SPRYCEL 100mg tablets medication leaflet

SPRYCEL 20 mg film-coated tablets

SPRYCEL 50 mg film-coated tablets

SPRYCEL 70 mg film-coated tablets

SPRYCEL 80 mg film-coated tablets

SPRYCEL 100 mg film-coated tablets

SPRYCEL 140 mg film-coated tablets

SPRYCEL 20 mg film-coated tablets

Each film-coated tablet contains 20 mg dasatinib (as monohydrate).

Each film-coated tablet contains 27 mg of lactose monohydrate.

SPRYCEL 50 mg film-coated tablets

Each film-coated tablet contains 50 mg dasatinib (as monohydrate).

Each film-coated tablet contains 67.5 mg of lactose monohydrate.

SPRYCEL 70 mg film-coated tablets

Each film-coated tablet contains 70 mg dasatinib (as monohydrate).

Each film-coated tablet contains 94.5 mg of lactose monohydrate.

SPRYCEL 80 mg film-coated tablets

Each film-coated tablet contains 80 mg dasatinib (as monohydrate).

Each film-coated tablet contains 108 mg of lactose monohydrate.

SPRYCEL 100 mg film-coated tablets

Each film-coated tablet contains 100 mg dasatinib (as monohydrate).

Each film-coated tablet contains 135.0 mg of lactose monohydrate.

SPRYCEL 140 mg film-coated tablets

Each film-coated tablet contains 140 mg dasatinib (as monohydrate).

Each film-coated tablet contains 189 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

SPRYCEL 20 mg film-coated tablets

White to off-white, biconvex, round film-coated tablet with 'BMS' debossed on one side and '527' onthe other side.

SPRYCEL 50 mg film-coated tablets

White to off-white, biconvex, oval film-coated tablet with 'BMS' debossed on one side and '528' onthe other side.

SPRYCEL 70 mg film-coated tablets

White to off-white, biconvex, round film-coated tablet with 'BMS' debossed on one side and '524' onthe other side.

SPRYCEL 80 mg film-coated tablets

White to off-white, biconvex, triangular film-coated tablet with 'BMS 80' debossed on one side and'855' on the other side.

SPRYCEL 100 mg film-coated tablets

White to off-white, biconvex, oval film-coated tablet with 'BMS 100' debossed on one side and '852'on the other side.

SPRYCEL 140 mg film-coated tablets

White to off-white, biconvex, round film-coated tablet with 'BMS 140' debossed on one side and'857' on the other side.

SPRYCEL is indicated for the treatment of adult patients with:

▪ newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia(CML) in the chronic phase.

▪ chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy includingimatinib.

▪ Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intoleranceto prior therapy.

SPRYCEL is indicated for the treatment of paediatric patients with:

▪ newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant orintolerant to prior therapy including imatinib.

▪ newly diagnosed Ph+ ALL in combination with chemotherapy.

Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients withleukaemia.

Adult patients

The recommended starting dose for chronic phase CML is 100 mg dasatinib once daily.

The recommended starting dose for accelerated, myeloid or lymphoid blast phase (advanced phase)

CML or Ph+ ALL is 140 mg once daily (see section 4.4).

Paediatric population (Ph+ CML-CP and Ph+ ALL)

Dosing for children and adolescents is on the basis of body weight (see Table 1). Dasatinib isadministered orally once daily in the form of either SPRYCEL film-coated tablets or SPRYCELpowder for oral suspension (see Summary of Product Characteristics for SPRYCEL powder for oralsuspension). The dose should be recalculated every 3 months based on changes in body weight, ormore often if necessary. The tablet is not recommended for patients weighing less than 10 kg; thepowder for oral suspension should be used for these patients. Dose increase or reduction isrecommended based on individual patient response and tolerability. There is no experience with

SPRYCEL treatment in children under 1 year of age.

SPRYCEL film-coated tablets and SPRYCEL powder for oral suspension are not bioequivalent.

Patients who are able to swallow tablets and who desire to switch from SPRYCEL powder for oralsuspension to SPRYCEL tablets or patients who are not able to swallow tablets and who desire toswitch from tablets to oral suspension, may do so, provided that the correct dosing recommendationsfor the dosage form are followed.

The recommended starting daily dosage of SPRYCEL tablets in paediatric patients is shown in

Table 1.

Table 1: Dosage of SPRYCEL tablets for paediatric patients with Ph+ CML-CP or Ph+ ALL

Body weight (kg)a Daily dose (mg)10 to less than 20 kg 40 mg20 to less than 30 kg 60 mg30 to less than 45 kg 70 mgat least 45 kg 100 mga The tablet is not recommended for patients weighing less than 10 kg; the powder for oral suspension should be used forthese patients.

In clinical studies, treatment with SPRYCEL in adults with Ph+ CML-CP, accelerated, myeloid orlymphoid blast phase (advanced phase) CML, or Ph+ ALL and paediatric patients with Ph+ CML-CPwas continued until disease progression or until no longer tolerated by the patient. The effect ofstopping treatment on long-term disease outcome after the achievement of a cytogenetic or molecularresponse [including complete cytogenetic response (CCyR), major molecular response (MMR) and

MR4.5] has not been investigated.

In clinical studies, treatment with SPRYCEL in paediatric patients with Ph+ ALL was administeredcontinuously, added to successive blocks of backbone chemotherapy, for a maximum duration of twoyears. In patients that receive a subsequent stem cell transplantation, SPRYCEL can be administeredfor an additional year post-transplantation.

To achieve the recommended dose, SPRYCEL is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mgand 140 mg film-coated tablets and powder for oral suspension (10 mg/mL suspension uponconstitution). Dose increase or reduction is recommended based on patient response and tolerability.

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

The following dose escalations shown in Table 2 are recommended in paediatric patients with

Ph+ CML-CP who do not achieve a haematologic, cytogenetic and molecular response at therecommended time points, per current treatment guidelines, and who tolerate the treatment.

Table 2: Dose escalation for paediatric patients with Ph+ CML-CP

Dose (maximum dose per day)

Starting dose Escalation

Tablets 40 mg 50 mg60 mg 70 mg70 mg 90 mg100 mg 120 mg

Dose escalation is not recommended for paediatric patients with Ph+ ALL, as SPRYCEL isadministered in combination with chemotherapy in these patients.

Dose adjustment for adverse reactions

In clinical studies, myelosuppression was managed by dose interruption, dose reduction, ordiscontinuation 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 in adults are summarised in Table 3 and in paediatric patients with

Ph+ CML-CP in Table 4. Guidelines for paediatric patients with Ph+ ALL treated in combination withchemotherapy are in a separate paragraph following the tables.

Table 3: Dose adjustments for neutropaenia and thrombocytopaenia in adults1 Stop treatment until ANC ≥ 1.0 x 109/L andplatelets ≥ 50 x 109/L.

2 Resume treatment at the original startingdose.

Adults with chronic phase 9 3 If platelets < 25 x 109/L and/or recurrence of

ANC < 0.5 x 10 /L

CML ANC < 0.5 x 109/L for > 7 days, repeat stepand/or(starting dose 100 mg once 9 1 and resume treatment at a reduced dose ofplatelets < 50 x 10 /Ldaily) 80 mg once daily for second episode. Forthird episode, further reduce dose to 50 mgonce daily (for newly diagnosed patients) ordiscontinue (for patients resistant orintolerant to prior therapy includingimatinib).

1 Check if cytopaenia is related to leukaemia(marrow aspirate or biopsy).

2 If cytopaenia is unrelated to leukaemia, stoptreatment until ANC ≥ 1.0 x 109/L andplatelets ≥ 20 x 109/L and resume at the

Adults with accelerated original starting dose.

and blast phase CML and ANC < 0.5 x 109/L

Ph+ ALL and/or 3 If recurrence of cytopaenia, repeat step 1 and(starting dose 140 mg once platelets < 10 x 109/L resume treatment at a reduced dose ofdaily) 100 mg once daily (second episode) or80 mg once daily (third episode).

4 If cytopaenia is related to leukaemia,consider dose escalation to 180 mg oncedaily.

ANC: absolute neutrophil count

Table 4: Dose adjustments for neutropaenia and thrombocytopaenia in paediatric patientswith Ph+ CML-CP1. If cytopaenia persists for Dose (maximum dose per day)more than 3 weeks, check if Original One-level dose Two-level dosecytopaenia is related to starting dose reduction reductionleukaemia (marrow aspirate Tablets 40 mg 20 mg *or biopsy). 60 mg 40 mg 20 mg70 mg 60 mg 50 mg2. If cytopaenia is unrelated 100 mg 80 mg 70 mgto leukaemia, stop treatmentuntil ANC ≥1.0 × 109/L andplatelets ≥75 × 109/L andresume at the originalstarting dose or at a reduceddose.

3. If cytopaenia recurs,repeat marrowaspirate/biopsy and resumetreatment at a reduced dose.

ANC: absolute neutrophil count

*lower tablet dose not available

For paediatric patients with Ph+ CML-CP, if Grade ≥3 neutropaenia or thrombocytopaenia recursduring complete haematologic response (CHR), SPRYCEL should be interrupted, and may besubsequently resumed at a reduced dose. Temporary dose reductions for intermediate degrees ofcytopaenia and disease response should be implemented as needed.

For paediatric patients with Ph+ ALL, no dose modification is recommended in cases of haematologic

Grade 1 to 4 toxicities. If neutropaenia and/or thrombocytopaenia result in delay of the next block oftreatment by more than 14 days, SPRYCEL should be interrupted and resumed at the same dose levelonce the next block of treatment is started. If neutropaenia and/or thrombocytopaenia persist and thenext block of treatment is delayed another 7 days, a bone marrow assessment should be performed toassess cellularity and percentage of blasts. If marrow cellularity is <10%, treatment with SPRYCELshould be interrupted until ANC >500/μL (0.5 x 109/L), at which time treatment may be resumed atfull dose. If marrow cellularity is >10%, resumption of treatment with SPRYCEL may be considered.

Non-haematologic adverse reactions

If a moderate, grade 2, non-haematologic adverse reaction develops with dasatinib, treatment shouldbe interrupted until the adverse reaction has resolved or returned to baseline. The same dose should beresumed if this is the first occurrence and the dose should be reduced if this is a recurrent adversereaction. If a severe grade 3 or 4, non-haematologic adverse reaction develops with dasatinib,treatment must be withheld until the adverse reaction has resolved. Thereafter, treatment can beresumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction. Forpatients with chronic phase CML who received 100 mg once daily, dose reduction to 80 mg once dailywith further reduction from 80 mg once daily to 50 mg once daily, if needed, is recommended. Forpatients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to100 mg once daily with further reduction from 100 mg once daily to 50 mg once daily, if needed, isrecommended. In CML-CP paediatric patients with non-haematologic adverse reactions, the dosereduction recommendations for haematologic adverse reactions that are described above should befollowed. In Ph+ ALL paediatric patients with non-haematologic adverse reactions, if needed, onelevel of dose reduction should be followed, according to the dose reduction recommendations forhaematologic adverse reactions that are described above.

Pleural effusion

If a pleural effusion is diagnosed, dasatinib should be interrupted until patient is examined,asymptomatic or has returned to baseline. If the episode does not improve within approximately oneweek, a course of diuretics or corticosteroids or both concurrently should be considered (seesections 4.4 and 4.8). Following resolution of the first episode, reintroduction of dasatinib at the samedose level should be considered. Following resolution of a subsequent episode, dasatinib at one doselevel reduction should be reintroduced. Following resolution of a severe (grade 3 or 4) episode,treatment can be resumed as appropriate at a reduced dose depending on the initial severity of theadverse reaction.

