Sprycel

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
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 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
SPRYCEL 20 mg film-coated tablets 
Each film-coated tablet contains 20 mg dasatinib (as monohydrate). 
 
Excipient with known effect 
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). 
 
Excipient with known effect 
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). 
 
Excipient with known effect 
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). 
 
Excipient with known effect 
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). 
 
Excipient with known effect 
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). 
 
Excipient with known effect 
Each film-coated tablet contains 189 mg of lactose monohydrate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 



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SPRYCEL 20 mg film-coated tablets 
White to off-white, biconvex, round film-coated tablet with "BMS" debossed on one side and "527" on 
the 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" on 
the 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" on 
the 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. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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 including 

imatinib. 
 Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance 

to 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 or 

intolerant to prior therapy including imatinib. 
 newly diagnosed Ph+ ALL in combination with chemotherapy. 
 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with 
leukaemia. 
 
Posology 
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 is 
administered orally once daily in the form of either SPRYCEL film-coated tablets or SPRYCEL 



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powder for oral suspension (see Summary of Product Characteristics for SPRYCEL powder for oral 
suspension). The dose should be recalculated every 3 months based on changes in body weight, or 
more often if necessary. The tablet is not recommended for patients weighing less than 10 kg; the 
powder for oral suspension should be used for these patients. Dose increase or reduction is 
recommended 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 oral 
suspension to SPRYCEL tablets or patients who are not able to swallow tablets and who desire to 
switch from tablets to oral suspension, may do so, provided that the correct dosing recommendations 
for 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 mg 
20 to less than 30 kg 60 mg 
30 to less than 45 kg 70 mg 

at least 45 kg 100 mg 
a The tablet is not recommended for patients weighing less than 10 kg; the powder for oral suspension should be used for 

these patients. 
 
Treatment duration 
In clinical studies, treatment with SPRYCEL in adults with Ph+ CML-CP, accelerated, myeloid or 
lymphoid blast phase (advanced phase) CML, or Ph+ ALL and paediatric patients with Ph+ CML-CP 
was continued until disease progression or until no longer tolerated by the patient. The effect of 
stopping treatment on long-term disease outcome after the achievement of a cytogenetic or molecular 
response [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 administered 
continuously, added to successive blocks of backbone chemotherapy, for a maximum duration of two 
years. In patients that receive a subsequent stem cell transplantation, SPRYCEL can be administered 
for an additional year post-transplantation. 
 
To achieve the recommended dose, SPRYCEL is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mg 
and 140 mg film-coated tablets and powder for oral suspension (10 mg/mL suspension upon 
constitution). Dose increase or reduction is recommended based on patient response and tolerability. 
 
Dose escalation 
In clinical studies in adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic 
phase CML) or 180 mg once daily (advanced phase CML or Ph+ ALL) was allowed in patients who 
did 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 the 
recommended time points, per current treatment guidelines, and who tolerate the treatment.  
 



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Table 2: Dose escalation for paediatric patients with Ph+ CML-CP 
 Dose (maximum dose per day) 
 Starting dose Escalation 

Tablets 40 mg 50 mg 
 60 mg 70 mg 
 70 mg 90 mg 
 100 mg 120 mg 

 
Dose escalation is not recommended for paediatric patients with Ph+ ALL, as SPRYCEL is 
administered in combination with chemotherapy in these patients. 
 
Dose adjustment for adverse reactions 
Myelosuppression 
In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or 
discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate. 
Haematopoietic growth factor has been used in patients with resistant myelosuppression. 
Guidelines for dose modifications 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 with 
chemotherapy are in a separate paragraph following the tables. 
 
Table 3: Dose adjustments for neutropaenia and thrombocytopaenia in adults 

Adults with chronic phase 
CML 
(starting dose 100 mg once 
daily) 

ANC < 0.5 x 109/L 
and/or 
platelets < 50 x 109/L 

1 Stop treatment until ANC ≥ 1.0 x 109/L and 
platelets ≥ 50 x 109/L. 

 
2 Resume treatment at the original starting 

dose. 
 
3 If platelets < 25 x 109/L and/or recurrence of 

ANC < 0.5 x 109/L for > 7 days, repeat step 
1 and resume treatment at a reduced dose of 
80 mg once daily for second episode. For 
third episode, further reduce dose to 50 mg 
once daily (for newly diagnosed patients) or 
discontinue (for patients resistant or 
intolerant to prior therapy including 
imatinib). 

 

Adults with accelerated 
and blast phase CML and 
Ph+ ALL 
(starting dose 140 mg once 
daily) 

ANC < 0.5 x 109/L 
and/or 
platelets < 10 x 109/L 

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

 
2 If cytopaenia is unrelated to leukaemia, stop 

treatment until ANC ≥ 1.0 x 109/L and 
platelets ≥ 20 x 109/L and resume at the 
original starting dose. 

 
3 If recurrence of cytopaenia, repeat step 1 and 

resume treatment at a reduced dose of 
100 mg once daily (second episode) or 
80 mg once daily (third episode). 

 
4 If cytopaenia is related to leukaemia, 

consider dose escalation to 180 mg once 
daily. 

 
ANC: absolute neutrophil count 
 



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Table 4: Dose adjustments for neutropaenia and thrombocytopaenia in paediatric patients 
with Ph+ CML-CP 

1. If cytopaenia persists for 
more than 3 weeks, check if 
cytopaenia is related to 
leukaemia (marrow aspirate 
or biopsy). 
 
2. If cytopaenia is unrelated 
to leukaemia, stop treatment 
until ANC ≥1.0 × 109/L and 
platelets ≥75 × 109/L and 
resume at the original 
starting dose or at a reduced 
dose. 
 
3. If cytopaenia recurs, 
repeat marrow 
aspirate/biopsy and resume 
treatment at a reduced dose. 

 Dose (maximum dose per day) 
 Original 

starting dose 
One-level dose 

reduction 
Two-level dose 

reduction 
Tablets 40 mg 20 mg * 

 60 mg 40 mg 20 mg 
 70 mg 60 mg 50 mg 
 100 mg 80 mg 70 mg 

ANC: absolute neutrophil count 
*lower tablet dose not available 
 
For paediatric patients with Ph+ CML-CP, if Grade ≥3 neutropaenia or thrombocytopaenia recurs 
during complete haematologic response (CHR), SPRYCEL should be interrupted, and may be 
subsequently resumed at a reduced dose. Temporary dose reductions for intermediate degrees of 
cytopaenia 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 of 
treatment by more than 14 days, SPRYCEL should be interrupted and resumed at the same dose level 
once the next block of treatment is started. If neutropaenia and/or thrombocytopaenia persist and the 
next block of treatment is delayed another 7 days, a bone marrow assessment should be performed to 
assess cellularity and percentage of blasts. If marrow cellularity is <10%, treatment with SPRYCEL 
should be interrupted until ANC >500/μL (0.5 x 109/L), at which time treatment may be resumed at 
full 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 should 
be interrupted until the adverse reaction has resolved or returned to baseline. The same dose should be 
resumed if this is the first occurrence and the dose should be reduced if this is a recurrent adverse 
reaction. 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 be 
resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction. For 
patients with chronic phase CML who received 100 mg once daily, dose reduction to 80 mg once daily 
with further reduction from 80 mg once daily to 50 mg once daily, if needed, is recommended. For 
patients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to 
100 mg once daily with further reduction from 100 mg once daily to 50 mg once daily, if needed, is 
recommended. In CML-CP paediatric patients with non-haematologic adverse reactions, the dose 
reduction recommendations for haematologic adverse reactions that are described above should be 
followed. In Ph+ ALL paediatric patients with non-haematologic adverse reactions, if needed, one 
level of dose reduction should be followed, according to the dose reduction recommendations for 
haematologic 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 one 
week, a course of diuretics or corticosteroids or both concurrently should be considered (see 



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sections 4.4 and 4.8). Following resolution of the first episode, reintroduction of dasatinib at the same 
dose level should be considered. Following resolution of a subsequent episode, dasatinib at one dose 
level 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 the 
adverse reaction. 
 
Dose reduction for concomitant use of strong CYP3A4 inhibitors 
The concomitant use of strong CYP3A4 inhibitors and grapefruit juice with SPRYCEL should be 
avoided (see section 4.5). If possible, an alternative concomitant medication with no or minimal 
enzyme 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 SPRYCEL 
until the CYP3A4 inhibitor is discontinued, or switching to a lower dose with the powder for oral 
suspension formulation (see Summary of Product Characteristics for SPRYCEL powder for oral 
suspension). Allow a washout period of approximately 1 week after the inhibitor is stopped before 
reinitiating SPRYCEL.  
 
These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the range 
observed without CYP3A4 inhibitors; however, clinical data are not available with these dose 
adjustments in patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dose 
reduction, either discontinue the strong CYP3A4 inhibitor or interrupt SPRYCEL until the inhibitor is 
discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the 
SPRYCEL dose is increased. 
 
Special populations 
Elderly 
No clinically relevant age-related pharmacokinetic differences have been observed in these patients. 
No specific dose recommendation is necessary in elderly. 
 
Hepatic impairment 
Patients with mild, moderate or severe hepatic impairment may receive the recommended starting 
dose. However, SPRYCEL should be used with caution in patients with hepatic impairment (see 
section 5.2). 
 
Renal impairment 
No clinical studies were conducted with SPRYCEL in patients with decreased renal function (the 
study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine 
concentration > 3 times the upper limit of the normal range, and studies in patients with chronic phase 
CML with resistance or intolerance to prior imatinib therapy excluded patients with serum creatinine 
concentration > 1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib 
and its metabolites is < 4%, a decrease in total body clearance is not expected in patients with renal 
insufficiency. 
 
Method of administration 
SPRYCEL must be administered orally. 
The film-coated tablets must not be crushed, cut or chewed in order to maintain dosing consistency 
and minimise the risk of dermal exposure; they must be swallowed whole. Film-coated tablets should 
not be dispersed as the exposure in patients receiving a dispersed tablet is lower than in those 
swallowing 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 morning 
or in the evening (see section 5.2). SPRYCEL should not be taken with grapefruit or grapefruit juice 
(see section 4.5). 



