Efficacy results presented in Table 3 refer to the subset of these patients who achieved CCyR. Efficacy was also assessed in patients who were intolerant to imatinib. In this population of patients who received 100 mg once daily, MCyR was achieved in 77% and CCyR in 67% with a minimum of 2 years follow-up. In the intolerant population receiving 100 mg once daily, MMR in all patients assessed for MMR was achieved in 43% within 2 years and 53% within 5 years. Based on the Kaplan-Meier estimates, all imatinib-intolerant patients (100%) maintained MCyR for 1 year and 85% (95% CI: [69%-100%]) maintained MCyR for 2 years. The estimated rate of PFS in this population was 97% (95% CI: [92%-100%]) at 1 year, 87% (95% CI: [76%-99%]) at 2 years and 56% (95% CI: [37%-76%]) at 5 years. The estimated rate of overall survival was 100% at 1 year, 95% (95% CI: [88%-100%]) at 2 years and 82% (95% CI: [70%-94%]) at 5 years. In the Phase III, randomized, open-label study in patients with advanced phase CML and Ph+ALL, whose disease was resistant to or who were intolerant to imatinib, the primary endpoint was MaHR. A total of 611 patients were randomised to either the SPRYCEL 140 mg once daily or 70 mg twice daily group. Median duration of treatment was approximately 6 months (range <1-31 months). The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MaHR 0.8%; 95% confidence interval [-7.1%- 8.7%]). The response rates are presented in Table 5.

Table 5: Efficacy of SPRYCEL in Phase III Dose-Optimisation Study: Advanced Phase CML and Ph+ ALL

a

Not a recommended starting dosage for advanced phase CML and Ph+ALL.

b

Haematologic response criteria (all responses confirmed after 4 weeks): Major haematologic response (MaHR) = complete haematologic response (CHR) + no evidence of leukaemia (NEL).

CHR: WBC <= institutional ULN, ANC >= 1.0 x 109/L, platelets >= 100 x 109/L, no blasts or promyelocytes in peripheral

blood, bone marrow blasts <= 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.

NEL: same criteria as for CHR but ANC >= 0.5 x 109/Land < 1.0 x 109/L, or platelets >= 20 x 109/L and <= 100 x 109/L.

c

MCyR combines both complete (0% Ph+ metaphases) and partial (> 0%-35%) responses. CI = confidence interval ULN = upper limit of normal range.

The median duration of MaHR in patients with accelerated phase CML was not reached for either group; the median PFS was 25 months and 26 months for the 140 mg once daily group and the 70 mg twice daily group, respectively; and the median overall survival was not reached for the 140 mg once daily group and 31 months for the 70 mg twice daily group. In patients with myeloid blast phase CML, the median duration of MaHR was 8 months and 9 months for the 140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was 4 months for both groups; and the median overall survival was 8 months for both groups. In patients with lymphoid blast phase CML, the median duration of MaHR was 5 months and 8 months for the 140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was 5 months for both groups, and the median overall survival was 11 months and 9 months, respectively. In patients with Ph+ALL, the median duration of MaHR was 5 months and 12 months for the 140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was 4 months and 3 months respectively, and the median overall survival was 7 months and 9 months, respectively.

CONTRAINDICATIONS

Use of SPRYCEL(r) is contraindicated in patients with hypersensitivity to dasatinib or to any other component of SPRYCEL(r).

PRECAUTIONS

General

Myelosuppression

Treatment with SPRYCEL(r) is associated with thrombocytopenia, neutropenia and anaemia. Their occurrence is more frequent in patients with advanced phase 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(r) temporarily or dose reduction (see DOSAGE and ADMINISTRATION and Effect on Laboratory Tests). CTC Grade 3 or 4 (severe) cases of anaemia were managed with blood transfusions. In a Phase III dose-optimisation study in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with SPRYCEL(r) 100 mg once daily than in patients treated with SPRYCEL(r) 70 mg twice daily (See Table 8).