Dose reduction for concomitant use of strong CYP3A4 inhibitors

The concomitant use of strong CYP3A4 inhibitors and grapefruit juice with SPRYCEL should beavoided (see section 4.5). If possible, an alternative concomitant medication with no or minimalenzyme inhibition potential should be selected. If SPRYCEL must be administered with a strong

CYP3A4 inhibitor, consider a dose decrease to:

* 40 mg daily for patients taking SPRYCEL 140 mg tablet daily.

* 20 mg daily for patients taking SPRYCEL 100 mg tablet daily.

* 20 mg daily for patients taking SPRYCEL 70 mg tablet daily.

For patients taking SPRYCEL 60 mg or 40 mg daily, consider interrupting the dose of SPRYCELuntil the CYP3A4 inhibitor is discontinued, or switching to a lower dose with the powder for oralsuspension formulation (see Summary of Product Characteristics for SPRYCEL powder for oralsuspension). Allow a washout period of approximately 1 week after the inhibitor is stopped beforereinitiating SPRYCEL.

These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the rangeobserved without CYP3A4 inhibitors; however, clinical data are not available with these doseadjustments in patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dosereduction, either discontinue the strong CYP3A4 inhibitor or interrupt SPRYCEL until the inhibitor isdiscontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the

SPRYCEL dose is increased.

No clinically relevant age-related pharmacokinetic differences have been observed in these patients.

No specific dose recommendation is necessary in elderly.

Patients with mild, moderate or severe hepatic impairment may receive the recommended startingdose. However, SPRYCEL should be used with caution in patients with hepatic impairment (seesection 5.2).

No clinical studies were conducted with SPRYCEL in patients with decreased renal function (thestudy in patients with newly diagnosed chronic phase CML excluded patients with serum creatinineconcentration > 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 creatinineconcentration > 1.5 times the upper limit of the normal range). Since the renal clearance of dasatiniband its metabolites is < 4%, a decrease in total body clearance is not expected in patients with renalinsufficiency.

SPRYCEL must be administered orally.

The film-coated tablets must not be crushed, cut or chewed in order to maintain dosing consistencyand minimise the risk of dermal exposure; they must be swallowed whole. Film-coated tablets shouldnot be dispersed as the exposure in patients receiving a dispersed tablet is lower than in thoseswallowing a whole tablet. SPRYCEL powder for oral suspension is also available for paediatric

Ph+ CML-CP and Ph+ ALL patients, and adult CML-CP patients, who cannot swallow tablets.

SPRYCEL can be taken with or without a meal and should be taken consistently either in the morningor in the evening (see section 5.2). SPRYCEL should not be taken with grapefruit or grapefruit juice(see section 4.5).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is apotential for interaction with other concomitantly administered medicinal products that aremetabolised primarily by or modulate the activity of CYP3A4 (see section 4.5).

Concomitant use of dasatinib and medicinal products or substances that potently inhibit CYP3A4 (e.g.

ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice)may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, coadministration of apotent CYP3A4 inhibitor is not recommended (see section 4.5).

Concomitant use of dasatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone,phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing Hypericumperforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentiallyincreasing the risk of therapeutic failure. Therefore, in patients receiving dasatinib, coadministration ofalternative medicinal products with less potential for CYP3A4 induction should be selected (seesection 4.5).

Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4substrate. Therefore, caution is warranted when dasatinib is coadministered with CYP3A4 substratesof narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridilor ergot alkaloids (ergotamine, dihydroergotamine) (see section 4.5).

The concomitant use of dasatinib and a histamine-2 (H2) antagonist (e.g. famotidine), proton pumpinhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposureto dasatinib. Thus, H2 antagonists and proton pump inhibitors are not recommended and aluminiumhydroxide/magnesium hydroxide products should be administered up to 2 hours prior to, or 2 hoursfollowing the administration of dasatinib (see section 4.5).

Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate orsevere hepatic impairment may receive the recommended starting dose (see section 5.2). Due to thelimitations of this clinical study, caution is recommended when administering dasatinib to patientswith hepatic impairment.

Important adverse reactions

Treatment with dasatinib is associated with anaemia, neutropaenia and thrombocytopaenia. Theiroccurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than inchronic phase CML. In adult patients with advanced phase CML or Ph+ ALL treated with dasatinib asmonotherapy, complete blood counts (CBCs) should be performed weekly for the first 2 months, andthen monthly thereafter, or as clinically indicated. In adult and paediatric patients with chronic phase

CML, complete blood counts should be performed every 2 weeks for 12 weeks, then every 3 monthsthereafter or as clinically indicated. In paediatric patients with Ph+ ALL treated with dasatinib incombination with chemotherapy, CBCs should be performed prior to the start of each block ofchemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, CBCsshould be performed every 2 days until recovery (see sections 4.2 and 4.8). Myelosuppression isgenerally reversible and usually managed by withholding dasatinib temporarily or by dose reduction.

In patients with chronic phase CML (n=548), 5 patients (1%) receiving dasatinib hadgrade 3 or 4 haemorrhage. In clinical studies in patients with advanced phase CML receiving therecommended dose of SPRYCEL (n=304), severe central nervous system (CNS) haemorrhageoccurred in 1% of patients. One case was fatal and was associated with Common Toxicity Criteria(CTC) grade 4 thrombocytopaenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 6% ofpatients with advanced phase CML and generally required treatment interruptions and transfusions.

Other grade 3 or 4 haemorrhage occurred in 2% of patients with advanced phase CML. Most bleedingrelated adverse reactions in these patients were typically associated withgrade 3 or 4 thrombocytopaenia (see section 4.8). Additionally, in vitro and in vivo platelet assayssuggest that SPRYCEL treatment reversibly affects platelet activation.

Caution should be exercised if patients are required to take medicinal products that inhibit plateletfunction or anticoagulants.

Fluid retention

Dasatinib is associated with fluid retention. In the Phase III clinical study in patients with newlydiagnosed chronic phase CML, grade 3 or 4 fluid retention was reported in 13 patients (5%) in thedasatinib-treatment group and in 2 patients (1%) in the imatinib-treatment group after a minimum of60 months follow-up (see section 4.8). In all SPRYCEL treated patients with chronic phase CML,severe fluid retention occurred in 32 patients (6%) receiving SPRYCEL at the recommended dose(n=548). In clinical studies in patients with advanced phase CML or Ph+ ALL receiving SPRYCEL atthe recommended dose (n=304), grade 3 or 4 fluid retention was reported in 8% of patients, includinggrade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients, respectively. In thesepatients grade 3 or 4 pulmonary oedema and pulmonary hypertension were each reported in 1% ofpatients.

Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough shouldbe evaluated by chest X-ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygentherapy. Fluid retention adverse reactions were typically managed by supportive care measures thatinclude diuretics and short courses of steroids (see sections 4.2 and 4.8). Patients aged 65 years andolder are more likely than younger patients to experience pleural effusion, dyspnoea, cough,pericardial effusion and congestive heart failure, and should be monitored closely. Cases ofchylothorax have also been reported in patients presenting with pleural effusion (see section 4.8).

Pulmonary arterial hypertension (PAH)

PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has beenreported in association with dasatinib treatment (see section 4.8). In these cases, PAH was reportedafter initiation of dasatinib therapy, including after more than one year of treatment.

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior toinitiating dasatinib therapy. An echocardiography should be performed at treatment initiation in everypatient presenting symptoms of cardiac disease and considered in patients with risk factors for cardiacor pulmonary disease. Patients who develop dyspnoea and fatigue after initiation of therapy should beevaluated for common etiologies including pleural effusion, pulmonary oedema, anaemia, or lunginfiltration. In accordance with recommendations for management of non-haematologic adversereactions (see section 4.2) the dose of dasatinib should be reduced or therapy interrupted during thisevaluation. If no explanation is found, or if there is no improvement with dose reduction orinterruption, the diagnosis of PAH should be considered. The diagnostic approach should followstandard practice guidelines. If PAH is confirmed, dasatinib should be permanently discontinued.

Follow up should be performed according to standard practice guidelines. Improvements inhaemodynamic and clinical parameters have been observed in dasatinib-treated patients with PAHfollowing cessation of dasatinib therapy.

QT Prolongation

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT

Interval) (see section 5.3). In 258 dasatinib-treated patients and 258 imatinib-treated patients with aminimum of 60 months follow-up in the Phase III study in newly diagnosed chronic phase CML, 1patient (< 1%) in each group had QTc prolongation reported as an adverse reaction. The medianchanges in QTcF from baseline were 3.0 msec in dasatinib-treated patients compared to 8.2 msec inimatinib-treated patients. One patient (< 1%) in each group experienced a QTcF > 500 msec. In865 patients with leukaemia treated with dasatinib in Phase II clinical studies, the mean changes frombaseline in QTc interval using Fridericia's method (QTcF) were 4 - 6 msec; the upper 95% confidenceintervals for all mean changes from baseline were < 7 msec (see section 4.8).

Of the 2,182 patients with resistance or intolerance to prior imatinib therapy who received dasatinib inclinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one of thesepatients (1%) experienced a QTcF > 500 msec.

Dasatinib should be administered with caution to 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 medicinal products or other medicinal products whichlead to QT prolongation, and cumulative high dose anthracycline therapy. Hypokalaemia orhypomagnesaemia should be corrected prior to dasatinib administration.

Cardiac adverse reactions

Dasatinib was studied in a randomised clinical study of 519 patients with newly diagnosed CML inchronic phase which included patients with prior cardiac disease. The cardiac adverse reactions ofcongestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QTprolongation and myocardial infarction (including fatal) were reported in patients taking dasatinib.

Cardiac adverse reactions were more frequent in patients with risk factors or a history of cardiacdisease. Patients with risk factors (e.g. hypertension, hyperlipidaemia, diabetes) or a history of cardiacdisease (e.g. prior percutaneous coronary intervention, documented coronary artery disease) should bemonitored carefully for clinical signs or symptoms consistent with cardiac dysfunction such as chestpain, shortness of breath, and diaphoresis.

If these clinical signs or symptoms develop, physicians are advised to interrupt dasatinibadministration and consider the need for alternative CML-specific treatment. After resolution, afunctional assessment should be performed prior to resuming treatment with dasatinib. Dasatinib maybe resumed at the original dose for mild/moderate adverse reactions (≤ grade 2) and resumed at a doselevel reduction for severe adverse reactions (≥ grade 3) (see section 4.2). Patients continuing treatmentshould be monitored periodically.

Patients with uncontrolled or significant cardiovascular disease were not included in the clinicalstudies.

BCR-ABL tyrosine kinase inhibitors have been associated with thrombotic microangiopathy (TMA),including individual case reports for SPRYCEL (see section 4.8). If laboratory or clinical findingsassociated with TMA occur in a patient receiving SPRYCEL, treatment with SPRYCEL should bediscontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-

ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevatedin conjunction with low ADAMTS13 activity, treatment with SPRYCEL should not be resumed.

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after thesepatients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure orfulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with SPRYCEL. Experts inliver disease and in the treatment of hepatitis B should be consulted before treatment is initiated inpatients with positive hepatitis B serology (including those with active disease) and for patients whotest positive for HBV infection during treatment. Carriers of HBV who require treatment with

SPRYCEL should be closely monitored for signs and symptoms of active HBV infection throughouttherapy and for several months following termination of therapy (see section 4.8).

Effects on growth and development in paediatric patients

In paediatric trials of SPRYCEL in imatinib-resistant/intolerant Ph+ CML-CP paediatric patients andtreatment-naive Ph+ CML-CP paediatric patients after at least 2 years of treatment, treatment-relatedadverse events associated with bone growth and development were reported in 6 (4.6%) patients, oneof which was severe in intensity (Growth Retardation Grade 3). These 6 cases included cases ofepiphyses delayed fusion, osteopaenia, growth retardation, and gynecomastia (see section 5.1). Theseresults are difficult to interpret in the context of chronic diseases such as CML, and require long-termfollow-up.