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4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Clinically relevant interactions 
Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is a 
potential for interaction with other concomitantly administered medicinal products that are 
metabolised 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 a 
potent 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 Hypericum 
perforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentially 
increasing the risk of therapeutic failure. Therefore, in patients receiving dasatinib, coadministration of 
alternative medicinal products with less potential for CYP3A4 induction should be selected (see 
section 4.5). 
 
Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 
substrate. Therefore, caution is warranted when dasatinib is coadministered with CYP3A4 substrates 
of narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil 
or ergot alkaloids (ergotamine, dihydroergotamine) (see section 4.5). 
 
The concomitant use of dasatinib and a histamine-2 (H2) antagonist (e.g. famotidine), proton pump 
inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure 
to dasatinib. Thus, H2 antagonists and proton pump inhibitors are not recommended and aluminium 
hydroxide/magnesium hydroxide products should be administered up to 2 hours prior to, or 2 hours 
following the administration of dasatinib (see section 4.5). 
 
Special populations 
Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or 
severe hepatic impairment may receive the recommended starting dose (see section 5.2). Due to the 
limitations of this clinical study, caution is recommended when administering dasatinib to patients 
with hepatic impairment. 
 
Important adverse reactions 
Myelosuppression 
Treatment with dasatinib is associated with anaemia, neutropaenia and thrombocytopaenia. Their 
occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in 
chronic phase CML. In adult patients with advanced phase CML or Ph+ ALL treated with dasatinib as 
monotherapy, complete blood counts (CBCs) should be performed weekly for the first 2 months, and 
then 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 months 
thereafter or as clinically indicated. In paediatric patients with Ph+ ALL treated with dasatinib in 
combination with chemotherapy, CBCs should be performed prior to the start of each block of 
chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, CBCs 
should be performed every 2 days until recovery (see sections 4.2 and 4.8). Myelosuppression is 
generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction. 
 



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Bleeding 
In patients with chronic phase CML (n=548), 5 patients (1%) receiving dasatinib had 
grade 3 or 4 haemorrhage. In clinical studies in patients with advanced phase CML receiving the 
recommended dose of SPRYCEL (n=304), severe central nervous system (CNS) haemorrhage 
occurred 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% of 
patients 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 bleeding 
related adverse reactions in these patients were typically associated with 
grade 3 or 4 thrombocytopaenia (see section 4.8). Additionally, in vitro and in vivo platelet assays 
suggest that SPRYCEL treatment reversibly affects platelet activation. 
 
Caution should be exercised if patients are required to take medicinal products that inhibit platelet 
function or anticoagulants. 
 
Fluid retention 
Dasatinib is associated with fluid retention. In the Phase III clinical study in patients with newly 
diagnosed chronic phase CML, grade 3 or 4 fluid retention was reported in 13 patients (5%) in the 
dasatinib-treatment group and in 2 patients (1%) in the imatinib-treatment group after a minimum of 
60 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 at 
the recommended dose (n=304), grade 3 or 4 fluid retention was reported in 8% of patients, including 
grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients, respectively. In these 
patients grade 3 or 4 pulmonary oedema and pulmonary hypertension were each reported in 1% of 
patients. 
 
Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should 
be evaluated by chest X-ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygen 
therapy. Fluid retention adverse reactions were typically managed by supportive care measures that 
include diuretics and short courses of steroids (see sections 4.2 and 4.8). Patients aged 65 years and 
older are more likely than younger patients to experience pleural effusion, dyspnoea, cough, 
pericardial effusion and congestive heart failure, and should be monitored closely. 
 
Pulmonary arterial hypertension (PAH) 
PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been 
reported in association with dasatinib treatment (see section 4.8). In these cases, PAH was reported 
after 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 to 
initiating dasatinib therapy. An echocardiography should be performed at treatment initiation in every 
patient presenting symptoms of cardiac disease and considered in patients with risk factors for cardiac 
or pulmonary disease. Patients who develop dyspnoea and fatigue after initiation of therapy should be 
evaluated for common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung 
infiltration. In accordance with recommendations for management of non-haematologic adverse 
reactions (see section 4.2) the dose of dasatinib should be reduced or therapy interrupted during this 
evaluation. If no explanation is found, or if there is no improvement with dose reduction or 
interruption, the diagnosis of PAH should be considered. The diagnostic approach should follow 
standard practice guidelines. If PAH is confirmed, dasatinib should be permanently discontinued. 
Follow up should be performed according to standard practice guidelines. Improvements in 
haemodynamic and clinical parameters have been observed in dasatinib-treated patients with PAH 
following 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 a 
minimum of 60 months follow-up in the Phase III study in newly diagnosed chronic phase CML, 1 



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patient (< 1%) in each group had QTc prolongation reported as an adverse reaction. The median 
changes in QTcF from baseline were 3.0 msec in dasatinib-treated patients compared to 8.2 msec in 
imatinib-treated patients. One patient (< 1%) in each group experienced a QTcF > 500 msec. In 
865 patients with leukaemia treated with dasatinib in Phase II clinical studies, the mean changes from 
baseline in QTc interval using Fridericia's method (QTcF) were 4 - 6 msec; the upper 95% confidence 
intervals 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 in 
clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one of these 
patients (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 which 
lead to QT prolongation, and cumulative high dose anthracycline therapy. Hypokalaemia or 
hypomagnesaemia 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 in 
chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of 
congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QT 
prolongation and myocardial infarction (including fatal) were reported in patients taking dasatinib. 
Cardiac adverse reactions were more frequent in patients with risk factors or a history of cardiac 
disease. Patients with risk factors (e.g. hypertension, hyperlipidaemia, diabetes) or a history of cardiac 
disease (e.g. prior percutaneous coronary intervention, documented coronary artery disease) should be 
monitored carefully for clinical signs or symptoms consistent with cardiac dysfunction such as chest 
pain, shortness of breath, and diaphoresis. 
 
If these clinical signs or symptoms develop, physicians are advised to interrupt dasatinib 
administration and consider the need for alternative CML-specific treatment. After resolution, a 
functional assessment should be performed prior to resuming treatment with dasatinib. Dasatinib may 
be resumed at the original dose for mild/moderate adverse reactions (≤ grade 2) and resumed at a dose 
level reduction for severe adverse reactions (≥ grade 3) (see section 4.2). Patients continuing treatment 
should be monitored periodically. 
 
Patients with uncontrolled or significant cardiovascular disease were not included in the clinical 
studies. 
 
Thrombotic microangiopathy (TMA) 
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 findings 
associated with TMA occur in a patient receiving SPRYCEL, treatment with SPRYCEL should be 
discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-
ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated 
in conjunction with low ADAMTS13 activity, treatment with SPRYCEL should not be resumed. 
 
Hepatitis B reactivation 
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these 
patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or 
fulminant hepatitis leading to liver transplantation or a fatal outcome.  
Patients should be tested for HBV infection before initiating treatment with SPRYCEL. Experts in 
liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in 
patients with positive hepatitis B serology (including those with active disease) and for patients who 
test 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 throughout 
therapy and for several months following termination of therapy (see section 4.8). 
 



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Effects on growth and development in paediatric patients 
In paediatric trials of SPRYCEL in imatinib-resistant/intolerant Ph+ CML-CP paediatric patients and 
treatment-naive Ph+ CML-CP paediatric patients after at least 2 years of treatment, treatment-related 
adverse events associated with bone growth and development were reported in 6 (4.6%) patients, one 
of which was severe in intensity (Growth Retardation Grade 3). These 6 cases included cases of 
epiphyses delayed fusion, osteopaenia, growth retardation, and gynecomastia (see section 5.1). These 
results are difficult to interpret in the context of chronic diseases such as CML, and require long-term 
follow-up. 
 
In paediatric trials of SPRYCEL in combination with chemotherapy in newly diagnosed Ph+ ALL 
paediatric patients after a maximum of 2 years of treatment, treatment-related adverse events 
associated with bone growth and development were reported in 1 (0.6%) patient. This case was a 
Grade 1 osteopenia. 
 
Excipients 
Lactose 
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of 
galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this 
medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Active substances that may increase dasatinib plasma concentrations 
In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and 
medicinal products or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, 
erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to 
dasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4 
inhibitor is not recommended (see section 4.2). 
 
At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on 
the basis of in vitro experiments. No studies have been performed to evaluate dasatinib interaction 
with other protein-bound medicinal products. The potential for displacement and its clinical relevance 
are unknown. 
 
Active substances that may decrease dasatinib plasma concentrations 
When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a 
potent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%. Other medicinal products that 
induce CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, phenobarbital or herbal 
preparations containing Hypericum perforatum, also known as St. John´s Wort) may also increase 
metabolism 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 potential 
should be used. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is 
allowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use of 
dexamethasone, 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 healthy 
subjects, the administration of famotidine 10 hours prior to a single dose of SPRYCEL reduced 
dasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100-mg dose 
of SPRYCEL 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC of 
dasatinib by 43% and the Cmax of dasatinib by 42%. The use of antacids should be considered in place 
of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy (see section 4.4). 
 



 12

Antacids 
Non-clinical data demonstrate that the solubility of dasatinib is pH-dependent. In healthy subjects, the 
concomitant use of aluminium hydroxide/magnesium hydroxide antacids with SPRYCEL reduced the 
AUC of a single dose of SPRYCEL by 55% and the Cmax by 58%. However, when antacids were 
administered 2 hours prior to a single dose of SPRYCEL, no relevant changes in dasatinib 
concentration or exposure were observed. Thus, antacids may be administered up to 2 hours prior to or 
2 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 CYP3A4 
substrate. In a study in healthy subjects, a single 100 mg dose of dasatinib increased AUC and Cmax 
exposure to simvastatin, a known CYP3A4 substrate, by 20 and 37% respectively. It cannot be 
excluded that the effect is larger after multiple doses of dasatinib. Therefore, CYP3A4 substrates 
known to have a narrow therapeutic index (e.g. astemizole, terfenadine, cisapride, pimozide, 
quinidine, bepridil or ergot alkaloids [ergotamine, dihydroergotamine]) should be administered with 
caution in patients receiving dasatinib (see section 4.4). 
In vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones. 
 