Bleeding

In the Phase III study in patients with newly diagnosed chronic phase CML, 2 patients (1%) receiving SPRYCEL(r) compared to 3 patients (1%) receiving imatinib had Grade 3 or 4 haemorrhage. In clinical studies in patients with resistance or intolerance to prior imatinib therapy, severe CNS haemorrhage, including fatalities, occurred in < 1% of patients receiving SPRYCEL(r). Eight cases were fatal and 6 of them were associated with Common Toxicity Criteria (CTC) Grade 4 thrombocytopenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 4% of patients with resistance or intolerance to prior imatinib therapy and generally required treatment interruptions and transfusions. Other cases of Grade 3 or 4 haemorrhage occurred in 2% of patients with resistance or intolerance to prior imatinib therapy. Most bleeding reactions in these patients were typically associated with Grade 3 or 4 thrombocytopenia. Additionally, in vitro and in vivo platelet assays suggest that SPRYCEL(r) treatment reversibly affects platelet activation. Patients were excluded from participation in the initial SPRYCEL(r) (dasatinib) clinical studies if they took medications that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, acetylsalicylic acid, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL(r) if the platelet count was > 50 - 75 x 109/L. Caution should be exercised if patients are required to take medications that inhibit platelet function or anticoagulants.

Fluid Retention

SPRYCEL(r) is associated with fluid retention. In the Phase III clinical study in patients with newly diagnosed chronic phase CML, Grade 3 or 4 fluid retention was reported in 7 patients (3%) receiving SPRYCEL(r) compared to 2 patients (1%) receiving imatinib (ADVERSE EFFECTS). In clinical studies in patients with resistance or intolerance to prior imatinib therapy, Grade 3 or 4 fluid retention was reported in 11% of patients, including pleural and pericardial effusion reported in 7% and 2% of patients, respectively. Severe congestive heart failure/cardiac dysfunction was reported in 2% of patients. In these studies, Grade 3 or 4 ascites and generalized oedema were each reported in < 1% of patients and Grade 3 or 4 pulmonary oedema was reported in 1% of patients. Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should be evaluated by chest X- ray. Severe pleural effusion may require oxygen therapy and thoracentesis. Fluid retention reactions were typically managed with dasatinib dose interruption or reduction and supportive care measures that include diuretics or short courses of steroids. While the safety profile of SPRYCEL in the elderly population was similar to that in the younger population, patients aged 65 years and older are more likely to experience pleural effusion, congestive heart failure, gastrointestinal bleeding, and dyspnoea, and should be monitored closely. Fluid retention reactions were reported less frequently in patients treated with once daily schedule than in patients treated with twice daily schedule in two Phase III dose-optimisation studies.

QT Prolongation

In vitro

data showing inhibition of the hERG K+ channel expressed in mammalian cells and action potential prolongation in rabbit Purkinje fibres by dasatinib and a number of its metabolites suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT interval).

In 258 SPRYCEL(r) -treated patients and 258 imatinib-treated patients in the Phase III study in newly diagnosed chronic phase CML, 1 patient (< 1%) in each group had QTc prolongation reported as an adverse reaction. The median changes in QTcF from baseline were 3.0 msec in SPRYCEL(r) -treated patients compared to 8.2 msec in imatinib-treated patients. One patient (< 1%) in each group experienced a QTcF > 500 msec. In 865 patients with leukaemia treated with SPRYCEL in Phase II, single-arm clinical studies, the mean QTc interval changes from baseline using Fridericia's method (QTcF) were 4-6 msec; the upper 95% confidence intervals for all mean changes from baseline were <7 msec. Of the 2,182 patients with resistance or intolerance to prior imatinib therapy treated with SPRYCEL, 15 (1%) had QT prolongation reported as an adverse reaction. Twenty-one (21) of these patients (1%) experienced a QTcF >500 msec. SPRYCEL(r) should be administered with caution in patients who have or may develop prolongation of QTc. These include patients with hypokalaemia or hypomagnesaemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products which lead to QT prolongation and cumulative high dose anthracycline therapy. Hypokalaemia or hypomagnesaemia should be corrected prior to SPRYCEL administration.

Cardiac Adverse Reactions

SPRYCEL(r) was studied in a randomised trial of 519 patients with newly diagnosed CML in chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of congestive heart failure/cardiac dysfunction and fatal myocardial infarction were reported in patients taking SPRYCEL(r). Adverse cardiac reactions were more frequent in patients with risk factors or a previous medical history of cardiac disease. Patients with risk factors or a history of cardiac disease should be monitored carefully for signs or symptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately. Patients with uncontrolled or significant cardiovascular disease were not included in the clinical studies.

Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH), confirmed by right heart catheterization, has been reported in association with SPRYCEL(r) treatment in post-marketing reports. In these cases, PAH was reported after initiation of SPRYCEL(r) therapy, including after more than one year of treatment. Patients with PAH reported during SPRYCEL(r) treatment were often taking concomitant medications or had co-morbidities in addition to the underlying malignancy. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL(r) therapy. Patients who develop dyspnoea and fatigue after initiation of therapy should be evaluated for more common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. During this evaluation, guidelines for non-hematologic adverse reactions should be followed (see DOSAGE AND ADMINISTRATION): if the adverse reaction is severe, treatment must be withheld until the event has resolved or improved. If no alternative diagnosis is found, the diagnosis of PAH should be considered. If PAH is confirmed, SPRYCEL(r) should be permanently discontinued. Follow up should be performed according to standard practice guidelines. Improvements in hemodynamic and clinical parameters have been observed in SPRYCEL(r) treated patients with PAH following cessation of SPRYCEL(r) therapy.

Lactose Content

SPRYCEL(r) contains 135 mg of lactose monohydrate in a 100 mg daily dose and 189 mg of lactose monohydrate in a 140 mg daily dose.

Effects on Fertility

Dasatinib did not affect male or female fertility in a conventional rat fertility and early embryonic development study at approximately 1x human clinical exposure (100 or 140 mg dose). However, embryolethality was evident at these doses. Dasatinib caused atrophy/degeneration of the testis in rats and monkeys and an increase in the number of corpora lutea in the ovaries in rats at doses producing plasma exposure levels below or close to that anticipated in patients receiving SPRYCEL(r) therapy.

Use in Pregnancy Pregnancy Category D

Dasatinib may cause foetal harm when administered to a pregnant woman. In non-clinical studies, at exposure levels that are readily achievable in humans receiving therapeutic doses of 100 mg of SPRYCEL(r) serious embryo foetal toxicity was observed in both pregnant rats and rabbits. Malformations and foetal death were observed in rats treated with dasatinib. SPRYCEL(r) is therefore not recommended for use in women who are pregnant or contemplating pregnancy. Women must be advised to avoid becoming pregnant while on therapy. If SPRYCEL(r) is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL(r), the patient should be apprised of the potential hazard to the foetus. The potential effects of SPRYCEL(r) on sperm have not been studied. Sexually active male or female patients of child bearing potential taking SPRYCEL(r) should use adequate contraception.

Embryofoetal Toxicity

Dasatinib can cause foetal harm when administered to a pregnant woman. There have been post-marketing reports of spontaneous abortion and foetal and infant anomalies from women who have taken SPRYCEL(r) during pregnancy. (See Carcinogenesis, Genotoxicity and Effects on Fertility).

Use in Lactation

It is unknown whether SPRYCEL(r) is excreted in human milk. Women who are taking SPRYCEL(r) should not breastfeed. In an exploratory peri- and postnatal development study in rats, dasatinib was detectable in the plasma of breast-fed pups with level 30-40% of the maternal levels. Pleural effusion and deaths were seen in maternally-exposed rat pups.

Paediatric Use

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

Use in the Elderly

In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and older and 7 patients (3%) were 75 years of age and older. Of the 2,182 patients in clinical studies of SPRYCEL(r) with resistance or intolerance to prior imatinib therapy, 547 (25%) were 65 years of age and older and 105 (5%) were 75 years of age and older. While the safety profile of SPRYCEL in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience pleural effusion (43% vs. 24%), congestive heart failure (6% vs. 2%), gastrointestinal bleeding (12% vs. 7%), and dyspnoea (37% vs. 20%) and should be monitored closely. No differences in efficacy were observed between older and younger patients. However, in the two randomized studies in patients with chronic phase CML, the rates of major cytogenetic response (MCyR) were lower among patients aged 65 years and older.

Carcinogenicity

In a two year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level generally equivalent to or slightly lower than calculated human exposure at the recommended range of starting doses 100 mg or 140 mg daily. A statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose female rats and of prostate adenoma in low-dose male rats was noted.

Genotoxicity

Dasatinib was not mutagenic when tested in in vitro bacterial cell assays (Ames test) and was not clastogenic in an in vivo rat micronucleus study. Clastogenicity was observed with dasatinib in vitro in assays with Chinese hamster ovary cells in the absence and presence of metabolic activation.

Effect on Laboratory Tests

Haematology and Biochemistry in patients with newly diagnosed chronic phase CML

The comparative frequency of Grade 3 and 4 laboratory abnormalities in patients with newly diagnosed chronic phase CML is presented in Table 6. There were no discontinuations of SPRYCEL(r) therapy due to these biochemical laboratory parameters.