In paediatric trials of SPRYCEL in combination with chemotherapy in newly diagnosed Ph+ ALLpaediatric patients after a maximum of 2 years of treatment, treatment-related adverse eventsassociated with bone growth and development were reported in 1 (0.6%) patient. This case was a

Grade 1 osteopenia.

Growth retardation has been observed in paediatric patients treated with SPRYCEL in clinical trials(see section 4.8). After a maximum of 2 years of treatment, a downward trend in expected height hasbeen observed, at the same degree as observed with the use of chemotherapy alone, without impactingexpected weight and BMI and no association with hormones abnormalities or other laboratoryparameters. Monitoring of bone growth and development in paediatric patients is recommended.

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems ofgalactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take thismedicinal product.

Active substances that may increase dasatinib plasma concentrations

In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib andmedicinal products or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole,erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure todasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4inhibitor is not recommended (see section 4.2).

At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% onthe basis of in vitro experiments. No studies have been performed to evaluate dasatinib interactionwith other protein-bound medicinal products. The potential for displacement and its clinical relevanceare unknown.

Active substances that may decrease dasatinib plasma concentrations

When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, apotent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%. Other medicinal products thatinduce CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, phenobarbital or herbalpreparations containing Hypericum perforatum, also known as St. John´s Wort) may also increasemetabolism and decrease dasatinib plasma concentrations. Therefore, concomitant use of potent

CYP3A4 inducers with dasatinib is not recommended. In patients in whom rifampicin or other

CYP3A4 inducers are indicated, alternative medicinal products with less enzyme induction potentialshould be used. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib isallowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use ofdexamethasone, which is not likely to be clinically meaningful.

Histamine-2 antagonists and proton pump inhibitors

Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e.g.

famotidine and omeprazole) is likely to reduce dasatinib exposure. In a single-dose study in healthysubjects, the administration of famotidine 10 hours prior to a single dose of SPRYCEL reduceddasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100-mg doseof SPRYCEL 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC ofdasatinib by 43% and the Cmax of dasatinib by 42%. The use of antacids should be considered in placeof H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy (see section 4.4).

Antacids

Non-clinical data demonstrate that the solubility of dasatinib is pH-dependent. In healthy subjects, theconcomitant use of aluminium hydroxide/magnesium hydroxide antacids with SPRYCEL reduced the

AUC of a single dose of SPRYCEL by 55% and the Cmax by 58%. However, when antacids wereadministered 2 hours prior to a single dose of SPRYCEL, no relevant changes in dasatinibconcentration or exposure were observed. Thus, antacids may be administered up to 2 hours prior to or2 hours following SPRYCEL (see section 4.4).

Active substances that may have their plasma concentrations altered by dasatinib

Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4substrate. In a study in healthy subjects, a single 100 mg dose of dasatinib increased AUC and Cmaxexposure to simvastatin, a known CYP3A4 substrate, by 20 and 37% respectively. It cannot beexcluded that the effect is larger after multiple doses of dasatinib. Therefore, CYP3A4 substratesknown to have a narrow therapeutic index (e.g. astemizole, terfenadine, cisapride, pimozide,quinidine, bepridil or ergot alkaloids [ergotamine, dihydroergotamine]) should be administered withcaution in patients receiving dasatinib (see section 4.4).

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

Interaction studies have only been performed in adults.

Women of childbearing potential/contraception in males and females

Both sexually active men and women of childbearing potential should use effective methods ofcontraception during treatment.

Based on human experience, dasatinib is suspected to cause congenital malformations including neuraltube defects, and harmful pharmacological effects on the foetus when administered during pregnancy.

Studies in animals have shown reproductive toxicity (see section 5.3).

SPRYCEL should not be used during pregnancy unless the clinical condition of the woman requirestreatment with dasatinib. If SPRYCEL is used during pregnancy, the patient must be informed of thepotential risk to the foetus.

There is insufficient/limited information on the excretion of dasatinib in human or animal breast milk.

Physico-chemical and available pharmacodynamic/toxicological data on dasatinib point to excretion inbreast milk and a risk to the suckling child cannot be excluded.

Breast-feeding should be stopped during treatment with SPRYCEL.

In animal studies, the fertility of male and female rats was not affected by treatment with dasatinib(see section 5.3). Physicians and other healthcare providers should counsel male patients ofappropriate age about possible effects of SPRYCEL on fertility, and this counseling may includeconsideration of semen deposition.

SPRYCEL has minor influence on the ability to drive and use machines. Patients should be advisedthat they may experience adverse reactions such as dizziness or blurred vision during treatment withdasatinib. Therefore, caution should be recommended when driving a car or operating machines.

The data described below reflect the exposure to SPRYCEL as single-agent therapy at all doses testedin clinical studies (N=2,900), including 324 adult patients with newly diagnosed chronic phase CML,2,388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or

Ph+ ALL, and 188 paediatric patients.

In the 2,712 adult patients with either chronic phase CML, advanced phase CML or Ph+ ALL, themedian duration of therapy was 19.2 months (range 0 to 93.2 months). In a randomized trial in patientswith newly diagnosed chronic phase CML, the median duration of therapy was approximately60 months. The median duration of therapy in 1,618 adult patients with chronic phase CML was29 months (range 0 to 92.9 months). The median duration of therapy in 1,094 adult patients withadvanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). Among 188 patients inpaediatric studies, the median duration of therapy was 26.3 months (range 0 to 99.6 months). In thesubset of 130 chronic phase CML SPRYCEL-treated paediatric patients, the median duration oftherapy was 42.3 months (range 0.1 to 99.6 months).

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the overallpopulation of 2,712 SPRYCEL-treated adult subjects, 520 (19%) experienced adverse reactionsleading to treatment discontinuation.

The overall safety profile of SPRYCEL in the paediatric Ph+ CML-CP population was similar to thatof the adult population, regardless of formulation, with the exception of no reported pericardialeffusion, pleural effusion, pulmonary oedema, or pulmonary hypertension in the paediatric population.

Of the 130 SPRYCEL-treated paediatric subjects with CML-CP, 2 (1.5%) experienced adversereactions leading to treatment discontinuation.

The following adverse reactions, excluding laboratory abnormalities, were reported in patients treatedwith SPRYCEL used as single-agent therapy in clinical studies and post-marketing experience(Table 5). These reactions are presented by system organ class and by frequency. Frequencies aredefined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from available post-marketing data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5: Tabulated summary of adverse reactions

Very common infection (including bacterial, viral, fungal, non-specified)

Common pneumonia (including bacterial, viral, and fungal), upper respiratory tractinfection/inflammation, herpes virus infection (including cytomegalovirus - CMV),enterocolitis infection, sepsis (including uncommon cases with fatal outcomes)

Not known hepatitis B reactivation

Very Common myelosuppression (including anaemia, neutropaenia, thrombocytopaenia)

Common febrile neutropaenia

Uncommon lymphadenopathy, lymphopaenia

Rare aplasia pure red cell

Uncommon hypersensitivity (including erythema nodosum)

Rare anaphylactic shock

Uncommon hypothyroidism

Rare hyperthyroidism, thyroiditis

Common appetite disturbancesa, hyperuricaemia

Uncommon tumour lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia

Rare diabetes mellitus

Common depression, insomnia

Uncommon anxiety, confusional state, affect lability, libido decreased

Very common headache

Common neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence

Uncommon CNS bleeding*b, syncope, tremor, amnesia, balance disorder

Rare cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis, VIIthnerve paralysis, dementia, ataxia

Common visual disorder (including visual disturbance, vision blurred, and visual acuityreduced), dry eye

Uncommon visual impairment, conjunctivitis, photophobia, lacrimation increased

Ear and labyrinth disorders

Common tinnitus

Uncommon hearing loss, vertigo

Common congestive heart failure/cardiac dysfunction*c, pericardial effusion*, arrhythmia(including tachycardia), palpitations

Uncommon myocardial infarction (including fatal outcome)*, electrocardiogram QT prolonged*,pericarditis, ventricular arrhythmia (including ventricular tachycardia), anginapectoris, cardiomegaly, electrocardiogram T wave abnormal, troponin increased

Rare cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest,electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis

Not known atrial fibrillation/atrial flutter

Very common haemorrhage*d

Common hypertension, flushing

Uncommon hypotension, thrombophlebitis, thrombosis

Rare deep vein thrombosis, embolism, livedo reticularis

Not known thrombotic microangiopathy

Very common pleural effusion*, dyspnoea

Common pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis, cough

Uncommon pulmonary arterial hypertension, bronchospasm, asthma, chylothorax*

Rare pulmonary embolism, acute respiratory distress syndrome

Not known interstitial lung disease

Very common diarrhoea, vomiting, nausea, abdominal pain

Common gastrointestinal bleeding*, colitis (including neutropaenic colitis), gastritis, mucosalinflammation (including mucositis/stomatitis), dyspepsia, abdominal distension,constipation, oral soft tissue disorder

Uncommon pancreatitis (including acute pancreatitis), upper gastrointestinal ulcer, oesophagitis,ascites*, anal fissure, dysphagia, gastroesophageal reflux disease

Rare protein-losing gastroenteropathy, ileus, anal fistula

Not known fatal gastrointestinal haemorrhage*

Uncommon hepatitis, cholecystitis, cholestasis

Very common skin rashe

Common alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria,hyperhidrosis

Uncommon neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skinulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome,hair disorder

Rare leukocytoclastic vasculitis, skin fibrosis

Not known Stevens-Johnson syndromef

Very common musculoskeletal paing

Common arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm

Uncommon rhabdomyolysis, osteonecrosis, muscle inflammation, tendonitis, arthritis

Rare epiphyses delayed fusion,h growth retardationh

Uncommon renal impairment (including renal failure), urinary frequency, proteinuria

Not known nephrotic syndrome

Pregnancy, puerperium and perinatal conditions

Rare abortion

Uncommon gynecomastia, menstrual disorder

Very common peripheral oedemai, fatigue, pyrexia, face oedemaj

Common asthenia, pain, chest pain, generalised oedema*k, chills

Uncommon malaise, other superficial oedemal

Rare gait disturbance

Common weight decreased, weight increased

Uncommon blood creatine phosphokinase increased, gamma-glutamyltransferase increased

Injury, poisoning, and procedural complications

Common contusiona Includes decreased appetite, early satiety, increased appetite.b Includes central nervous system haemorrhage, cerebral haematoma, cerebral haemorrhage, extradural haematoma,haemorrhage intracranial, haemorrhagic stroke, subarachnoid haemorrhage, subdural haematoma, and subduralhaemorrhage.c Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular dysfunction, right ventriculardysfunction, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiomyopathy,congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased and ventricular failure, left ventricularfailure, right ventricular failure, and ventricular hypokinesia.d Excludes gastrointestinal bleeding and CNS bleeding; these adverse reactions are reported under the gastrointestinaldisorders system organ class and the nervous system disorders system organ class, respectively.e Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalised erythema, genital rash,heat rash, milia, miliaria, pustular psoriaisis, rash, rash erythematous, rash follicular, rash generalised, rash macular, rashmaculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, toxic skineruption, urticaria vesiculosa, and vasculitic rash.f In the post-marketing setting, individual cases of Stevens-Johnson syndrome have been reported. It could not bedetermined whether these mucocutaneous adverse reactions were directly related to SPRYCEL or to concomitantmedicinal product.g Musculoskeletal pain reported during or after discontinuing treatment.h Frequency reported as common in paediatric studies.i Gravitational oedema, localised oedema, oedema peripheral.j Conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, lip oedema, macular oedema, oedemamouth, orbital oedema, periorbital oedema, swelling face.k Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, peripheral swelling, oedema, oedema due tocardiac disease, perinephric effusion, post procedural oedema, visceral oedema.l Genital swelling, incision site oedema, oedema genital, penile oedema, penile swelling, scrotal oedema, skin swelling,testicular swelling, vulvovaginal swelling.