Paediatric population 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/contraception in males and females 
Both sexually active men and women of childbearing potential should use effective methods of 
contraception during treatment. 
 
Pregnancy 
Based on human experience, dasatinib is suspected to cause congenital malformations including neural 
tube 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 requires 
treatment with dasatinib. If SPRYCEL is used during pregnancy, the patient must be informed of the 
potential risk to the foetus. 
 
Breast-feeding 
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 in 
breast milk and a risk to the suckling child cannot be excluded. 
Breast-feeding should be stopped during treatment with SPRYCEL. 
 
Fertility 
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 of 
appropriate age about possible effects of SPRYCEL on fertility, and this counseling may include 
consideration of semen deposition. 
 
4.7 Effects on ability to drive and use machines 
 
SPRYCEL has minor influence on the ability to drive and use machines. Patients should be advised 
that they may experience adverse reactions such as dizziness or blurred vision during treatment with 
dasatinib. Therefore, caution should be recommended when driving a car or operating machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The data described below reflect the exposure to SPRYCEL as single-agent therapy at all doses tested 



 13

in 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, the 
median duration of therapy was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients 
with newly diagnosed chronic phase CML, the median duration of therapy was approximately 
60 months. The median duration of therapy in 1,618 adult patients with chronic phase CML was 
29 months (range 0 to 92.9 months). The median duration of therapy in 1,094 adult patients with 
advanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). Among 188 patients in 
paediatric studies, the median duration of therapy was 26.3 months (range 0 to 99.6 months). In the 
subset of 130 chronic phase CML SPRYCEL-treated paediatric patients, the median duration of 
therapy 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 overall 
population of 2,712 SPRYCEL-treated adult subjects, 520 (19%) experienced adverse reactions 
leading to treatment discontinuation. 
 
The overall safety profile of SPRYCEL in the paediatric Ph+ CML-CP population was similar to that 
of the adult population, regardless of formulation, with the exception of no reported pericardial 
effusion, 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 adverse 
reactions leading to treatment discontinuation. 
 
Tabulated list of adverse reactions 
The following adverse reactions, excluding laboratory abnormalities, were reported in patients treated 
with 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 are 
defined 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 

Infections and infestations 
Very common infection (including bacterial, viral, fungal, non-specified) 
Common pneumonia (including bacterial, viral, and fungal), upper respiratory tract 

infection/inflammation, herpes virus infection (including cytomegalovirus - CMV), 
enterocolitis infection, sepsis (including uncommon cases with fatal outcomes) 

Not known hepatitis B reactivation 
Blood and lymphatic system disorders 
Very Common myelosuppression (including anaemia, neutropaenia, thrombocytopaenia) 
Common febrile neutropaenia 
Uncommon lymphadenopathy, lymphopaenia 
Rare aplasia pure red cell 
Immune system disorders 
Uncommon hypersensitivity (including erythema nodosum) 
Rare anaphylactic shock 
Endocrine disorders 
Uncommon hypothyroidism 
Rare hyperthyroidism, thyroiditis 
Metabolism and nutrition disorders 
Common appetite disturbancesa, hyperuricaemia 
Uncommon tumour lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia 
Rare diabetes mellitus 



 14

Psychiatric disorders 
Common depression, insomnia 
Uncommon anxiety, confusional state, affect lability, libido decreased 
Nervous system disorders 
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, VIIth 

nerve paralysis, dementia, ataxia 
Eye disorders 
Common visual disorder (including visual disturbance, vision blurred, and visual acuity 

reduced), dry eye 
Uncommon visual impairment, conjunctivitis, photophobia, lacrimation increased 
Ear and labyrinth disorders 
Common tinnitus 
Uncommon hearing loss, vertigo 
Cardiac disorders 
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), angina 
pectoris, 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 
Vascular disorders 
Very common haemorrhage*d 
Common hypertension, flushing 
Uncommon hypotension, thrombophlebitis, thrombosis 
Rare deep vein thrombosis, embolism, livedo reticularis 
Not known thrombotic microangiopathy 
Respiratory, thoracic and mediastinal disorders 
Very common pleural effusion*, dyspnoea 
Common pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis, cough 
Uncommon pulmonary arterial hypertension, bronchospasm, asthma 
Rare pulmonary embolism, acute respiratory distress syndrome 
Not known interstitial lung disease 
Gastrointestinal disorders 
Very common diarrhoea, vomiting, nausea, abdominal pain 
Common gastrointestinal bleeding*, colitis (including neutropaenic colitis), gastritis, mucosal 

inflammation (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* 
Hepatobiliary disorders  
Uncommon hepatitis, cholecystitis, cholestasis 
Skin and subcutaneous tissue disorders 
Very common skin rashe 
Common alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, 

hyperhidrosis 
Uncommon neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin 

ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome, 
hair disorder 



 15

Rare leukocytoclastic vasculitis, skin fibrosis 
Not known Stevens-Johnson syndromef 
Musculoskeletal and connective tissue disorders 
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 
Renal and urinary disorders 
Uncommon renal impairment (including renal failure), urinary frequency, proteinuria 
Not known nephrotic syndrome 
Pregnancy, puerperium and perinatal conditions 
Rare abortion 
Reproductive system and breast disorders 
Uncommon gynecomastia, menstrual disorder 
General disorders and administration site conditions 
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 
Investigations 
Common weight decreased, weight increased 
Uncommon blood creatine phosphokinase increased, gamma-glutamyltransferase increased 
Injury, poisoning, and procedural complications 
Common contusion 

a 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 subdural 
haemorrhage. 

c Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular dysfunction, right ventricular 
dysfunction, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiomyopathy, 
congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased and ventricular failure, left ventricular 
failure, right ventricular failure, and ventricular hypokinesia. 

d Excludes gastrointestinal bleeding and CNS bleeding; these adverse reactions are reported under the gastrointestinal 
disorders system organ class and the nervous system disorders system organ class, respectively. 

e Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalised erythema, genital rash, 
heat rash, milia, miliaria, pustular psoriaisis, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash 
maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, toxic skin 
eruption, urticaria vesiculosa, and vasculitic rash. 

f In the post-marketing setting, individual cases of Stevens-Johnson syndrome have been reported. It could not be 
determined whether these mucocutaneous adverse reactions were directly related to SPRYCEL or to concomitant 
medicinal 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, oedema 

mouth, orbital oedema, periorbital oedema, swelling face. 
k Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, peripheral swelling, oedema, oedema due to 

cardiac 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" 
 
Description of selected adverse reactions 
Myelosuppression 
Treatment with SPRYCEL is associated with anaemia, neutropaenia and thrombocytopaenia. Their 
occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in 
chronic phase CML (see section 4.4).  
 



 16

Bleeding 
Bleeding drug-related adverse reactions, ranging from petechiae and epistaxis to 
grade 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 pericardial 
effusion with or without superficial oedema may be collectively described as “fluid retention”. In the 
newly diagnosed chronic phase CML study after a minimum of 60 months follow-up, dasatinib-related 
fluid retention adverse reactions included pleural effusion (28%), superficial oedema (14%), 
pulmonary hypertension (5%), generalised oedema (4%), and pericardial effusion (4%). Congestive 
heart 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 of 
46 dasatinib-treated patients had recurrent pleural effusions. Seventeen patients had 2 separate adverse 
reactions, 6 had 3 adverse reactions, 18 had 4 to 8 adverse reactions and 5 had > 8 episodes of pleural 
effusions. 
The median time to first dasatinib-related grade 1 or 2 pleural effusion was 114 weeks (range:  4 to 
299 weeks). Less than 10% of patients with pleural effusion had severe (grade 3 or 4) dasatinib-related 
pleural effusions. The median time to first occurrence of grade ≥ 3 dasatinib-related pleural effusion 
was 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 using 
diuretics or other appropriate supportive care measures (see sections 4.2 and 4.4). Among 
dasatinib-treated patients with drug-related pleural effusion (n=73), 45 (62%) had dose interruptions 
and 30 (41%) had dose reductions. Additionally, 34 (47%) received diuretics, 23 (32%) received 
corticosteroids, and 20 (27%) received both corticosteroids and diuretics. Nine (12%) patients 
underwent 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-treated 
patients 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 CML 
or Ph+ ALL. 
 
Pulmonary arterial hypertension (PAH) 
PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been 
reported in association with dasatinib exposure. In these cases, PAH was reported after initiation of 
dasatinib therapy, including after more than one year of treatment. Patients with PAH reported during 
dasatinib treatment were often taking concomitant medicinal products or had co-morbidities in 
addition to the underlying malignancy. Improvements in haemodynamic and clinical parameters have 
been 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 (see 
section 4.4). No additional patients were reported to have QTcF > 500 msec after a minimum of 
60 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 centrally 
for 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 QTcF 
interval were 4 - 6 msec, with associated upper 95% confidence intervals < 7 msec. Of the 
2,182 patients with resistance or intolerance to prior imatinib therapy who received SPRYCEL in 
clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one patients 
(1%) experienced a QTcF > 500 msec (see section 4.4). 
 



 17

Cardiac adverse reactions 
Patients with risk factors or a history of cardiac disease should be monitored carefully for signs or 
symptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately (see 
section 4.4).  
 
Hepatitis B reactivation 
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in 
acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see 
section 4.4). 
 
In the Phase III dose-optimisation study in patients with chronic phase CML with resistance or 
intolerance to prior imatinib therapy (median duration of treatment of 30 months), the incidence of 
pleural 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 group 
was 37 months (range 1-91 months). Cumulative rates of selected adverse reactions that were reported 
in 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 (imatinib 

intolerant or resistant chronic phase CML)a  

 Minimum of 2 years follow up 
Minimum of 5 years 

follow up 
Minimum of 7 years 

follow up 
 All 

grades 
Grade 

3/4 
All 

grades 
Grade 

3/4 
All 

grades 
Grade 

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 
 Pulmonary 

hypertension 0 0 0 0 2 1 

Haemorrhage 11 1 11 1 12 1 
 Gastrointestinal 

bleeding 2 1 2 1 2 1 
a 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, the 
median 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 that 
were reported in the recommended starting dose of 140 mg once daily are shown in Table 6b. A 70 mg 
twice daily regimen was also studied. The 140 mg once daily regimen showed a comparable efficacy 
profile to the 70 mg twice daily regimen but a more favourable safety profile. 
 