Haematology and Biochemistry in patients with resistance or intolerance to prior imatinib therapy:

Table 7 shows laboratory findings from SPRYCEL(r) clinical trials in which 2,182 patients received SPRYCEL(r) for a median of 15 months.

Myelosuppression was commonly reported in all patient populations. In newly diagnosed chronic phase CML, myelosupression was less frequently reported than in chronic phase CML patients with resistance or intolerance to prior imatinib therapy. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anaemia was higher in patients with advanced CML or Ph+ ALL than in chronic phase CML. In patients who experienced Grade 3 or 4 myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of newly diagnosed chronic phase CML patients and in 5% of patients with resistance or intolerance to prior imatinib therapy. Grade 3 or 4 elevations in transaminases or bilirubin and Grade 3 or 4 hypocalcaemia, hypokalaemia, and hypophosphataemia were reported in all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL. Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption. In general, decreased calcium levels were not associated with clinical symptoms. Patients developing Grade 3 or 4 hypocalcaemia often had recovery with oral calcium supplementation. In the Phase III dose-optimisation study in patients with chronic phase CML, the frequency of neutropenia, thrombocytopenia and anaemia was lower in the SPRYCEL 100 mg once daily than in the SPRYCEL 70 mg twice daily group. Laboratory abnormalities reported in the Phase III dose-optimisation study are shown in Table 8.

* Haematology parameters for 100 mg once daily reflect 60 month follow-up. a Not a recommended starting dosage of SPRYCEL(r) for chronic phase CML.

/

9 9

CTC grades: neutropenia (Grade 3 >=0.5-<1.0 x 109/L, Grade 4 <0.5 x 109 L); thrombocytopenia (Grade 3 >=25-<50

x10 /L, Grade 4 <25 x 10 /L); anaemia (haemoglobin Grade 3 >=65-<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3-6 x upper limit of normal range (ULN), Grade 4 >6 x ULN); elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10x ULN); elevated SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN); hypocalcaemia (Grade 3

<7.0-6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphataemia (Grade 3 <2.0-1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalaemia (Grade 3<3.0-2.5 mmol/L, Grade 4<2.5 mmol/L.

INTERACTIONS WITH OTHER MEDICINES

Drugs that may increase dasatinib plasma concentrations

CYP3A4 Inhibitors: In vitro, dasatinib is a CYP3A4 substrate. Concomitant use of SPRYCEL(r) and substances that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, lopinavir, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving treatment with SPRYCEL(r), systemic administration of a potent CYP3A4 inhibitor is not recommended. Selection of an alternate concomitant medication with no or minimal CYP3A4 inhibition potential is recommended. If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, the patient should be closely monitored for toxicity.

Drugs that may decrease dasatinib plasma concentrations

CYP3A4 Inducers:

Drugs that induce CYP3A4 activity may increase metabolism and

decrease dasatinib plasma concentration. Therefore, concomitant use of potent CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John's Wort) with SPRYCEL(r) is not recommended. In healthy subjects, the concomitant use of SPRYCEL(r) and rifampicin, a potent CYP3A4 inducer, resulted in a five-fold decrease in dasatinib exposure. In patients for whom rifampicin or other CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be used. Antacids: Non-clinical data demonstrate that the solubility of dasatinib is pH dependent. In healthy subjects, the concomitant use of aluminium hydroxide/magnesium hydroxide antacids with SPRYCEL(r) reduced the AUC of a single dose of SPRYCEL(r) by 55% and the Cmax by 58%. However, when antacids were administered 2 hours prior to a single dose of SPRYCEL, no relevant changes in SPRYCEL(r), concentration or exposure were observed. Thus, antacids may be administered up to 2 hours prior to or 2 hours following SPRYCEL(r). Simultaneous administration of SPRYCEL with antacids should be avoided. Histamine-2 Antagonists /Proton Pump Inhibitors: Long-term suppression of gastric secretion by Histamine-2 Antagonists or proton pump inhibitors (e.g. famotidine and omeprazole) is likely to reduce dasatinib exposure. The concomitant use of Histamine-2 Antagonists or proton pump inhibitors with SPRYCEL is not recommended. In a single- dose study in healthy subjects, the administration of famotidine 10 hours prior to a single dose of SPRYCEL(r) reduced dasatinib exposure by 61%. The use of antacids should be considered in place of Histamine-2 Antagonists or proton pump inhibitors in patients receiving SPRYCEL(r) therapy.