* For additional details, see section 'Description of selected adverse reactions'

Treatment with SPRYCEL is associated with anaemia, neutropaenia and thrombocytopaenia. Theiroccurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than inchronic phase CML (see section 4.4).

Bleeding drug-related adverse reactions, ranging from petechiae and epistaxis tograde 3 or 4 gastrointestinal haemorrhage and CNS bleeding, were reported in patients taking

SPRYCEL (see section 4.4).

Fluid retention

Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and pericardialeffusion with or without superficial oedema may be collectively described as “fluid retention”. In thenewly diagnosed chronic phase CML study after a minimum of 60 months follow-up, dasatinib-relatedfluid retention adverse reactions included pleural effusion (28%), superficial oedema (14%),pulmonary hypertension (5%), generalised oedema (4%), and pericardial effusion (4%). Congestiveheart failure/cardiac dysfunction and pulmonary oedema were reported in < 2% of patients.

The cumulative rate of dasatinib-related pleural effusion (all grades) over time was 10% at 12 months,14% at 24 months, 19% at 36 months, 24% at 48 months and 28% at 60 months. A total of46 dasatinib-treated patients had recurrent pleural effusions. Seventeen patients had 2 separate adversereactions, 6 had 3 adverse reactions, 18 had 4 to 8 adverse reactions and 5 had > 8 episodes of pleuraleffusions.

The median time to first dasatinib-related grade 1 or 2 pleural effusion was 114 weeks (range: 4 to299 weeks). Less than 10% of patients with pleural effusion had severe (grade 3 or 4) dasatinib-relatedpleural effusions. The median time to first occurrence of grade ≥ 3 dasatinib-related pleural effusionwas 175 weeks (range: 114 to 274 weeks). The median duration of dasatinib-related pleural effusion(all grades) was 283 days (~40 weeks).

Pleural effusion was usually reversible and managed by interrupting SPRYCEL treatment and usingdiuretics or other appropriate supportive care measures (see sections 4.2 and 4.4). Amongdasatinib-treated patients with drug-related pleural effusion (n=73), 45 (62%) had dose interruptionsand 30 (41%) had dose reductions. Additionally, 34 (47%) received diuretics, 23 (32%) receivedcorticosteroids, and 20 (27%) received both corticosteroids and diuretics. Nine (12%) patientsunderwent therapeutic thoracentesis.

Six percent of dasatinib-treated patients discontinued treatment due to drug-related pleural effusion.

Pleural effusion did not impair the ability of patients to obtain a response. Among the dasatinib-treatedpatients with pleural effusion, 96% achieved a cCCyR, 82% achieved a MMR, and 50% achieved a

MR4.5 despite dose interruptions or dose adjustment.

See section 4.4 for further information on patients with chronic phase CML and advanced phase CMLor Ph+ ALL.

Cases of chylothorax have been reported in patients presenting with pleural effusion. Some cases ofchylothorax resolved upon dasatinib discontinuation, interruption, or dose reduction, but most casesalso required additional treatment.

Pulmonary arterial hypertension (PAH)

PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has beenreported in association with dasatinib exposure. In these cases, PAH was reported after initiation ofdasatinib therapy, including after more than one year of treatment. Patients with PAH reported duringdasatinib treatment were often taking concomitant medicinal products or had co-morbidities inaddition to the underlying malignancy. Improvements in haemodynamic and clinical parameters havebeen observed in patients with PAH following discontinuation of dasatinib.

QT Prolongation

In the Phase III study in patients with newly diagnosed chronic phase CML, one patient (< 1%) of the

SPRYCEL-treated patients had a QTcF > 500 msec after a minimum of 12 months follow-up (seesection 4.4). No additional patients were reported to have QTcF > 500 msec after a minimum of60 months follow-up.

In 5 Phase II clinical studies in patients with resistance or intolerance to prior imatinib therapy,repeated baseline and on-treatment ECGs were obtained at pre-specified time points and read centrallyfor 865 patients receiving SPRYCEL 70 mg twice daily. QT interval was corrected for heart rate by

Fridericia's method. At all post-dose time points on day 8, the mean changes from baseline in QTcFinterval were 4 - 6 msec, with associated upper 95% confidence intervals < 7 msec. Of the2,182 patients with resistance or intolerance to prior imatinib therapy who received SPRYCEL inclinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one patients(1%) experienced a QTcF > 500 msec (see section 4.4).

Cardiac adverse reactions

Patients with risk factors or a history of cardiac disease should be monitored carefully for signs orsymptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately (seesection 4.4).

Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted inacute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (seesection 4.4).

In the Phase III dose-optimisation study in patients with chronic phase CML with resistance orintolerance to prior imatinib therapy (median duration of treatment of 30 months), the incidence ofpleural effusion and congestive heart failure/cardiac dysfunction was lower in patients treated with

SPRYCEL 100 mg once daily than in those treated with SPRYCEL 70 mg twice daily.

Myelosuppression was also reported less frequently in the 100 mg once daily treatment group (see

Laboratory test abnormalities below). The median duration of therapy in the 100 mg once daily groupwas 37 months (range 1-91 months). Cumulative rates of selected adverse reactions that were reportedin the 100 mg once daily recommended starting dose are shown in Table 6a.

Table 6a: Selected adverse reactions reported in a phase 3 dose optimisation study (imatinibintolerant or resistant chronic phase CML)a

Minimum of 2 years Minimum of 5 years Minimum of 7 yearsfollow up follow up follow up

All Grade All Grade All Gradegrades 3/4 grades 3/4 grades 3/4

Preferred term Percent (%) of patients

Diarrhoea 27 2 28 2 28 2

Fluid retention 34 4 42 6 48 7

Superficial oedema 18 0 21 0 22 0

Pleural effusion 18 2 24 4 28 5

Generalised oedema 3 0 4 0 4 0

Pericardial effusion 2 1 2 1 3 1

Pulmonary0 0 0 0 2 1hypertension

Haemorrhage 11 1 11 1 12 1

Gastrointestinal2 1 2 1 2 1bleedinga Phase 3 dose optimisation study results reported in recommended starting dose of 100 mg once daily (n=165) population

In the Phase III dose-optimisation study in patients with advanced phase CML and Ph+ ALL, themedian duration of treatment was 14 months for accelerated phase CML, 3 months for myeloid blast

CML, 4 months for lymphoid blast CML and 3 months for Ph+ ALL. Selected adverse reactions thatwere reported in the recommended starting dose of 140 mg once daily are shown in Table 6b. A 70 mgtwice daily regimen was also studied. The 140 mg once daily regimen showed a comparable efficacyprofile to the 70 mg twice daily regimen but a more favourable safety profile.

Table 6b: Selected adverse reactions reported in phase III dose-optimisation study:

Advanced phase CML and Ph+ ALLa140 mg once dailyn = 304

All grades Grade 3/4

Percent (%) of patients

Preferred term

Diarrhoea 28 3

Fluid retention 33 7

Superficial oedema 15 < 1

Pleural effusion 20 6

Generalised oedema 2 0

Congestive heart failure 1 0/cardiac dysfunctionb

Pericardial effusion 2 1

Pulmonary oedema 1 1

Haemorrhage 23 8

Gastrointestinal bleeding 8 6a Phase 3 dose optimisation study results reported at the recommended starting dose of 140 mg once daily (n=304)population at 2 year final study follow up.b Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,diastolic dysfunction, ejection fraction decreased, and ventricular failure.

In addition, there were two studies in a total of 161 paediatric patients with Ph+ ALL in which

SPRYCEL was administered in combination with chemotherapy. In the pivotal study, 106 paediatricpatients received SPRYCEL in combination with chemotherapy on a continuous dosing regimen. In asupportive study, of 55 paediatric patients, 35 received SPRYCEL in combination with chemotherapyon a discontinuous dosing regimen (two weeks on treatment followed by one to two weeks off) and20 received SPRYCEL in combination with chemotherapy on a continuous dosing regimen. Amongthe 126 Ph+ ALL paediatric patients treated with SPRYCEL on a continuous dosing regimen, themedian duration of therapy was 23.6 months (range 1.4 to 33 months).

Of the 126 Ph+ ALL paediatric patients on a continuous dosing regimen, 2 (1.6%) experiencedadverse reactions leading to treatment discontinuation. Adverse reactions reported in these twopaediatric studies at a frequency of 10% in patients on a continuous dosing regimen are shown in

Table 7. Of note, pleural effusion was reported in 7 (5.6%) patients in this group, and is therefore notincluded in the table.

Table 7: Adverse reactions reported in ≥10% of paediatric patients with Ph+ ALL treatedwith SPRYCEL on a continuous dosing regimen in combination with chemotherapy(N=126)a

Percent (%) of patients

Adverse reaction All grades Grade 3/4

Febrile neutropaenia 27.0 26.2

Nausea 20.6 5.6

Vomiting 20.6 4.8

Abdominal pain 14.3 3.2

Diarrhoea 12.7 4.8

Pyrexia 12.7 5.6

Headache 11.1 4.8

Decreased appetite 10.3 4.8

Fatigue 10.3 0a In the pivotal study, among 106 total patients, 24 patients received the powder for oral suspension at least once, 8 of whomreceived the powder for oral suspension formulation exclusively.

Laboratory test abnormalities

In the Phase III newly diagnosed chronic phase CML study, the following grade 3 or 4 laboratoryabnormalities were reported after a minimum of 12 months follow-up in patients taking SPRYCEL:

neutropaenia (21%), thrombocytopaenia (19%), and anaemia (10%). After a minimum of 60 monthsfollow-up, the cumulative rates of neutropaenia, thrombocytopaenia, and anaemia were 29%, 22% and13%, respectively.

In SPRYCEL-treated patients with newly diagnosed chronic phase CML who experiencedgrade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/orreductions and permanent discontinuation of treatment occurred in 1.6% of patients after a minimumof 12 months follow-up. After a minimum of 60 months follow-up the cumulative rate of permanentdiscontinuation due to grade 3 or 4 myelosuppression was 2.3%.

In patients with CML with resistance or intolerance to prior imatinib therapy, cytopaenias(thrombocytopaenia, neutropaenia, and anaemia) were a consistent finding. However, the occurrenceof cytopaenias was also clearly dependent on the stage of the disease. The frequency ofgrade 3 and 4 haematological abnormalities is presented in Table 8.

Table 8: CTC grades 3/4 haematological laboratory abnormalities in clinical studies inpatients with resistance or intolerance to prior imatinib therapya

Lymphoid blast

Accelerated Myeloid phase and

Chronic phase phase blast phase Ph+ ALL(n= 165)b (n= 157)c (n= 74)c (n= 168)c

Percent (%) of patients

Haematology parameters

Neutropaenia 36 58 77 76

Thrombocytopaenia 23 63 78 74

Anaemia 13 47 74 44a Phase 3 dose optimisation study results reported at 2 year study follow up.b CA180-034 study results in recommended starting dose of 100 mg once daily.c CA180-035 study results in recommended starting dose of 140 mg once daily.

CTC grades: neutropaenia (Grade 3 ≥ 0.5- < 1.0 × 109/l, Grade 4 < 0.5 × 109/l); thrombocytopaenia (Grade 3 ≥ 25 - < 50× 109/l, Grade 4 < 25 × 109/l); anaemia (haemoglobin Grade 3 ≥ 65 - < 80 g/l, Grade 4 < 65 g/l).