 18

Table 6b: Selected adverse reactions reported in phase III dose-optimisation study: 
Advanced phase CML and Ph+ ALLa 

 140 mg once daily 
n = 304

 All grades Grade 3/4 
 
Preferred term Percent (%) of patients 

Diarrhoea 28 3 
Fluid retention 33 7 
 Superficial oedema 15 < 1 
 Pleural effusion 20 6 
 Generalised oedema 2 0 
 Congestive heart failure 
 /cardiac dysfunctionb 

1 0 

 Pericardial effusion 2 1 
 Pulmonary oedema 1 1 
Haemorrhage 23 8 
 Gastrointestinal bleeding 8 6 

a 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 paediatric 
patients received SPRYCEL in combination with chemotherapy on a continuous dosing regimen. In a 
supportive study, of 55 paediatric patients, 35 received SPRYCEL in combination with chemotherapy 
on a discontinuous dosing regimen (two weeks on treatment followed by one to two weeks off) and 
20 received SPRYCEL in combination with chemotherapy on a continuous dosing regimen. Among 
the 126 Ph+ ALL paediatric patients treated with SPRYCEL on a continuous dosing regimen, the 
median 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%) experienced 
adverse reactions leading to treatment discontinuation. Adverse reactions reported in these two 
paediatric 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 not 
included in the table. 
 

Table 7: Adverse reactions reported in ≥10% of paediatric patients with Ph+ ALL treated 
with 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 0 

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

 



 19

Laboratory test abnormalities 
Haematology  
In the Phase III newly diagnosed chronic phase CML study, the following grade 3 or 4 laboratory 
abnormalities 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 months 
follow-up, the cumulative rates of neutropaenia, thrombocytopaenia, and anaemia were 29%, 22% and 
13%, respectively. 
 
In SPRYCEL-treated patients with newly diagnosed chronic phase CML who experienced 
grade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/or 
reductions and permanent discontinuation of treatment occurred in 1.6% of patients after a minimum 
of 12 months follow-up. After a minimum of 60 months follow-up the cumulative rate of permanent 
discontinuation 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 occurrence 
of cytopaenias was also clearly dependent on the stage of the disease. The frequency of 
grade 3 and 4 haematological abnormalities is presented in Table 8.  
 
Table 8: CTC grades 3/4 haematological laboratory abnormalities in clinical studies in 

patients with resistance or intolerance to prior imatinib therapya  
 

Chronic phase
(n= 165)b 

Accelerated 
phase 

(n= 157)c 

Myeloid 
blast phase

(n= 74)c 

Lymphoid blast 
phase and 
Ph+ ALL 
(n= 168)c 

 Percent (%) of patients 
Haematology parameters     
 Neutropaenia 36 58 77 76 
 Thrombocytopaenia 23 63 78 74 
 Anaemia 13 47 74 44 

a 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 at 
2 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 following 
brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 
5% 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 reported 
in 4% of SPRYCEL-treated patients, and grade 3 or 4 elevations of transaminases, creatinine, and 
bilirubin were reported in ≤ 1% of patients after a minimum of 12 months follow-up. After a minimum 
of 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 transaminases 
remained 1%. There were no discontinuations of SPRYCEL therapy due to these biochemical 
laboratory parameters. 
 
2 year follow-up 
Grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% of patients with chronic 
phase CML (resistant or intolerant to imatinib), but elevations were reported with an increased 
frequency of 1 to 7% of patients with advanced phase CML and Ph+ ALL. It was usually managed 
with 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 similar 



 20

low 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% of 
patients across treatment groups. 
 
Approximately 5% of the SPRYCEL-treated patients who had normal baseline levels experienced 
grade 3 or 4 transient hypocalcaemia at some time during the course of the study. In general, there was 
no association of decreased calcium with clinical symptoms. Patients developing 
grade 3 or 4 hypocalcaemia often had recovery with oral calcium supplementation. 
Grade 3 or 4 hypocalcaemia, hypokalaemia, and hypophosphataemia were reported in patients with all 
phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid 
blast phase CML and Ph+ ALL. Grade 3 or 4 elevations in creatinine were reported in < 1% of 
patients with chronic phase CML and were reported with an increased frequency of 1 to 4% of patients 
with advanced phase CML. 
 
Paediatric population 
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 SPRYCEL 
administered in combination with chemotherapy in paediatric patients with Ph+ ALL was consistent 
with the known safety profile of SPRYCEL in adults and the expected effects of chemotherapy, with 
the 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 known 
profile for laboratory parameters in adults. 
 
In the paediatric ALL studies, the rates of laboratory abnormalities were consistent with the known 
profile for laboratory parameters in adults, within the context of an acute leukaemia patient receiving a 
background chemotherapy regimen. 
 
Special population 
While the safety profile of SPRYCEL in elderly was similar to that in the younger population, patients 
aged 65 years and older are more likely to experience the commonly reported adverse reactions such 
as fatigue, pleural effusion, dyspnoea, cough, lower gastrointestinal haemorrhage, and appetite 
disturbance and more likely to experience less frequently reported adverse reactions such as 
abdominal distention, dizziness, pericardial effusion, congestive heart failure, and weight decrease and 
should be monitored closely (see section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. The highest 
overdose of 280 mg per day for one week was reported in two patients and both developed a 
significant decrease in platelet counts. Since dasatinib is associated with 
grade 3 or 4 myelosuppression (see section 4.4), patients who ingest more than the recommended dose 
should be closely monitored for myelosuppression and given appropriate supportive treatment. 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE06 
 
Pharmacodynamics 



 21

Dasatinib inhibits the activity of the BCR-ABL kinase and SRC family kinases along with a number of 
other selected oncogenic kinases including c-KIT, ephrin (EPH) receptor kinases, and PDGFβ 
receptor. Dasatinib is a potent, subnanomolar inhibitor of the BCR-ABL kinase with potency at 
concentration of 0.6-0.8 nM. It binds to both the inactive and active conformations of the BCR-ABL 
enzyme. 
 
Mechanism of action 
In vitro, dasatinib is active in leukaemic cell lines representing variants of imatinib-sensitive and 
resistant disease. These non-clinical studies show that dasatinib can overcome imatinib resistance 
resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate 
signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene 
overexpression. Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations. 
 
In vivo, in separate experiments using murine models of CML, dasatinib prevented the progression of 
chronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell lines 
grown at various sites, including the central nervous system. 
 
Clinical efficacy and safety 
In the Phase I study, haematologic and cytogenetic responses were observed in all phases of CML and 
in Ph+ ALL in the first 84 patients treated and followed for up to 27 months. Responses were durable 
across all phases of CML and Ph+ ALL.  
 
Four single-arm, uncontrolled, open-label Phase II clinical studies were conducted to determine the 
safety 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 was 
conducted in chronic phase patients who failed initial treatment with 400 or 600 mg imatinib. The 
starting dose was 70 mg dasatinib twice daily. Dose modifications were allowed for improving activity 
or management of toxicity (see section 4.2). 
Two randomised, open-label Phase III studies were conducted to evaluate the efficacy of dasatinib 
administered once daily compared with dasatinib administered twice daily. In addition, one 
open-label, randomised, comparative Phase III study was conducted in adult patients with newly 
diagnosed chronic phase CML. 
 
The efficacy of dasatinib is based on haematological and cytogenetic response rates. 
Durability of response and estimated survival rates provide additional evidence of dasatinib clinical 
benefit. 
 
A total of 2,712 patients were evaluated in clinical studies; of these 23% were ≥ 65 years of age and 
5% were ≥ 75 years of age.  
 
Chronic phase CML - Newly diagnosed 
An international open-label, multicentre, randomised, comparative Phase III study was conducted in 
adult 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 of 
confirmed complete cytogenetic response (cCCyR) within 12 months. Secondary endpoints included 
time in cCCyR (measure of durability of response), time to cCCyR, major molecular response (MMR) 
rate, time to MMR, progression free survival (PFS) and overall survival (OS). Other relevant efficacy 
results included CCyR and complete molecular response (CMR) rates. 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% and 
11% of patients 65 years of age or older, respectively), gender (women 44% and 37%, respectively), 
and race (Caucasian 51% and 55%; Asian 42% and 37%, respectively). At baseline, the distribution of 
Hasford Scores was similar in the SPRYCEL and imatinib treatment groups (low risk: 33% and 34%; 
intermediate risk 48% and 47%; high risk: 19% and 19%, respectively).  



 22

With a minimum of 12 months follow-up, 85% of patients randomised to the SPRYCEL group and 
81% 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-treated 
patients and 5% of imatinib-treated patients. 
 
With a minimum of 60 months follow-up, 60% of patients randomised to the SPRYCEL group and 
63% 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-treated 
patients and 14% of imatinib-treated patients. 
 
Efficacy results are presented in Table 9. A statistically significantly greater proportion of patients in 
the SPRYCEL group achieved a cCCyR compared with patients in the imatinib group within the first 
12 months of treatment. Efficacy of SPRYCEL was consistently demonstrated across different 
subgroups, including age, gender, and baseline Hasford score.  
 



 23

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

 SPRYCEL 
n= 259 

imatinib 
n= 260 

p-value 

 Response rate (95% CI)  
Cytogenetic response     

within 12 months    
 cCCyRa  76.8% (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 months    
cCCyRa 80.3% 74.2%  
CCyRb 87.3% 82.3%  

within 36 months    
cCCyRa 82.6% 77.3%  
CCyRb 88.0% 83.5%  

within 48 months    
cCCyRa 82.6% 78.5%  
CCyRb 87.6% 83.8%  

within 60 months    
cCCyRa 83.0% 78.5%  
CCyRb 88.0% 83.8%  

Major molecular responsec    
12 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< 0.035 
 within 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=0.1983 
a Confirmed complete cytogenetic response (cCCyR) is defined as a response noted on two consecutive occasions (at least 

28 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 samples 

standardised on the International scale. These are cumulative rates representing minimum follow up for the timeframe 
specified. 