Drugs that may have their plasma concentration altered by dasatinib

CYP3A4 Substrates: In a study in healthy subjects, a single 100 mg dose of SPRYCEL(r) increased exposure to simvastatin, a known CYP3A4 substrate, by 20%. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving SPRYCEL(r). (See PHARMACOLOGY).

In vitro

data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones.

Hepatic Impairment

Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose (see DOSAGE and ADMINISTRATION and PHARMACOKINETICS- Special Populations). Due to the limitations of this clinical study, caution is recommended when SPRYCEL(r) is administered to patients with hepatic impairment.

Renal Impairment

There are currently no clinical studies with SPRYCEL(r) in patients with impaired renal function (the study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine > 3 times the upper limit of the normal range, and clinical studies in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy 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.

DOSAGE AND ADMINISTRATION

The recommended starting dosage of SPRYCEL (dasatinib) for chronic phase CML is 100 mg administered orally once daily (QD). The recommended starting dosage of SPRYCEL for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg/day administered orally once daily and should be taken consistently either in the morning or the evening. In clinical studies, treatment with SPRYCEL(r) was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment after the achievement of a CCyR has not been investigated. To achieve the recommended dose, SPRYCEL is available as 20 mg, 50 mg, 70 mg and 100 mg film-coated tablets. Dose increase or reduction is recommended based on patient response and tolerability.

Dose escalation

In clinical studies in adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a haematologic or cytogenetic response at the recommended starting dosage.

Dose adjustment for adverse reactions

Myelosuppression

In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate. Haematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications are summarized in Table 11.

Non-haematological adverse reactions

If a severe non-haematological adverse reaction develops with SPRYCEL(r) 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. Paediatric population: The safety and efficacy of SPRYCEL(r) in children and adolescents below 18 years of age have not yet been established. No data are available (see PRECAUTIONS).

Elderly population:

No clinically relevant age-related pharmacokinetic differences have been observed in these patients. No specific dose recommendation is necessary in the elderly (see PRECAUTIONS).

Hepatic impairment: Patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose. However, caution is recommended when SPRYCEL(r) is administered to patients with hepatic impairment. (see PRECAUTIONS). Renal impairment: No clinical trials were conducted with SPRYCEL(r) in patients with decreased renal function (the study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine > 3 times the upper limit of the normal range, and studies in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib and its metabolites is <4%, a decrease in total body clearance is not expected in patients with renal insufficiency (see PRECAUTIONS). Method of Administration: To be administered orally. Tablets must not be crushed or cut in order to minimize risk of dermal exposure, they must be swallowed whole. SPRYCEL can be taken with or without a meal and should be taken consistently either in the morning or the evening.

OVERDOSAGE

Experience with overdose of SPRYCEL(r) in clinical studies is limited to isolated cases. The highest overdosage of 280 mg per day for one week was reported in two patients and both developed a significant decrease in platelet counts. Since SPRYCEL(r) is associated with severe myelosuppression, patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment. For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

PRESENTATION

SPRYCEL(r) (dasatinib) tablets are available as film-coated, white to off-white, biconvex, round tablets with "BMS" debossed on one side and "527" (20 mg), or "524" (70 mg) on the other side. The 50 mg tablets are oval shaped and debossed "BMS" on one side and "528" on the other side. The 100 mg tablets are oval shaped and debossed "BMS 100" on one side and "852" on the other side. 20 mg, 50 mg and 70 mg Tablets are available in bottles or blisters of 60 tablets. 100 mg Tablets are available in bottles or blisters of 30 tablets. Not all pack sizes may be marketed.

Storage Conditions

SPRYCEL(r) (dasatinib) tablets should be stored below 30 degC.

Handling and Disposal

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

NAME AND ADDRESS OF THE SPONSOR:

Bristol-Myers Squibb Australia Pty Ltd 4 Nexus Court, Mulgrave, Victoria 3170, Australia.

POISON SCHEDULE

Schedule 4

DATE OF FIRST INCLUSION IN THE ARTG (20 mg, 50 mg, 70 mg):

15 January 2007

DATE OF FIRST INCLUSION IN THE ARTG (100 mg):

16 February 2010

DATE OF MOST RECENT AMENDMENT:

2 September 2013