Cumulative grade 3 or 4 cytopaenias among patients treated with 100 mg once daily were similar at2 and 5 years including: neutropaenia (35% vs. 36%), thrombocytopaenia (23% vs. 24%) and anaemia(13% vs. 13%).

In patients who experienced grade 3 or 4 myelosuppression, recovery generally occurred followingbrief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in5% of patients. Most patients continued treatment without further evidence of myelosuppression.

Biochemistry

In the newly diagnosed chronic phase CML study, grade 3 or 4 hypophosphataemia was reportedin 4% of SPRYCEL-treated patients, and grade 3 or 4 elevations of transaminases, creatinine, andbilirubin were reported in ≤ 1% of patients after a minimum of 12 months follow-up. After a minimumof 60 months follow-up the cumulative rate of grade 3 or 4 hypophosphataemia was 7%,grade 3 or 4 elevations of creatinine and bilirubin was 1% and grade 3 or 4 elevations of transaminasesremained 1%. There were no discontinuations of SPRYCEL therapy due to these biochemicallaboratory parameters.

2 year follow-up

Grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% of patients with chronicphase CML (resistant or intolerant to imatinib), but elevations were reported with an increasedfrequency of 1 to 7% of patients with advanced phase CML and Ph+ ALL. It was usually managedwith dose reduction or interruption. In the Phase III dose-optimisation study in chronic phase CML,grade 3 or 4 elevations of transaminases or bilirubin were reported in ≤ 1% of patients with similarlow incidence in the four treatment groups. In the Phase III dose-optimisation study in advanced phase

CML and Ph+ALL, grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% to 5% ofpatients across treatment groups.

Approximately 5% of the SPRYCEL-treated patients who had normal baseline levels experiencedgrade 3 or 4 transient hypocalcaemia at some time during the course of the study. In general, there wasno association of decreased calcium with clinical symptoms. Patients developinggrade 3 or 4 hypocalcaemia often had recovery with oral calcium supplementation.

Grade 3 or 4 hypocalcaemia, hypokalaemia, and hypophosphataemia were reported in patients with allphases of CML but were reported with an increased frequency in patients with myeloid or lymphoidblast phase CML and Ph+ ALL. Grade 3 or 4 elevations in creatinine were reported in < 1% ofpatients with chronic phase CML and were reported with an increased frequency of 1 to 4% of patientswith advanced phase CML.

The safety profile of SPRYCEL administered as single-agent therapy in paediatric patients with

Ph+ CML-CP was comparable to the safety profile in adults. The safety profile of SPRYCELadministered in combination with chemotherapy in paediatric patients with Ph+ ALL was consistentwith the known safety profile of SPRYCEL in adults and the expected effects of chemotherapy, withthe exception of a lower pleural effusion rate in paediatric patients as compared to adults.

In the paediatric CML studies, the rates of laboratory abnormalities were consistent with the knownprofile for laboratory parameters in adults.

In the paediatric ALL studies, the rates of laboratory abnormalities were consistent with the knownprofile for laboratory parameters in adults, within the context of an acute leukaemia patient receiving abackground chemotherapy regimen.

Special population

While the safety profile of SPRYCEL in elderly was similar to that in the younger population, patientsaged 65 years and older are more likely to experience the commonly reported adverse reactions suchas fatigue, pleural effusion, dyspnoea, cough, lower gastrointestinal haemorrhage, and appetitedisturbance and more likely to experience less frequently reported adverse reactions such asabdominal distention, dizziness, pericardial effusion, congestive heart failure, and weight decrease andshould be monitored closely (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. The highestoverdose of 280 mg per day for one week was reported in two patients and both developed asignificant decrease in platelet counts. Since dasatinib is associated withgrade 3 or 4 myelosuppression (see section 4.4), patients who ingest more than the recommended doseshould be closely monitored for myelosuppression and given appropriate supportive treatment.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EA02

Pharmacodynamics

Dasatinib inhibits the activity of the BCR-ABL kinase and SRC family kinases along with a number ofother selected oncogenic kinases including c-KIT, ephrin (EPH) receptor kinases, and PDGFβreceptor. Dasatinib is a potent, subnanomolar inhibitor of the BCR-ABL kinase with potency atconcentration of 0.6-0.8 nM. It binds to both the inactive and active conformations of the BCR-ABLenzyme.

In vitro, dasatinib is active in leukaemic cell lines representing variants of imatinib-sensitive andresistant disease. These non-clinical studies show that dasatinib can overcome imatinib resistanceresulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternatesignalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance geneoverexpression. Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations.

In vivo, in separate experiments using murine models of CML, dasatinib prevented the progression ofchronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell linesgrown at various sites, including the central nervous system.

In the Phase I study, haematologic and cytogenetic responses were observed in all phases of CML andin Ph+ ALL in the first 84 patients treated and followed for up to 27 months. Responses were durableacross all phases of CML and Ph+ ALL.

Four single-arm, uncontrolled, open-label Phase II clinical studies were conducted to determine thesafety and efficacy of dasatinib in patients with CML in chronic, accelerated, or myeloid blast phase,who were either resistant or intolerant to imatinib. One randomised non-comparative study wasconducted in chronic phase patients who failed initial treatment with 400 or 600 mg imatinib. Thestarting dose was 70 mg dasatinib twice daily. Dose modifications were allowed for improving activityor management of toxicity (see section 4.2).

Two randomised, open-label Phase III studies were conducted to evaluate the efficacy of dasatinibadministered once daily compared with dasatinib administered twice daily. In addition, oneopen-label, randomised, comparative Phase III study was conducted in adult patients with newlydiagnosed chronic phase CML.

The efficacy of dasatinib is based on haematological and cytogenetic response rates.

Durability of response and estimated survival rates provide additional evidence of dasatinib clinicalbenefit.

A total of 2,712 patients were evaluated in clinical studies; of these 23% were ≥ 65 years of age and5% were ≥ 75 years of age.

Chronic phase CML - Newly diagnosed

An international open-label, multicentre, randomised, comparative Phase III study was conducted inadult patients with newly diagnosed chronic phase CML. Patients were randomised to receive either

SPRYCEL 100 mg once daily or imatinib 400 mg once daily. The primary endpoint was the rate ofconfirmed complete cytogenetic response (cCCyR) within 12 months. Secondary endpoints includedtime 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 efficacyresults included CCyR and complete molecular response (CMR) rates. The study is ongoing.

A total of 519 patients were randomised to a treatment group: 259 to SPRYCEL 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 group and 49 years for the imatinib group with 10% and11% 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 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 group and81% of patients randomised to the imatinib group were still receiving first-line treatment.

Discontinuation within 12 months due to disease progression occurred in 3% of SPRYCEL-treatedpatients and 5% of imatinib-treated patients.

With a minimum of 60 months follow-up, 60% of patients randomised to the SPRYCEL group and63% of patients randomised to the imatinib group were still receiving first-line treatment.

Discontinuation within 60 months due to disease progression occurred in 11% of SPRYCEL-treatedpatients and 14% of imatinib-treated patients.

Efficacy results are presented in Table 9. A statistically significantly greater proportion of patients inthe SPRYCEL group achieved a cCCyR compared with patients in the imatinib group within the first12 months of treatment. Efficacy of SPRYCEL was consistently demonstrated across differentsubgroups, including age, gender, and baseline Hasford score.

Table 9: Efficacy results from a phase 3 study of newly diagnosed patients with chronicphase CML

SPRYCEL imatinib p-valuen= 259 n= 260

Response rate (95% CI)

Cytogenetic responsewithin 12 monthscCCyRa76.8% (71.2-81.8) 66.2% (60.1-71.9) p< 0.007*

CCyRb 85.3% (80.4-89.4) 73.5% (67.7-78.7) ⎯within 24 monthscCCyRa 80.3% 74.2% ⎯

CCyRb 87.3% 82.3% ⎯within 36 monthscCCyRa 82.6% 77.3% ⎯

CCyRb 88.0% 83.5% ⎯within 48 monthscCCyRa 82.6% 78.5% ⎯

CCyRb 87.6% 83.8% ⎯within 60 monthscCCyRa 83.0% 78.5% ⎯

CCyRb 88.0% 83.8% ⎯

Major molecular responsec12 months 52.1% (45.9-58.3) 33.8% (28.1-39.9) p< 0.00003*24 months 64.5% (58.3-70.3) 50% (43.8-56.2) ⎯36 months 69.1% (63.1-74.7) 56.2% (49.9-62.3) ⎯48 months 75.7% (70.0-80.8) 62.7% (56.5-68.6) ⎯60 months 76.4% (70.8-81.5) 64.2% (58.1-70.1) p=0.0021

Hazard ratio (HR)within 12 months (99.99% CI)

Time-to cCCyR 1.55 (1.0-2.3) p< 0.0001*

Time-to MMR 2.01 (1.2-3.4) p< 0.0001*

Durability of cCCyR 0.7 (0.4-1.4) p< 0.035within 24 months (95% CI)

Time-to cCCyR 1.49 (1.22-1.82) ⎯

Time-to MMR 1.69 (1.34-2.12) ⎯

Durability of cCCyR 0.77 (0.55-1.10) ⎯within 36 months (95% CI)

Time-to cCCyR 1.48 (1.22-1.80) ⎯

Time-to MMR 1.59 (1.28-1.99) ⎯

Durability of cCCyR 0.77 (0.53-1.11) ⎯within 48 months (95% CI)

Time-to cCCyR 1.45 (1.20-1.77) ⎯

Time-to MMR 1.55 (1.26-1.91) ⎯

Durability of cCCyR 0.81 (0.56-1.17) ⎯within 60 months (95% CI)

Time-to cCCyR 1.46 (1.20-1.77) p=0.0001

Time-to MMR 1.54 (1.25-1.89) p<0.0001

Durability of cCCyR 0.79 (0.55-1.13) p=0.1983a Confirmed complete cytogenetic response (cCCyR) is defined as a response noted on two consecutive occasions (at least28 days apart).b Complete cytogenetic response (CCyR) is based on a single bone marrow cytogenetic evaluation.c Major molecular response (at any time) was defined as BCR ABL ratios ≤ 0.1% by RQ PCR in peripheral blood samplesstandardised on the International scale. These are cumulative rates representing minimum follow up for the timeframespecified.

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

CI = confidence interval

After 60 months of follow-up, median time to cCCyR was 3.1 months in the SPRYCEL group and5.8 months in the imatinib group in patients with a confirmed CCyR. Median time to MMR after60 months of follow-up was 9.3 months in the SPRYCEL group and 15.0 months in the imatinibgroup in patients with a MMR. These results are consistent with those seen at 12, 24 and 36 months.

The time to MMR is displayed graphically in Figure 1. The time to MMR was consistently shorter indasatinib-treated patients compared with imatinib-treated patients.

Figure 1: Kaplan-Meier estimate of time to major molecular response (MMR)

MONTHS___ Dasatinib ------ Imatinib

Censored Censored

GROUP # RESPONDERS/# RANDOMIZED HAZARD RATIO (95% CI)

Dasatinib 198/259

Imatinib 167/260

Dasatinib over imatinib 1.54(1.25 - 1.89)

The rates of cCCyR in the SPRYCEL 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%),36 months (83% and 77%), 48 months (83% and 79%) and 60 months (83% and 79%) were consistentwith the primary endpoint. The rates of MMR in the SPRYCEL 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%) , 36 months (67% and 55%), 48 months (73%and 60%) and 60 months (76% and 64%)were also consistent with the primary endpoint.