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



 24

After 60 months of follow-up, median time to cCCyR was 3.1 months in the SPRYCEL group and 
5.8 months in the imatinib group in patients with a confirmed CCyR. Median time to MMR after 
60 months of follow-up was 9.3 months in the SPRYCEL group and 15.0 months in the imatinib 
group 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 in 
dasatinib-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 consistent 
with 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 were 
consistently higher in dasatinib-treated patients compared with imatinib-treated patients. 
 

PR
O

PO
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TI
O

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 R

ES
PO

N
D

ER
S 



 25

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

 
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 was 
higher in the SPRYCEL group compared to the imatinib group (54.1% versus 45%). The proportion of 
patients 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 were 
consistently higher in dasatinib-treated patients compared with imatinib-treated patients. 
 

%
 w

ith
 M

M
R

 

By 1 year 
46%, p<.0001 

By 2 years 
64%, p<.0001 

By 3 years 
67%, p<.0055 

By 4 years 
73%, p<.0021 

By 5 years 
76%, p<.0022 



 26

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

 
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 of 
progression-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 

Dasatinib N = 235 
Patients with BCR-ABL 

≤ 10% at 3 months 
Patients with BCR-ABL > 

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 consistently 
higher in dasatinib treated patients who achieved BCR-ABL level ≤ 10% at 3 months than those who 
did not. 
 

%
 w

ith
 M

R
4.

5 

By 5 years 
42%, p<.0251 

By 1 year 
5%, p<.2394 

By 2 years 
19%, p<.0008 

By 3 years 
24%, p<.0013 

By 4 years 
34%, p<.0055 



 27

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 chronic 
phase 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 therapeutic 
management, loss of CHR, partial CyR or CCyR, progression to accelerated phase or blast phase, or 
death. The estimated 60-month PFS rate was 88.9% (CI: 84% - 92.4%) for both the dasatinib and 
imatinib treatment groups. At 60 months, transformation to accelerated or blast phase occurred in 
fewer dasatinib-treated patients (n=8; 3%) compared with imatinib-treated patients (n=15; 5.8%). The 
estimated 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 (HR 
1.01, 95% CI: 0.58-1.73, p= 0.9800) and PFS (HR 1.00, 95% CI: 0.58-1.72, p = 0.9998) between 
dasatinib and imatinib. 
 
In patients who report disease progression or discontinue dasatinib or imatinib therapy, BCR-ABL 
sequencing was performed on blood samples from patients where these are available. Similar rates of 
mutation were observed in both the treatment arms. The mutations detected among the 
dasatinib-treated patients were T315I, F317I/L and V299L. A different spectrum of mutation was 
detected 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 efficacy 
endpoint in these studies was Major Cytogenetic Response (MCyR).  
 
Study 1 
An open-label, randomised, non-comparative multicentre study was conducted in patients who failed 
initial treatment with 400 or 600 mg imatinib. They were randomised (2:1) to either dasatinib (70 mg 
twice daily) or imatinib (400 mg twice daily). Crossover to the alternative treatment arm was allowed 
if patients showed evidence of disease progression or intolerance that could not be managed by dose 
modification. The primary endpoint was MCyR at 12 weeks. Results are available for 150 patients: 
101 were randomised to dasatinib and 49 to imatinib (all imatinib-resistant). The median time from 
diagnosis to randomisation was 64 months in the dasatinib group and 52 months in the imatinib group. 
All patients were extensively pretreated. Prior complete haematologic response (CHR) to imatinib was 

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 28

achieved in 93% of the overall patient population. A prior MCyR to imatinib was achieved in 28% and 
29% of the patients in the dasatinib and imatinib arms, respectively. 
Median duration of treatment was 23 months for dasatinib (with 44% of patients treated for 
> 24 months to date) and 3 months for imatinib (with 10% of patients treated for > 24 months to date). 
Ninety-three percent of patients in the dasatinib arm and 82% of patients in the imatinib arm achieved 
a 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 while 
only 8% achieved a CCyR in the imatinib arm. With longer treatment and follow-up (median of 
24 months), MCyR was achieved in 53% of the dasatinib-treated patients (CCyR in 44%) and 33% of 
the imatinib-treated patients (CCyR in 18%) prior to crossover. Among patients who had received 
imatinib 400 mg prior to study entry, MCyR was achieved in 61% of patients in the dasatinib arm and 
50% in the imatinib arm. 
Based on the Kaplan-Meier estimates, the proportion of patients who maintained MCyR for 1 year was 
92% (95% CI: [85%-100%]) for dasatinib (CCyR 97%, 95% CI: [92%-100%]) and 74% (95% CI: 
[49%-100%]) for imatinib (CCyR 100%). The proportion of patients who maintained MCyR for 
18 months was 90% (95% CI: [82%-98%]) for 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%]) for 
imatinib. The proportion of patients who had PFS at 2 years was 86% (95% CI: [78%-93%]) for 
dasatinib 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 of 
study medicinal product, etc.). 
 
The rate of major molecular response (defined as BCR-ABL/control transcripts ≤ 0.1% by RQ-PCR in 
peripheral blood samples) prior to crossover was 29% for dasatinib and 12% for imatinib. 
 
Study 2 
An open-label, single-arm, multicentre study was conducted in patients resistant or intolerant to 
imatinib (i.e. patients who experienced significant toxicity during treatment with imatinib that 
precluded further treatment). 
A total of 387 patients received dasatinib 70 mg twice daily (288 resistant and 99 intolerant). The 
median time from diagnosis to start of treatment was 61 months. The majority of the patients (53%) 
had received prior imatinib treatment for more than 3 years. Most resistant patients (72%) had 
received > 600 mg imatinib. In addition to imatinib, 35% of patients had received prior cytotoxic 
chemotherapy, 65% had received prior interferon, and 10% had received a prior stem cell transplant. 
Thirty-eight percent of patients had baseline mutations known to confer imatinib resistance. Median 
duration of treatment on 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 patients 
and 82% of imatinib-intolerant patients. With a minimum of 24 months follow-up, 21 of the 
240 patients who had achieved a MCyR had progressed and the median duration of MCyR had not 
been reached. 
 
Based on the Kaplan-Meier estimates, 95% (95% CI: [92%-98%]) of the patients maintained MCyR 
for 1 year and 88% (95% CI: [83%-93%]) maintained MCyR for 2 years. The proportion of patients 
who maintained CCyR for 1 year was 97% (95% CI: [94%-99%]) and for 2 years was 90% (95% CI: 
[86%-95%]). 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. Complete 
haematologic response or MCyR was achieved in patients harbouring a variety of BCR-ABL 
mutations associated with imatinib resistance except T315I. The rates of MCyR at 2 years were similar 



 29

whether patients had any baseline BCR-ABL mutation, P-loop mutation, or no mutation (63%, 61% 
and 62%, respectively). 
 
Among imatinib-resistant patients, the estimated rate of PFS was 88% (95% CI: [84%-92%]) at 1 year 
and 75% (95% CI: [69%-81%]) at 2 years. Among imatinib-intolerant patients, the estimated rate of 
PFS was 98% (95% CI: [95%-100%]) at 1 year and 94% (95% CI: [88%-99%]) at 2 years. 
 
The rate of major molecular response at 24 months was 45% (35% for imatinib-resistant patients and 
74% for imatinib-intolerant patients). 
 
Accelerated phase CML 
An open-label, single-arm, multicentre study was conducted in patients intolerant or resistant to 
imatinib. A total of 174 patients received dasatinib 70 mg twice daily (161 resistant and 13 intolerant 
to imatinib). The median time from diagnosis to start of treatment was 82 months. Median duration of 
treatment on dasatinib was 14 months with 31% of patients treated for > 24 months to date. The rate of 
major molecular response (assessed in 41 patients with a CCyR) was 46% at 24 months. Further 
efficacy results are reported in Table 11. 
 
Myeloid blast phase CML 
An open-label, single-arm, multicentre study was conducted in patients intolerant or resistant to 
imatinib. A total of 109 patients received dasatinib 70 mg twice daily (99 resistant and 10 intolerant to 
imatinib). The median time from diagnosis to start of treatment was 48 months. Median duration of 
treatment on dasatinib was 3.5 months with 12% of patients treated for > 24 months to date. The rate 
of major molecular response (assessed in 19 patients with a CCyR) was 68% at 24 months. Further 
efficacy 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 patients 
with lymphoid blast CML received dasatinib 70 mg twice daily (42 resistant and 6 intolerant to 
imatinib). The median time from diagnosis to start of treatment was 28 months. Median duration of 
treatment on dasatinib was 3 months with 2% treated for > 24 months to date. The rate of major 
molecular response (all 22 treated patients with a CCyR) was 50% at 24 months. In addition, 
46 patients with Ph+ ALL received dasatinib 70 mg twice daily (44 resistant and 2 intolerant to 
imatinib). The median time from diagnosis to start of treatment was 18 months. Median duration of 
treatment on dasatinib was 3 months with 7% of patients treated for > 24 months to date. The rate of 
major molecular response (all 25 treated patients with a CCyR) was 52% at 24 months. Further 
efficacy results are reported in Table 11. Of note, major haematologic responses (MaHR) were 
achieved quickly (most within 35 days of first dasatinib administration for patients with lymphoid 
blast CML, and within 55 days for patients with Ph+ ALL). 
 



 30

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

 Chronic 
(n= 387) 

Accelerated
(n= 174) 

Myeloid 
blast 

(n= 109) 

Lymphoid 
blast 

(n= 48) 
Ph+ ALL 
(n= 46) 

Haematologic response rateb (%) 

MaHR (95% CI) n/a 64% (57-72) 
33% 

(24-43) 
35% 

(22-51) 
41% 

(27-57) 
 CHR (95% CI) 91% (88-94) 50% (42-58) 26% (18-35) 29% (17-44) 35% (21-50) 
 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 (%) 

MCyR (95% CI) 62% (57-67) 40% (33-48) 34% (25-44) 52% (37-67) 57% (41-71) 

 CCyR (95% CI) 54% (48-59) 33% (26-41) 27% (19-36) 46% (31-61) 54% (39-69) 
Survival (%; Kaplan-Meier estimates) 
Progression-Free  
 1 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) 
Overall  
 1 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 recommended 
starting 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) = complete 

haematologic response (CHR) + no evidence of leukaemia (NEL).  
CHR (chronic CML): WBC ≤ institutional ULN, platelets < 450,000/mm3, no blasts or promyelocytes in peripheral 
blood, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no 
extramedullary involvement. 
CHR (advanced CML/Ph+ ALL): WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts 
or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral 
blood, basophils in peripheral blood < 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 both 
complete 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 fully 
evaluated. 
 
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 administered 
once daily compared with dasatinib administered twice daily. Results described below are based on a 
minimum 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 of 
670 patients, of whom 497 were imatinib-resistant, were randomised to the dasatinib 100 mg once 
daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. The median duration of 
treatment for all patients still on therapy with a minimum of 5 years of follow-up (n=205) was 
59 months (range 28-66 months). Median duration of treatment for all patients at 7 years of follow-up 
was 29.8 months (range < 1-92.9 months).  
 



 31

Efficacy was achieved across all dasatinib treatment groups with the once daily schedule 
demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary 
efficacy endpoint (difference in MCyR 1.9%; 95% confidence interval [-6.8% - 10.6%]); however, the 
100 mg once daily regimen demonstrated improved safety and tolerability. Efficacy results are 
presented in Tables 12 and 13. 
 
Table 12: Efficacy of SPRYCEL in phase III dose-optimization study: imatinib resistant or 

intolerant 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 extramedullary 
involvement. 

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

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

 
Table 13: Long term efficacy of SPRYCEL in phase 3 dose optimisation study: imatinib resistant 

or intolerant chronic phase CML patientsa  
 Minimum follow-up period 
 1 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 including 
subsequent therapy. 

 
Based on the Kaplan-Meier estimates, the proportion of patients treated with dasatinib 100 mg once 
daily 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 patients 
who received 100 mg once daily, MCyR was achieved in 77% and CCyR in 67%.  
 



 32

Study 2 
In the study in advanced phase CML and Ph+ ALL, the primary endpoint was MaHR. A total of 
611 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 daily 
schedule 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 and 
tolerability. 
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 (n= 158) 
Myeloid blast 

(n= 75) 
Lymphoid blast 

(n= 33) 
Ph+ALL 
(n= 40) 

MaHRb  
 (95% 
CI) 

66%  
(59-74) 

28%  
(18-40) 

42%  
(26-61) 

38% 
(23-54) 

CHRb  
(95% CI) 

47%  
(40-56) 

17%  
(10-28) 

21%  
(9-39) 

33% 
(19-49) 

 NELb  
(95% CI) 

19%  
(13-26) 

11%  
(5-20) 

21%  
(9-39) 

5% 
(1-17) 

MCyRc  
(95% CI) 

39%  
(31-47) 

28%  
(18-40) 

52%  
(34-69) 

70% 
(54-83) 

 CCyR  
(95% CI) 

32%  
(25-40) 

17%  
(10-28) 

39%  
(23-58) 

50% 
(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) = complete 

haematologic response (CHR) + no evidence of leukaemia (NEL). 
CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or promyelocytes in 
peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in 
peripheral blood < 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 median 
duration of MaHR and the median overall survival was not reached and the median PFS was 
25 months. 
 
In patients with myeloid blast phase CML treated with the 140 mg once daily regimen, the median 
duration of MaHR was 8 months, the median PFS was 4 months, and the median overall survival was 
8 months. In patients with lymphoid blast phase CML treated with the 140 mg once daily regimen, the 
median duration of MaHR was 5 months, the median PFS was 5 months, and the median overall 
survival was 11 months. 
 
In patients with Ph+ ALL treated with the 140 mg once daily regimen, the median duration of MaHR 
was 5 months the median PFS was 4 months, and the median overall survival was 7 months. 
 
Paediatric population 
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 previous 
treatment 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. 



 33

 
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 period 
 3 months  6 months 12 months  24 months 

CCyR  
(95% CI)     
Newly diagnosed 
(N = 51)a 
 

43.1%  
(29.3, 57.8) 

66.7%  
(52.1, 79.2) 

96.1%  
(86.5, 99.5) 

96.1%  
(86.5, 99.5) 

Prior imatinib 
(N = 46)b 
 

45.7% 
(30.9, 61.0) 

71.7% 
(56.5, 84.0) 

78.3% 
(63.6, 89.1) 

82.6% 
(68.6, 92.2) 

MCyR  
(95% CI)     
Newly diagnosed 
(N = 51)a 
 

60.8%  
(46.1, 74.2) 

90.2%  
(78.6, 96.7) 

98.0%  
(89.6, 100) 

98.0%  
(89.6, 100) 

Prior imatinib 
(N = 46)b 
 

60.9% 
(45.4, 74.9) 

82.6% 
(68.6, 92.2) 

89.1% 
(76.4, 96.4) 

89.1% 
 (76.4, 96.4) 

MMR  
(95% CI) 

    

Newly diagnosed 
(N = 51)a 
 

7.8%  
(2.2, 18.9) 

31.4%  
(19.1, 45.9) 

56.9%  
(42.2, 70.7) 

74.5%  
(60.4, 85.7) 

Prior imatinib 
(N = 46)b 
 

15.2%  
(6.3, 28.9) 

26.1%  
(14.3, 41.1) 

39.1%  
(25.1, 54.6) 

52.2%  
(36.9, 67.1) 

a  Patients from Phase II paediatric study of newly diagnosed CML-CP receiving oral tablet formulation 
b  Patients from Phase I and Phase II paediatric studies of imatinib-resistant or intolerant CML-CP receiving oral tablet 

formulation 
 
In the Phase I paediatric study, after a minimum of 7 years of follow-up among the 17 patients with 
imatinib-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 PFS 
rate 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 intolerant 
patients progressed to blast phase CML. 
 
There were 33 newly diagnosed paediatric patients with CML-CP who received SPRYCEL powder 
for oral suspension at a dose of 72 mg/m2. This dose represents 30% lower exposure compared to the 
recommended dose (see section 5.2. of Summary of Product Characteristics for SPRYCEL powder for 
oral 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 mutations 
detected at the end of treatment were: T315A, E255K and F317L. However, E255K and F317L were 
also detected prior to treatment. There were no mutations detected in newly diagnosed CML-CP 
patients at the end of treatment. 
 



 34

Paediatric patients with ALL 
The efficacy of SPRYCEL in combination with chemotherapy was evaluated in a pivotal study in 
paediatric 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 to 
24 months, in combination with chemotherapy. Eighty-two patients received dasatinib tablets 
exclusively and 24 patients received dasatinib powder for oral suspension at least once, 8 of whom 
received dasatinib powder for oral suspension exclusively. The backbone chemotherapy regimen was 
the same as used in the AIEOP-BFM ALL 2000 trial (chemotherapeutic standard multi-agent 
chemotherapy protocol). The primary efficacy endpoint was 3-year event-free survival (EFS), which 
was 65.5% (55.5, 73.7).  
 
The minimal residual disease (MRD) negativity rate assessed by Ig/TCR rearrangement was 71.7% by 
the end of consolidation in all treated patients. When this rate was based on the 85 patients with 
evaluable Ig/TCR assessments, the estimate was 89.4%. The MRD negativity rates at the end of 
induction and consolidation as measured by flow cytometry were 66.0% and 84.0%, respectively. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of dasatinib were evaluated in 229 adult healthy subjects and in 84 patients. 
 
Absorption 
Dasatinib is rapidly absorbed in patients following oral administration, with peak concentrations 
between 0.5-3 hours. Following oral administration, the increase in the mean exposure (AUCτ) is 
approximately proportional to the dose increment across doses ranging from 25 mg to 120 mg twice 
daily. 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 a 
high-fat meal indicated a 14% increase in the mean AUC of dasatinib. A low-fat meal 30 minutes prior 
to dasatinib resulted in a 21% increase in the mean AUC of dasatinib. The observed food effects do 
not represent clinically relevant changes in exposure. Dasatinib exposure variability is higher under 
fasted 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 be 
mainly due to inter-occasion variability in bioavailability (44% CV) and, to a lesser extent, due to 
inter-individual variability in bioavailability and inter-individual variability in clearance (30% and 
32% CV, respectively). The random inter-occasion variability in exposure is not expected to affect the 
cumulative exposure and efficacy or safety. 
 
Distribution 
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 extravascular 
space. At clinically relevant concentrations of dasatinib, binding to plasma proteins was approximately 
96% on the basis of in vitro experiments. 
 
Biotransformation 
Dasatinib is extensively metabolised in humans with multiple enzymes involved in the generation of 
the metabolites. In healthy subjects administered 100 mg of [14C]-labelled dasatinib, unchanged 
dasatinib represented 29% of circulating radioactivity in plasma. Plasma concentration and measured 
in vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observed 
pharmacology of the product. CYP3A4 is a major enzyme responsible for the metabolism of dasatinib. 
 



 35

Elimination 
The mean terminal half-life of dasatinib is 3 hours to 5 hours. The mean apparent oral clearance is 
363.8 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% and 
85% of the radioactivity recovered in the urine and faeces, respectively. Unchanged dasatinib 
accounted for 0.1% and 19% of the dose in urine and faeces, respectively, with the remainder of the 
dose as metabolites. 
 