MMR rates by specific time point are displayed graphically in Figure 2. Rates of MMR wereconsistently higher in dasatinib-treated patients compared with imatinib-treated patients.

PROPORTION RESPONDERS

Figure 2: MMR rates over time - all randomised patients in a phase 3 study of newly diagnosedpatients with chronic phase CML

By 5 years

By 4 years 76%, p<.002273%, p<.0021

By 3 years

By 2 years 67%, p<.005564%, p<.0001

By 1 year46%, p<.0001

Months since randomisation

N______ Dasatinib 100 mg once daily 259

- -------- Imatinib 400 mg once daily 260

The proportion of patients achieving BCR-ABL ratio of ≤0.01% (4-log reduction) at any time washigher in the SPRYCEL group compared to the imatinib group (54.1% versus 45%). The proportion ofpatients achieving BCR-ABL ratio of ≤0.0032% (4.5-log reduction) at any time was higher in the

SPRYCEL group compared to the imatinib group (44% versus 34%).

MR4.5 rates over time are displayed graphically in Figure 3. Rates of MR4.5 over time wereconsistently higher in dasatinib-treated patients compared with imatinib-treated patients.

% with MMR

Figure 3: MR4.5 rates over time - all randomised patients in a phase 3 study of newlydiagnosed patients with chronic phase CML

By 5 years42%, p<.0251

By 4 years34%, p<.0055

By 3 years24%, p<.0013

By 2 years

By 1 year 19%, p<.00085%, p<.2394

Months since randomisation

N______ Dasatinib 100 mg once daily 259

- -------- Imatinib 400 mg once daily 260

The rate of MMR at any time in each risk group determined by Hasford score was higher in the

SPRYCEL group compared with the imatinib group (low risk: 90% and 69%; intermediate risk: 71%and 65%; high risk: 67% and 54%, respectively).

In an additional analysis, more dasatinib-treated patients (84%) achieved early molecular response(defined as BCR-ABL levels ≤ 10% at 3 months) compared with imatinib-treated patients (64%).

Patients achieving early molecular response had a lower risk of transformation, higher rate ofprogression-free survival (PFS) and higher rate of overall survival (OS), as shown in Table 10.

Table 10: Dasatinib patients with BCR-ABL ≤ 10% and > 10% at 3 months

Patients with BCR-ABL Patients with BCR-ABL >

Dasatinib N = 235 ≤ 10% at 3 months 10% at 3 months

Number of patients (%) 198 (84.3) 37 (15.7)

Transformation at 60 months, n/N (%) 6/198 (3.0) 5/37 (13.5)

Rate of PFS at 60 months (95% CI) 92.0% (89.6, 95.2) 73.8% (52.0, 86.8)

Rate of OS at 60 months (95% CI) 93.8% (89.3, 96.4) 80.6% (63.5, 90.2)

The OS rate by specific time point is displayed graphically in Figure 4. Rate of OS was consistentlyhigher in dasatinib treated patients who achieved BCR-ABL level ≤ 10% at 3 months than those whodid not.

% with MR4.5

Figure 4: Landmark plot for overall survival for dasatinib by BCR-ABL level (≤ 10% or> 10%) at 3 months in a phase 3 study of newly diagnosed patients with chronicphase CML

MONTHS

Patients at risk<=10% 198 198 197 196 195 193 193 191 191 190 188 187 187 184 182 181 180 179 179 177 171 96 54 29 3 0>10% 37 37 37 35 34 34 34 33 33 31 30 29 29 29 28 28 28 27 27 27 26 15 10 6 0 0___≤10% ------ >10%

Censored Censored

GROUP # DEATHS/# Land Patient MEDIAN (95% CI) HAZARD RATIO (95% CI)≤10% 14/198 .(. - .)>10% 8/37 .(. - .)0.29(0.12 - 0.69)

Disease progression was defined as increasing white blood cells despite appropriate therapeuticmanagement, loss of CHR, partial CyR or CCyR, progression to accelerated phase or blast phase, ordeath. The estimated 60-month PFS rate was 88.9% (CI: 84% - 92.4%) for both the dasatinib andimatinib treatment groups. At 60 months, transformation to accelerated or blast phase occurred infewer dasatinib-treated patients (n=8; 3%) compared with imatinib-treated patients (n=15; 5.8%). Theestimated 60-month survival rates for dasatinib and imatinib-treated patients were 90.9% (CI:

86.6% - 93.8%) and 89.6% (CI: 85.2% - 92.8%), respectively. There was no difference in OS (HR1.01, 95% CI: 0.58-1.73, p= 0.9800) and PFS (HR 1.00, 95% CI: 0.58-1.72, p = 0.9998) betweendasatinib and imatinib.

In patients who report disease progression or discontinue dasatinib or imatinib therapy, BCR-ABLsequencing was performed on blood samples from patients where these are available. Similar rates ofmutation were observed in both the treatment arms. The mutations detected among thedasatinib-treated patients were T315I, F317I/L and V299L. A different spectrum of mutation wasdetected in the imatinib treatment arm. Dasatinib does not appear to be active against the

T315I mutation, based on in vitro data.

Chronic phase CML - Resistance or intolerance to prior imatinib therapy

Two clinical studies were conducted in patients resistant or intolerant to imatinib; the primary efficacyendpoint in these studies was Major Cytogenetic Response (MCyR).

Study 1

An open-label, randomised, non-comparative multicentre study was conducted in patients who failedinitial treatment with 400 or 600 mg imatinib. They were randomised (2:1) to either dasatinib (70 mgtwice daily) or imatinib (400 mg twice daily). Crossover to the alternative treatment arm was allowedif patients showed evidence of disease progression or intolerance that could not be managed by dosemodification. The primary endpoint was MCyR at 12 weeks. Results are available for 150 patients:

101 were randomised to dasatinib and 49 to imatinib (all imatinib-resistant). The median time fromdiagnosis to randomisation was 64 months in the dasatinib group and 52 months in the imatinib group.

PROPORTION ALIVE

All patients were extensively pretreated. Prior complete haematologic response (CHR) to imatinib wasachieved in 93% of the overall patient population. A prior MCyR to imatinib was achieved in 28% and29% 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 of patients in the dasatinib arm and 82% of patients in the imatinib arm achieveda CHR prior to crossover.

At 3 months, a MCyR occurred more often in the dasatinib arm (36%) than in the imatinib arm (29%).

Notably, 22% of patients reported a complete cytogenetic response (CCyR) in the dasatinib arm whileonly 8% achieved a CCyR in the imatinib arm. With longer treatment and follow-up (median of24 months), MCyR was achieved in 53% of the dasatinib-treated patients (CCyR in 44%) and 33% ofthe imatinib-treated patients (CCyR in 18%) prior to crossover. Among patients who had receivedimatinib 400 mg prior to study entry, MCyR was achieved in 61% of patients in the dasatinib arm and50% in the imatinib arm.

Based on the Kaplan-Meier estimates, the proportion of patients who maintained MCyR for 1 year was92% (95% CI: [85%-100%]) for dasatinib (CCyR 97%, 95% CI: [92%-100%]) and 74% (95% CI:

[49%-100%]) for imatinib (CCyR 100%). The proportion of patients who maintained MCyR for18 months was 90% (95% CI: [82%-98%]) for dasatinib (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 dasatinib and 73% (95% CI: [54%-91%]) forimatinib. The proportion of patients who had PFS at 2 years was 86% (95% CI: [78%-93%]) fordasatinib 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, intolerance ofstudy medicinal product, etc.).

The rate of major molecular response (defined as BCR-ABL/control transcripts ≤ 0.1% by RQ-PCR inperipheral blood samples) prior to crossover was 29% for dasatinib and 12% for imatinib.

Study 2

An open-label, single-arm, multicentre study was conducted in patients resistant or intolerant toimatinib (i.e. patients who experienced significant toxicity during treatment with imatinib thatprecluded further treatment).

A total of 387 patients received dasatinib 70 mg twice daily (288 resistant and 99 intolerant). Themedian 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%) hadreceived > 600 mg imatinib. In addition to imatinib, 35% of patients had received prior cytotoxicchemotherapy, 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. Medianduration of treatment on dasatinib was 24 months with 51% of patients treated for > 24 months to date.

Efficacy results are reported in Table 11. MCyR was achieved in 55% of imatinib-resistant patientsand 82% of imatinib-intolerant patients. With a minimum of 24 months follow-up, 21 of the240 patients who had achieved a MCyR had progressed and the median duration of MCyR had notbeen reached.

Based on the Kaplan-Meier estimates, 95% (95% CI: [92%-98%]) of the patients maintained MCyRfor 1 year and 88% (95% CI: [83%-93%]) maintained MCyR for 2 years. The proportion of patientswho maintained CCyR for 1 year was 97% (95% CI: [94%-99%]) and for 2 years was 90% (95% CI:

[86%-95%]). Forty-two percent of the imatinib-resistant patients with no prior MCyR to imatinib(n= 188) achieved a MCyR with dasatinib.

There were 45 different BCR-ABL mutations in 38% of patients enrolled in this study. Completehaematologic response or MCyR was achieved in patients harbouring a variety of BCR-ABLmutations associated with imatinib resistance except T315I. The rates of MCyR at 2 years were similarwhether 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 yearand 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 and74% for imatinib-intolerant patients).

Accelerated phase CML

An open-label, single-arm, multicentre study was conducted in patients intolerant or resistant toimatinib. A total of 174 patients received dasatinib 70 mg twice daily (161 resistant and 13 intolerantto imatinib). The median time from diagnosis to start of treatment was 82 months. Median duration oftreatment on dasatinib was 14 months with 31% of patients treated for > 24 months to date. The rate ofmajor molecular response (assessed in 41 patients with a CCyR) was 46% at 24 months. Furtherefficacy results are reported in Table 11.

Myeloid blast phase CML

An open-label, single-arm, multicentre study was conducted in patients intolerant or resistant toimatinib. A total of 109 patients received dasatinib 70 mg twice daily (99 resistant and 10 intolerant toimatinib). The median time from diagnosis to start of treatment was 48 months. Median duration oftreatment on dasatinib was 3.5 months with 12% of patients treated for > 24 months to date. The rateof major molecular response (assessed in 19 patients with a CCyR) was 68% at 24 months. Furtherefficacy results are reported in Table 11.

Lymphoid blast phase CML and Ph+ ALL

An open-label, single-arm, multicentre 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 patientswith lymphoid blast CML received dasatinib 70 mg twice daily (42 resistant and 6 intolerant toimatinib). The median time from diagnosis to start of treatment was 28 months. Median duration oftreatment on dasatinib was 3 months with 2% treated for > 24 months to date. The rate of majormolecular response (all 22 treated patients with a CCyR) was 50% at 24 months. In addition,46 patients with Ph+ ALL received dasatinib 70 mg twice daily (44 resistant and 2 intolerant toimatinib). The median time from diagnosis to start of treatment was 18 months. Median duration oftreatment on dasatinib was 3 months with 7% of patients treated for > 24 months to date. The rate ofmajor molecular response (all 25 treated patients with a CCyR) was 52% at 24 months. Furtherefficacy results are reported in Table 11. Of note, major haematologic responses (MaHR) wereachieved quickly (most within 35 days of first dasatinib administration for patients with lymphoidblast CML, and within 55 days for patients with Ph+ ALL).

Table 11: Efficacy in phase II SPRYCEL single-arm clinical studiesa

Myeloid Lymphoid

Chronic Accelerated blast blast Ph+ ALL(n= 387) (n= 174) (n= 109) (n= 48) (n= 46)

Haematologic response rateb (%)64% 33% 35% 41%

MaHR (95% CI) n/a(57-72) (24-43) (22-51) (27-57)91%

CHR (95% CI) 50% (42-58) 26% (18-35) 29% (17-44) 35% (21-50)(88-94)

NEL (95% CI) n/a 14% (10-21) 7% (3-14) 6% (1-17) 7% (1-18)

Duration of MaHR (%; Kaplan-Meier estimates)1 year n/a 79% (71-87) 71% (55-87) 29% (3-56) 32% (8-56)2 year n/a 60% (50-70) 41% (21-60) 10% (0-28) 24% (2-47)

Cytogenetic responsec (%)62%

MCyR (95% CI) 40% (33-48) 34% (25-44) 52% (37-67) 57% (41-71)(57-67)

CCyR (95% CI) 54% (48-59) 33% (26-41) 27% (19-36) 46% (31-61) 54% (39-69)

Survival (%; Kaplan-Meier estimates)

Progression-Free1 year 91% (88-94) 64% (57-72) 35% (25-45) 14% (3-25) 21% (9-34)2 year 80% (75-84) 46% (38-54) 20% (11-29) 5% (0-13) 12% (2-23)

Overall1 year 97% (95-99) 83% (77-89) 48% (38-59) 30% (14-47) 35% (20-51)2 year 94% (91-97) 72% (64-79) 38% (27-50) 26% (10-42) 31% (16-47)

Data described in this table are from studies using a starting dose of 70 mg twice daily. See section 4.2 for the recommendedstarting dose.a Numbers in bold font are the results of primary endpoints.

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

CHR (chronic CML): WBC ≤ institutional ULN, platelets < 450,000/mm3, no blasts or promyelocytes in peripheralblood, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and noextramedullary involvement.

CHR (advanced CML/Ph+ ALL): WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blastsor promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheralblood, basophils in peripheral blood < 20%, and no extramedullary involvement.

NEL: same criteria as for CHR but ANC ≥ 500/mm3 and < 1,000/mm3, or platelets ≥ 20,000/mm3 and ≤ 100,000/mm3.c Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (> 0%-35%). MCyR (0%-35%) combines bothcomplete and partial responses.

n/a = not applicable; CI = confidence interval; ULN = upper limit of normal range.

The outcome of patients with bone marrow transplantation after dasatinib treatment has not been fullyevaluated.

Phase III clinical studies 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 dasatinib administeredonce daily compared with dasatinib administered twice daily. Results described below are based on aminimum of 2 years and 7 years follow-up after the start of dasatinib therapy.

Study 1

In the study in chronic phase CML, the primary endpoint was MCyR 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, PFS, and overall survival. A total of670 patients, of whom 497 were imatinib-resistant, were randomised to the dasatinib 100 mg oncedaily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. The median duration oftreatment for all patients still on therapy with a minimum of 5 years of follow-up (n=205) was59 months (range 28-66 months). Median duration of treatment for all patients at 7 years of follow-upwas 29.8 months (range < 1-92.9 months).

Efficacy was achieved across all dasatinib treatment groups with the once daily scheduledemonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primaryefficacy endpoint (difference in MCyR 1.9%; 95% confidence interval [-6.8% - 10.6%]); however, the100 mg once daily regimen demonstrated improved safety and tolerability. Efficacy results arepresented in Tables 12 and 13.

Table 12: Efficacy of SPRYCEL in phase III dose-optimization study: imatinib resistant orintolerant chronic phase CML (2-year results)a

All patients n=167

Imatinib-resistant patients n=124

Haematologic response rateb (%) (95% CI)

CHR 92% (86-95)

Cytogenetic responsec (%) (95% CI)

MCyR

All patients 63% (56-71)

Imatinib-resistant patients 59% (50-68)

CCyR

All patients 50% (42-58)

Imatinib-resistant patients 44% (35-53)

Major molecular response in patients achieving CCyRd (%) (95% CI)

All patients 69% (58-79)

Imatinib-resistant patients 72% (58-83)a Results reported in recommended starting dose of 100 mg once daily.b Haematologic response criteria (all responses confirmed after 4 weeks): Complete haematologic response (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 <20%, and no extramedullaryinvolvement.c Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (>0%-35%). MCyR (0%-35%) combines bothcomplete and partial responses.d Major molecular response criteria: Defined as BCR-ABL/control transcripts ≤0.1% by RQ-PCR in peripheral bloodsamples

Table 13: Long term efficacy of SPRYCEL in phase 3 dose optimisation study: imatinib resistantor intolerant chronic phase CML patientsa

Minimum follow-up period1 year 2 years 5 years 7 years

Major molecular response

All patients NA 37% (57/154) 44% (71/160) 46% (73/160)

Imatinib-resistant patients NA 35% (41/117) 42% (50/120) 43% (51/120)

Imatinib-intolerant patients NA 43% (16/37) 53% (21/40) 55% (22/40)

Progression-free survivalb

All patients 90% (86, 95) 80% (73, 87) 51% (41, 60) 42% (33, 51)

Imatinib-resistant patients 88% (82, 94) 77% (68, 85) 49% (39, 59) 39% (29, 49)

Imatinib-intolerant patients 97% (92, 100) 87% (76, 99) 56% (37, 76) 51% (32, 67)

Overall survival

All patients 96% (93, 99) 91% (86, 96) 78% (72, 85) 65% (56, 72)

Imatinib-resistant patients 94% (90, 98) 89% (84, 95) 77% (69, 85) 63% (53, 71)

Imatinib-intolerant patients 100% (100, 100) 95% (88, 100) 82% (70, 94) 70% (52, 82)a Results reported in recommended starting dose of 100 mg once daily.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 includingsubsequent therapy.

Based on the Kaplan-Meier estimates, the proportion of patients treated with dasatinib 100 mg oncedaily who maintained MCyR for 18 months was 93% (95% CI: [88%-98%]).

Efficacy was also assessed in patients who were intolerant to imatinib. In this population of patientswho received 100 mg once daily, MCyR was achieved in 77% and CCyR in 67%.

Study 2

In the study in advanced phase CML and Ph+ ALL, the primary endpoint was MaHR. A total of611 patients were randomised to either the dasatinib 140 mg once daily or 70 mg twice daily group.

Median duration of treatment was approximately 6 months (range 0.03-31 months).

The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice dailyschedule on the primary efficacy endpoint (difference in MaHR 0.8%; 95% confidence interval[-7.1% - 8.7%]); however, the 140 mg once daily regimen demonstrated improved safety andtolerability.

Response rates are presented in Table 14.

Table 14: Efficacy of SPRYCEL in phase III dose-optimisation study: advanced phase

CML and Ph+ ALL (2 year results)a

Accelerated Myeloid blast Lymphoid blast Ph+ALL(n= 158) (n= 75) (n= 33) (n= 40)

MaHRb66% 28% 42% 38%(95%(59-74) (18-40) (26-61) (23-54)

CI)

CHRb 47% 17% 21% 33%(95% CI) (40-56) (10-28) (9-39) (19-49)

NELb 19% 11% 21% 5%(95% CI) (13-26) (5-20) (9-39) (1-17)

MCyRc 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 Results reported in recommended starting dose of 140 mg once daily (see section 4.2).b Haematologic response criteria (all responses confirmed after 4 weeks): Major haematologic response (MaHR) = completehaematologic response (CHR) + no evidence of leukaemia (NEL).

CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or promyelocytes inperipheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils inperipheral blood < 20%, and no extramedullary involvement.

NEL: same criteria as for CHR but ANC ≥ 500/mm3 and < 1,000/mm3, or platelets ≥ 20,000/mm3 and≤ 100,000/mm3.c MCyR combines both complete (0% Ph+ metaphases) and partial (> 0%-35%) responses.

CI = confidence interval; ULN = upper limit of normal range.

In patients with accelerated phase CML treated with the 140 mg once daily regimen, the medianduration of MaHR and the median overall survival was not reached and the median PFS was25 months.

In patients with myeloid blast phase CML treated with the 140 mg once daily regimen, the medianduration of MaHR was 8 months, the median PFS was 4 months, and the median overall survival was8 months. In patients with lymphoid blast phase CML treated with the 140 mg once daily regimen, themedian duration of MaHR was 5 months, the median PFS was 5 months, and the median overallsurvival was 11 months.

In patients with Ph+ ALL treated with the 140 mg once daily regimen, the median duration of MaHRwas 5 months the median PFS was 4 months, and the median overall survival was 7 months.

Paediatric patients with CML

Among 130 patients with chronic phase CML (CML-CP) treated in two paediatric studies, a Phase I,open-label, nonrandomized dose-ranging trial and a Phase II, open-label, nonrandomized trial,84 patients (exclusively from the Phase II trial) were newly diagnosed with CML-CP and 46 patients(17 from the Phase I trial and 29 from the Phase II trial) were resistant or intolerant to previoustreatment with imatinib. Ninety-seven of the 130 paediatric patients with CML-CP were treated with

SPRYCEL tablets 60 mg/m2 once daily (maximum dose of 100 mg once daily for patients with high

BSA). Patients were treated until disease progression or unacceptable toxicity.

Key efficacy endpoints were: complete cytogenetic response (CCyR), major cytogenetic response(MCyR) and major molecular response (MMR). Results are shown in Table 15.

Table 15: Efficacy of SPRYCEL in paediatric patients with CML-CP

Cumulative response over time by minimum follow-up period3 months 6 months 12 months 24 months

CCyR(95% CI)

Newly diagnosed 43.1% 66.7% 96.1% 96.1%(N = 51)a (29.3, 57.8) (52.1, 79.2) (86.5, 99.5) (86.5, 99.5)

Prior imatinib 45.7% 71.7% 78.3% 82.6%(N = 46)b (30.9, 61.0) (56.5, 84.0) (63.6, 89.1) (68.6, 92.2)

MCyR(95% CI)

Newly diagnosed 60.8% 90.2% 98.0% 98.0%(N = 51)a (46.1, 74.2) (78.6, 96.7) (89.6, 100) (89.6, 100)

Prior imatinib 60.9% 82.6% 89.1% 89.1%(N = 46)b (45.4, 74.9) (68.6, 92.2) (76.4, 96.4) (76.4, 96.4)

MMR(95% CI)

Newly diagnosed 7.8% 31.4% 56.9% 74.5%(N = 51)a (2.2, 18.9) (19.1, 45.9) (42.2, 70.7) (60.4, 85.7)

Prior imatinib 15.2% 26.1% 39.1% 52.2%(N = 46)b (6.3, 28.9) (14.3, 41.1) (25.1, 54.6) (36.9, 67.1)a Patients from Phase II paediatric study of newly diagnosed CML-CP receiving oral tablet formulationb Patients from Phase I and Phase II paediatric studies of imatinib-resistant or intolerant CML-CP receiving oral tabletformulation

In the Phase I paediatric study, after a minimum of 7 years of follow-up among the 17 patients withimatinib-resistant or intolerant CML-CP, the median duration of PFS was 53.6 months and the rate of

OS was 82.4%.

In the Phase II paediatric study, in patients receiving the tablet formulation, estimated 24-month PFSrate among the 51 patients with newly diagnosed CML-CP was 94.0% (82.6, 98.0), and 81.7% (61.4,92.0) among the 29 patients with imatinib-resistant/intolerant CML-CP. After 24 months of follow-up,

OS in newly diagnosed patients was 100%, and 96.6% in imatinib-resistant or intolerant patients.

In the Phase II paediatric study, 1 newly diagnosed patient and 2 imatinib-resistant or intolerantpatients progressed to blast phase CML.