Hepatic and renal impairment 
The effect of hepatic impairment on the single-dose pharmacokinetics of dasatinib was assessed in 8 
moderately hepatic-impaired subjects who received a 50 mg dose and 5 severely hepatic-impaired 
subjects who received a 20 mg dose compared to matched healthy subjects who received a 70 mg dose 
of dasatinib. The mean Cmax and AUC of dasatinib adjusted for the 70 mg dose were decreased by 47% 
and 8%, respectively, in subjects with moderate hepatic impairment compared to subjects with normal 
hepatic function. In severely hepatic-impaired subjects, the mean Cmax and AUC adjusted for the 
70 mg dose were decreased by 43% and 28%, respectively, compared to subjects with normal hepatic 
function (see sections 4.2 and 4.4). 
 
Dasatinib and its metabolites are minimally excreted via the kidney. 
 
Paediatric population  
The pharmacokinetics of dasatinib have been evaluated in 104 paediatric patients with leukaemia or 
solid tumours (72 who received the tablet formulation and 32 who received the powder for oral 
suspension). 
 
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 with 
relapsed or refractory leukaemia or solid tumours at oral doses ranging from 60 to 120 mg/m2 once 
daily and 50 to 110 mg/m2 twice daily. Data was pooled across two studies and showed that dasatinib 
was rapidly absorbed. Mean Tmax was observed between 0.5 and 6 hours and mean half-life ranged 
from 2 to 5 hours across all dose levels and age groups. Dasatinib PK showed dose proportionality 
with a dose-related increase in exposure observed in paediatric patients. There was no significant 
difference 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 and 
adolescents at different dose levels. A PPK model-based simulation predicted that the body weight 
tiered dosing recommendation described for the tablet, in section 4.2, is expected to provide similar 
exposure to a tablet dose of 60 mg/m2. These data should be considered if patients are to switch from 
tablets to powder for oral suspension or vice versa. 
 
5.3 Preclinical safety data 
 
The non-clinical safety profile of dasatinib was assessed in a battery of in vitro and in vivo studies in 
mice, 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 target 
organ. In rats, minimal to mild decreases in erythrocyte parameters were accompanied by bone 
marrow changes; similar changes occurred in monkeys at a lower incidence. Lymphoid toxicity in rats 
consisted of lymphoid depletion of the lymph nodes, spleen, and thymus, and decreased lymphoid 
organ weights. Changes in the gastrointestinal, haematopoietic and lymphoid systems were reversible 
following cessation of treatment. 
 



 36

Renal changes in monkeys treated for up to 9 months were limited to an increase in background 
kidney mineralisation. Cutaneous haemorrhage was observed in an acute, single-dose oral study in 
monkeys but was not observed in repeat-dose studies in either monkeys or rats. In rats, dasatinib 
inhibited platelet aggregation in vitro and prolonged cuticle bleeding time in vivo, but did not invoke 
spontaneous haemorrhage. 
 
Dasatinib activity in vitro in hERG and Purkinje fiber assays suggested a potential for prolongation of 
cardiac ventricular repolarisation (QT interval). However, in an in vivo single-dose study in conscious 
telemetered 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 an 
in 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 embryonic 
development study, but induced embryolethality at dose levels approximating human clinical 
exposures. In embryofoetal development studies, dasatinib likewise induced embryolethality with 
associated 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 a 
selective reproductive toxicant from implantation through the completion of organogenesis. 
 
In mice, dasatinib induced immunosuppression, which was dose-related and effectively managed by 
dose reduction and/or changes in dosing schedule. Dasatinib had phototoxic potential in an in vitro 
neutral red uptake phototoxicity assay in mouse fibroblasts. Dasatinib was considered to be 
non-phototoxic in vivo after a single oral administration to female hairless mice at exposures up to 
3-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, and 
3 mg/kg/day. The highest dose resulted in a plasma exposure (AUC) level generally equivalent to the 
human exposure at the recommended range of starting doses from 100 mg to 140 mg daily. A 
statistically significant increase in the combined incidence of squamous cell carcinomas and 
papillomas in the uterus and cervix of high-dose females and of prostate adenoma in low-dose males 
was noted. The relevance of the findings from the rat carcinogenicity study for humans is not known. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients  
 
Tablet core 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Hydroxypropylcellulose 
Magnesium stearate 
 
Film-coating 
Hypromellose 
Titanium dioxide (E171) 
Macrogol 400 
 
6.2 Incompatibilities 
 
Not applicable. 
 



 37

6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
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. 
 
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 80 mg, SPRYCEL 100 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. 
 
6.6 Special precautions for disposal and other handling 
 
The film-coated tablets consist of a core tablet, surrounded by a film-coating to prevent exposure of 
healthcare professionals to the active substance. The use of latex or nitrile gloves for appropriate 
disposal when handling tablets that are inadvertently crushed or broken is recommended, to minimise 
the risk of dermal exposure. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
SPRYCEL 20 mg film-coated tablets 
EU/1/06/363/004 
EU/1/06/363/007 
EU/1/06/363/001 
 



 38

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 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 November 2006 
Date of latest renewal: 15 July 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



 39

1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 10 mg/mL powder for oral suspension 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One bottle of powder for oral suspension contains 990 mg of dasatinib (as monohydrate). 
After constitution, one bottle contains 99 mL of oral suspension. Each mL of oral suspension contains 
10 mg of dasatinib (as monohydrate). 
 
Excipient with known effect 
Each mL of oral suspension contains approximately 291 mg of sucrose, 2.1 mg of sodium, 0.25 mg of 
sodium benzoate, 0.25 mg of benzoic acid, 0.017 mg of benzyl alcohol and <10 ppm of sulphur 
dioxide (E220). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for oral suspension. 
White to off-white powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
SPRYCEL is indicated for the treatment of paediatric patients with: 
 newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukaemia in chronic 

phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib. 
  newly diagnosed Ph+ acute lymphoblastic leukaemia (ALL) in combination with chemotherapy. 
 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with 
leukaemia. 
 
Posology 
Dosing is on the basis of body weight (see Table 1). Dasatinib is administered orally once daily in the 
form of either SPRYCEL powder for oral suspension or film-coated tablets (see Summary of Product 
Characteristics for SPRYCEL film-coated tablets). The dose should be recalculated every 3 months 
based on changes in body weight, or more often if necessary. The tablet is not recommended for 
patients weighing less than 10 kg; the powder for oral suspension should be used for these patients. 
Dose increase or reduction is recommended 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 oral 
suspension to SPRYCEL tablets or patients who are not able to swallow tablets and who desire to 
switch from tablets to oral suspension, may do so, provided that the correct dosing recommendations 
for the dosage form are followed. 
 
The recommended starting daily dosage of SPRYCEL powder for oral suspension for paediatric 
patients with Ph+ CML-CP or Ph+ ALL and adult patients with Ph+ CML-CP who cannot swallow 
tablets is shown in Table 1. 



 40

 
Table 1: Dosage of SPRYCEL powder for oral suspension for patients with Ph+ CML-CP and 

paediatric patients with Ph+ ALL (10 mg/mL suspension upon constitution) 
Body weight (kg)  Daily dose, mL (mg) 
5 to less than 10 kg 4 mL (40 mg) 

10 to less than 20 kg 6 mL (60 mg) 
20 to less than 30 kg 9 mL (90 mg) 
30 to less than 45 kg 10.5 mL (105 mg) 

at least 45 kg 12 mL (120 mg) 
 
The dose for the use of powder for oral suspension in adult patients with accelerated, myeloid or 
lymphoid blast phase (advanced phase) CML or Ph+ ALL has not been determined. 
 
Treatment duration 
In clinical studies, treatment with SPRYCEL in adults with Ph+ CML-CP, accelerated, myeloid or 
lymphoid blast phase (advanced phase) CML, or Ph+ ALL and paediatric patients with Ph+ CML-CP 
was continued until disease progression or until no longer tolerated by the patient. The effect of 
stopping treatment on long-term disease outcome after the achievement of a cytogenetic or molecular 
response [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 administered 
continuously, added to successive blocks of backbone chemotherapy, for a maximum duration of two 
years. In patients that receive a subsequent stem cell transplantation, SPRYCEL can be administered 
for an additional year post-transplantation. 
 
To achieve the recommended dose, SPRYCEL is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mg 
and 140 mg film-coated tablets and powder for oral suspension (10 mg/mL suspension upon 
constitution). Dose increase or reduction is recommended based on patient response and tolerability. 
 
Dose escalation 
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 the 
recommended time points, per current treatment guidelines, and who tolerate the treatment. 
 
Table 2: Dose escalation for patients with Ph+ CML-CP
 Dose (maximum dose per day) 
 Starting dose Escalation 

Powder for oral suspension 4 mL (40 mg) 5 mL (50 mg) 
 6 mL (60 mg) 8 mL (80 mg) 
 9 mL (90 mg) 12 mL (120 mg) 
 10.5 mL (105 mg) 14 mL (140 mg) 
 12 mL (120 mg) 16 mL (160 mg) 

 
Dose escalation is not recommended for paediatric patients with Ph+ ALL, as SPRYCEL is 
administered in combination with chemotherapy in these patients. 
 
Dose adjustment for adverse reactions 
Myelosuppression 
In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or 
discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate. 
Haematopoietic growth factor has been used in patients with resistant myelosuppression. 
Guidelines for dose modifications in paediatric patients with CML-CP are summarised in 
Table 3.Guidelines for paediatric patients with Ph+ ALL treated in combination with chemotherapy 
are in a separate paragraph following the table. 
 



 41

Table 3:  Dose adjustments for neutropaenia and thrombocytopaenia in paediatric patients 
with Ph+ CML-CP 

1. If cytopaenia 
persists for more 
than 3 weeks, 
check if 
cytopaenia is 
related to 
leukaemia 
(marrow aspirate 
or biopsy).  
 
2. If cytopaenia is 
unrelated to 
leukaemia, stop 
treatment until 
ANC ≥1.0 × 109/L 
and platelets ≥75 
× 109/L and 
resume at the 
original starting 
dose or at a 
reduced dose.  
 