There were 33 newly diagnosed paediatric patients with CML-CP who received SPRYCEL powderfor oral suspension at a dose of 72 mg/m2. This dose represents 30% lower exposure compared to therecommended dose (see section 5.2. of Summary of Product Characteristics for SPRYCEL powder fororal suspension). In these patients, CCyR and MMR were CCyR: 87.9% [95% CI: (71.8-96.6)] and

MMR: 45.5% [95% CI: (28.1-63.6)] at 12 months.

Among dasatinib-treated CML-CP paediatric patients previously exposed to imatinib, the mutationsdetected at the end of treatment were: T315A, E255K and F317L. However, E255K and F317L werealso detected prior to treatment. There were no mutations detected in newly diagnosed CML-CPpatients at the end of treatment.

Paediatric patients with ALL

The efficacy of SPRYCEL in combination with chemotherapy was evaluated in a pivotal study inpaediatric patients over one year of age with newly diagnosed Ph+ ALL.

In this multicenter, historically-controlled Phase II study of dasatinib added to standard chemotherapy,106 paediatric patients with newly diagnosed Ph+ ALL, of whom 104 patients had confirmed

Ph+ ALL, received dasatinib at a daily dose of 60 mg/m2 on a continuous dosing regimen for up to24 months, in combination with chemotherapy. Eighty-two patients received dasatinib tabletsexclusively and 24 patients received dasatinib powder for oral suspension at least once, 8 of whomreceived dasatinib powder for oral suspension exclusively. The backbone chemotherapy regimen wasthe same as used in the AIEOP-BFM ALL 2000 trial (chemotherapeutic standard multi-agentchemotherapy protocol). The primary efficacy endpoint was 3-year event-free survival (EFS), whichwas 65.5% (55.5, 73.7).

The minimal residual disease (MRD) negativity rate assessed by Ig/TCR rearrangement was 71.7% bythe end of consolidation in all treated patients. When this rate was based on the 85 patients withevaluable Ig/TCR assessments, the estimate was 89.4%. The MRD negativity rates at the end ofinduction and consolidation as measured by flow cytometry were 66.0% and 84.0%, respectively.

The pharmacokinetics of dasatinib were evaluated in 229 adult healthy subjects and in 84 patients.

Dasatinib is rapidly absorbed in patients following oral administration, with peak concentrationsbetween 0.5-3 hours. Following oral administration, the increase in the mean exposure (AUCτ) isapproximately proportional to the dose increment across doses ranging from 25 mg to 120 mg twicedaily. The overall mean terminal half-life of dasatinib is approximately 5-6 hours in patients.

Data from healthy subjects administered a single 100 mg dose of dasatinib 30 minutes following ahigh-fat meal indicated a 14% increase in the mean AUC of dasatinib. A low-fat meal 30 minutes priorto dasatinib resulted in a 21% increase in the mean AUC of dasatinib. The observed food effects donot represent clinically relevant changes in exposure. Dasatinib exposure variability is higher underfasted conditions (47% CV) compared to light-fat meal (39% CV) and high-fat meal (32% CV)conditions.

Based on the patient population PK analysis, variability in dasatinib exposure was estimated to bemainly due to inter-occasion variability in bioavailability (44% CV) and, to a lesser extent, due tointer-individual variability in bioavailability and inter-individual variability in clearance (30% and32% CV, respectively). The random inter-occasion variability in exposure is not expected to affect thecumulative exposure and efficacy or safety.

In patients, dasatinib has a large apparent volume of distribution (2,505 L), coefficient of variation(CV% 93%), suggesting that the medicinal product is extensively distributed in the extravascularspace. At clinically relevant concentrations of dasatinib, binding to plasma proteins was approximately96% on the basis of in vitro experiments.

Dasatinib is extensively metabolised in humans with multiple enzymes involved in the generation ofthe metabolites. In healthy subjects administered 100 mg of [14C]-labelled dasatinib, unchangeddasatinib represented 29% of circulating radioactivity in plasma. Plasma concentration and measuredin vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observedpharmacology of the product. CYP3A4 is a major enzyme responsible for the metabolism of dasatinib.

The mean terminal half-life of dasatinib is 3 hours to 5 hours. The mean apparent oral clearance is363.8 L/hr (CV% 81.3%).

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% and85% of the radioactivity recovered in the urine and faeces, respectively. Unchanged dasatinibaccounted for 0.1% and 19% of the dose in urine and faeces, respectively, with the remainder of thedose as metabolites.

The effect of hepatic impairment on the single-dose pharmacokinetics of dasatinib was assessed in 8moderately hepatic-impaired subjects who received a 50 mg dose and 5 severely hepatic-impairedsubjects who received a 20 mg dose compared to matched healthy subjects who received a 70 mg doseof dasatinib. The mean Cmax and AUC of dasatinib adjusted for the 70 mg dose were decreased by 47%and 8%, respectively, in subjects with moderate hepatic impairment compared to subjects with normalhepatic function. In severely hepatic-impaired subjects, the mean Cmax and AUC adjusted for the70 mg dose were decreased by 43% and 28%, respectively, compared to subjects with normal hepaticfunction (see sections 4.2 and 4.4).

Dasatinib and its metabolites are minimally excreted via the kidney.

The pharmacokinetics of dasatinib have been evaluated in 104 paediatric patients with leukaemia orsolid tumours (72 who received the tablet formulation and 32 who received the powder for oralsuspension).

In a paediatric pharmacokinetics study, dose-normalized dasatinib exposure (Cavg, Cmin and Cmax)appears similar between 21 patients with CP-CML and 16 patients with Ph+ ALL.

Pharmacokinetics of the tablet formulation of dasatinib were evaluated for 72 paediatric patients withrelapsed or refractory leukaemia or solid tumours at oral doses ranging from 60 to 120 mg/m2 oncedaily and 50 to 110 mg/m2 twice daily. Data was pooled across two studies and showed that dasatinibwas rapidly absorbed. Mean Tmax was observed between 0.5 and 6 hours and mean half-life rangedfrom 2 to 5 hours across all dose levels and age groups. Dasatinib PK showed dose proportionalitywith a dose-related increase in exposure observed in paediatric patients. There was no significantdifference of dasatinib PK between children and adolescents. The geometric means of dose-normalized dasatinib Cmax, AUC (0-T), and AUC (INF) appeared to be similar between children andadolescents at different dose levels. A PPK model-based simulation predicted that the body weighttiered dosing recommendation described for the tablet, in section 4.2, is expected to provide similarexposure to a tablet dose of 60 mg/m2. These data should be considered if patients are to switch fromtablets to powder for oral suspension or vice versa.

The non-clinical safety profile of dasatinib was assessed in a battery of in vitro and in vivo studies inmice, rats, monkeys, and rabbits.

The primary toxicities occurred in the gastrointestinal, haematopoietic, and lymphoid systems.

Gastrointestinal toxicity was dose-limiting in rats and monkeys, as the intestine was a consistent targetorgan. In rats, minimal to mild decreases in erythrocyte parameters were accompanied by bonemarrow changes; similar changes occurred in monkeys at a lower incidence. Lymphoid toxicity in ratsconsisted of lymphoid depletion of the lymph nodes, spleen, and thymus, and decreased lymphoidorgan weights. Changes in the gastrointestinal, haematopoietic and lymphoid systems were reversiblefollowing cessation of treatment.

Renal changes in monkeys treated for up to 9 months were limited to an increase in backgroundkidney mineralisation. Cutaneous haemorrhage was observed in an acute, single-dose oral study inmonkeys but was not observed in repeat-dose studies in either monkeys or rats. In rats, dasatinibinhibited platelet aggregation in vitro and prolonged cuticle bleeding time in vivo, but did not invokespontaneous haemorrhage.

Dasatinib activity in vitro in hERG and Purkinje fiber assays suggested a potential for prolongation ofcardiac ventricular repolarisation (QT interval). However, in an in vivo single-dose study in conscioustelemetered monkeys, there were no changes in QT interval or ECG wave form.

Dasatinib was not mutagenic in in vitro bacterial cell assays (Ames test) and was not genotoxic in anin vivo rat micronucleus study. Dasatinib was clastogenic in vitro to dividing Chinese Hamster Ovary(CHO) cells.

Dasatinib did not affect male or female fertility in a conventional rat fertility and early embryonicdevelopment study, but induced embryolethality at dose levels approximating human clinicalexposures. In embryofoetal development studies, dasatinib likewise induced embryolethality withassociated decreases in litter size in rats, as well as foetal skeletal alterations in both rats and rabbits.

These effects occurred at doses that did not produce maternal toxicity, indicating that dasatinib is aselective reproductive toxicant from implantation through the completion of organogenesis.

In mice, dasatinib induced immunosuppression, which was dose-related and effectively managed bydose reduction and/or changes in dosing schedule. Dasatinib had phototoxic potential in an in vitroneutral red uptake phototoxicity assay in mouse fibroblasts. Dasatinib was considered to benon-phototoxic in vivo after a single oral administration to female hairless mice at exposures up to3-fold the human exposure following administration of the recommended therapeutic dose (based on

AUC).

In a two-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and3 mg/kg/day. The highest dose resulted in a plasma exposure (AUC) level generally equivalent to thehuman exposure at the recommended range of starting doses from 100 mg to 140 mg daily. Astatistically significant increase in the combined incidence of squamous cell carcinomas andpapillomas in the uterus and cervix of high-dose females and of prostate adenoma in low-dose maleswas noted. The relevance of the findings from the rat carcinogenicity study for humans is not known.

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Hydroxypropylcellulose

Magnesium stearate

Hypromellose

Titanium dioxide (E171)

Macrogol 400

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

SPRYCEL 20 mg, SPRYCEL 50 mg and SPRYCEL 70 mg film-coated tablets

Alu/Alu blisters (calendar blisters or perforated unit dose blisters).

HDPE bottle with a polypropylene child-resistant closure and a silica gel desiccant.

Carton containing 56 film-coated tablets in 4 calendar blisters of 14 film-coated tablets each.

Carton containing 60 x 1 film-coated tablets in perforated unit dose blisters.

Carton containing one bottle with 60 film-coated tablets.

SPRYCEL 100 mg film-coated tablets

Alu/Alu blisters (perforated unit dose blisters).

HDPE bottle with a polypropylene child-resistant closure and a silica gel desiccant.

Carton containing 30 x 1 film-coated tablets in perforated unit dose blisters.

Carton containing one bottle with 30 film-coated tablets.

SPRYCEL 80 mg and SPRYCEL 140 mg film-coated tablets

Alu/Alu blisters (perforated unit dose blisters).

HDPE bottle with a polypropylene child-resistant closure.

Carton containing 30 x 1 film-coated tablets in perforated unit dose blisters.

Carton containing one bottle with 30 film-coated tablets.

Not all pack sizes may be marketed.

The film-coated tablets consist of a core tablet, surrounded by a film-coating to prevent exposure ofhealthcare professionals to the active substance. The use of latex or nitrile gloves for appropriatedisposal when handling tablets that are inadvertently crushed or broken is recommended, to minimisethe risk of dermal exposure.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

SPRYCEL 20 mg film-coated tablets

EU/1/06/363/004

EU/1/06/363/007

EU/1/06/363/001

SPRYCEL 50 mg film-coated tablets

EU/1/06/363/005

EU/1/06/363/008

EU/1/06/363/002

SPRYCEL 70 mg film-coated tablets

EU/1/06/363/006

EU/1/06/363/009

EU/1/06/363/003

SPRYCEL 80 mg film-coated tablets

EU/1/06/363/013

EU/1/06/363/012

SPRYCEL 100 mg film-coated tablets

EU/1/06/363/011

EU/1/06/363/010

SPRYCEL 140 mg film-coated tablets

EU/1/06/363/015

EU/1/06/363/014

Date of first authorisation: 20 November 2006

Date of latest renewal: 15 July 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.