3. If cytopaenia 
recurs, repeat 
marrow 
aspirate/biopsy 
and resume 
treatment at a 
reduced dose. 

 Dose (maximum dose per day) 
  

Original starting 
dose 

 
One-level dose 

reduction 

 
Two-level dose 

reduction 
Powder for oral 
suspension 

4 mL (40 mg) 3 mL (30 mg) 2 mL (20 mg) 
6 mL (60 mg) 5 mL (50 mg) 4 mL (40 mg) 

 9 mL (90 mg) 7 mL (70 mg) 6 mL (60 mg) 
 10.5 mL (105 mg) 9 mL (90 mg) 7 mL (70 mg) 
 12 mL (120 mg) 10 mL (100 mg) 8 mL (80 mg) 

ANC: absolute neutrophil count 
 
For paediatric patients with Ph+ CML-CP, if Grade ≥3 neutropaenia or thrombocytopaenia recurs 
during complete haematologic response (CHR), SPRYCEL should be interrupted, and may be 
subsequently resumed at a reduced dose. Temporary dose reductions for intermediate degrees of 
cytopaenia 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 of 
treatment by more than 14 days, SPRYCEL should be interrupted and resumed at the same dose level 
once the next block of treatment is started. If neutropaenia and/or thrombocytopaenia persist and the 
next block of treatment is delayed another 7 days, a bone marrow assessment should be performed to 
assess cellularity and percentage of blasts. If marrow cellularity is <10%, treatment with SPRYCEL 
should be interrupted until ANC >500/μL (0.5 x 109/L), at which time treatment may be resumed at 
full 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 should 
be interrupted until the adverse reaction has resolved or returned to baseline. The same dose should be 
resumed if this is the first occurrence and the dose should be reduced if this is a recurrent adverse 
reaction. 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 be 
resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction. In 
CML-CP paediatric patients with non-haematologic adverse reactions, the dose reduction 
recommendations for haematologic adverse reactions that are described above should be followed. In 
Ph+ ALL paediatric patients with non-haematologic adverse reactions, if needed, one level of dose 



 42

reduction should be followed, according to the dose reduction recommendations for haematologic 
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 one 
week, a course of diuretics or corticosteroids or both concurrently should be considered (see 
sections 4.4 and 4.8). Following resolution of the first episode, reintroduction of dasatinib at the same 
dose level should be considered. Following resolution of a subsequent episode, dasatinib at one dose 
level 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 the 
adverse reaction. 
 
Dose reduction for concomitant use of strong CYP3A4 inhibitors 
The concomitant use of strong CYP3A4 inhibitors and grapefruit juice with SPRYCEL should be 
avoided (see section 4.5). If possible, an alternative concomitant medication with no or minimal 
enzyme 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 SPRYCEL 
until the CYP3A4 inhibitor is discontinued, or switching to a lower dose with the powder for oral 
suspension formulation. Allow a washout period of approximately 1 week after the inhibitor is stopped 
before reinitiating SPRYCEL.  
 
These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the range 
observed without CYP3A4 inhibitors; however, clinical data are not available with these dose 
adjustments in patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dose 
reduction, either discontinue the strong CYP3A4 inhibitor or interrupt SPRYCEL until the inhibitor is 
discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the 
SPRYCEL dose is increased. 
 
Guidelines for dose reduction for paediatric patients in whom SPRYCEL powder for oral suspension 
must be administered with a strong CYP3A4 inhibitor are shown in Table 4. 
 
Table 4: Dose reduction for concomitant use of strong CYP3A4 inhibitors in paediatric 

patients 
 Dose 
Body weight (kg) Original dose Dose reduction 
Powder for oral suspension 
5 to less than 10 4 mL (40 mg) 1 mL (10 mg) 
10 to less than 20 6 mL (60 mg) 1 mL (10 mg) 
20 to less than 30 9 mL (90 mg) 2 mL (20 mg) 
30 to less than 45 10.5 mL (105 mg) 2 mL (20 mg) 
at least 45 12 mL (120 mg) 2.5 mL (25 mg) 

 
Special populations 
Elderly 
No clinically relevant age-related pharmacokinetic differences have been observed in these patients. 
No specific dose recommendation is necessary in elderly. 
 
Hepatic impairment 
Patients with mild, moderate or severe hepatic impairment may receive the recommended starting 
dose. However, SPRYCEL should be used with caution in patients with hepatic impairment (see 
section 5.2). 



 43

 
Renal impairment 
No clinical studies were conducted with SPRYCEL in patients with decreased renal function (the 
study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine 
concentration > 3 times the upper limit of the normal range, and studies in patients with chronic phase 
CML with resistance or intolerance to prior imatinib therapy excluded patients with serum creatinine 
concentration > 1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib 
and its metabolites is < 4%, a decrease in total body clearance is not expected in patients with renal 
insufficiency. 
 
Method of administration 
SPRYCEL must be administered orally. It can be taken with or without a meal and should be taken 
consistently either in the morning or in the evening (see section 5.2). The oral suspension should not 
be taken with grapefruit or grapefruit juice (see section 4.5). Constituted oral suspension may be 
further mixed with milk, yogurt, apple juice, or applesauce. 
 
For details on preparation and administration of this medicinal product and instructions for use, see 
section 6.6.  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Clinically relevant interactions 
Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. Therefore, there is a 
potential for interaction with other concomitantly administered medicinal products that are 
metabolised 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 a 
potent 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 Hypericum 
perforatum, also known as St. John's Wort) may substantially reduce exposure to dasatinib, potentially 
increasing the risk of therapeutic failure. Therefore, in patients receiving dasatinib, coadministration of 
alternative medicinal products with less potential for CYP3A4 induction should be selected (see 
section 4.5). 
 
Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 
substrate. Therefore, caution is warranted when dasatinib is coadministered with CYP3A4 substrates 
of narrow therapeutic index, such as astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil 
or ergot alkaloids (ergotamine, dihydroergotamine) (see section 4.5). 
 
The concomitant use of dasatinib and a histamine-2 (H2) antagonist (e.g. famotidine), proton pump 
inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure 
to dasatinib. Thus, H2 antagonists and proton pump inhibitors are not recommended and aluminium 
hydroxide/magnesium hydroxide products should be administered up to 2 hours prior to, or 2 hours 
following the administration of dasatinib (see section 4.5). 
 
Special populations 
Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or 
severe hepatic impairment may receive the recommended starting dose (see section 5.2). Due to the 



 44

limitations of this clinical study, caution is recommended when administering dasatinib to patients 
with hepatic impairment. 
 
Important adverse reactions 
Myelosuppression 
Treatment with dasatinib is associated with anaemia, neutropaenia and thrombocytopaenia. Their 
occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in 
chronic phase CML. In adult patients with advanced phase CML or Ph+ ALL treated with dasatinib as 
monotherapy, complete blood counts (CBCs) should be performed weekly for the first 2 months, and 
then 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 months 
thereafter or as clinically indicated. In paediatric patients with Ph+ ALL treated with dasatinib in 
combination with chemotherapy, CBCs should be performed prior to the start of each block of 
chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, CBCs 
should be performed every 2 days until recovery (see sections 4.2 and 4.8). Myelosuppression is 
generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction. 
 
Bleeding 
In patients with chronic phase CML (n=548), 5 patients (1%) receiving dasatinib had 
grade 3 or 4 haemorrhage. In clinical studies in patients with advanced phase CML receiving the 
recommended dose of SPRYCEL (n=304), severe central nervous system (CNS) haemorrhage 
occurred 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% of 
patients 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 bleeding 
related adverse reactions in these patients were typically associated with 
grade 3 or 4 thrombocytopaenia (see section 4.8). Additionally, in vitro and in vivo platelet assays 
suggest that SPRYCEL treatment reversibly affects platelet activation. 
 
Caution should be exercised if patients are required to take medicinal products that inhibit platelet 
function or anticoagulants. 
 
Fluid retention 
Dasatinib is associated with fluid retention. In the Phase III clinical study in patients with newly 
diagnosed chronic phase CML, grade 3 or 4 fluid retention was reported in 13 patients (5%) in the 
dasatinib-treatment group and in 2 patients (1%) in the imatinib-treatment group after a minimum of 
60 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 at 
the recommended dose (n=304), grade 3 or 4 fluid retention was reported in 8% of patients, including 
grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients, respectively. In these 
patients grade 3 or 4 pulmonary oedema and pulmonary hypertension were each reported in 1% of 
patients. 
 
Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should 
be evaluated by chest X-ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygen 
therapy. Fluid retention adverse reactions were typically managed by supportive care measures that 
include diuretics and short courses of steroids (see sections 4.2 and 4.8). Patients aged 65 years and 
older are more likely than younger patients to experience pleural effusion, dyspnoea, cough, 
pericardial effusion and congestive heart failure, and should be monitored closely. 
 
Pulmonary arterial hypertension (PAH) 
PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been 
reported in association with dasatinib treatment (see section 4.8). In these cases, PAH was reported 
after initiation of dasatinib therapy, including after more than one year of treatment. 
 



 45

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to 
initiating dasatinib therapy. An echocardiography should be performed at treatment initiation in every 
patient presenting symptoms of cardiac disease and considered in patients with risk factors for cardiac 
or pulmonary disease. Patients who develop dyspnoea and fatigue after initiation of therapy should be 
evaluated for common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung 
infiltration. In accordance with recommendations for management of non-haematologic adverse 
reactions (see section 4.2) the dose of dasatinib should be reduced or therapy interrupted during this 
evaluation. If no explanation is found, or if there is no improvement with dose reduction or 
interruption, the diagnosis of PAH should be considered. The diagnostic approach should follow 
standard practice guidelines. If PAH is confirmed, dasatinib should be permanently discontinued. 
Follow up should be performed according to standard practice guidelines. Improvements in 
haemodynamic and clinical parameters have been observed in dasatinib-treated patients with PAH 
following 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 a 
minimum of 60 months follow-up in the Phase III study in newly diagnosed chronic phase CML, 1 
patient (< 1%) in each group had QTc prolongation reported as an adverse reaction. The median 
changes in QTcF from baseline were 3.0 msec in dasatinib-treated patients compared to 8.2 msec in 
imatinib-treated patients. One patient (< 1%) in each group experienced a QTcF > 500 msec. In 
865 patients with leukaemia treated with dasatinib in Phase II clinical studies, the mean changes from 
baseline in QTc interval using Fridericia's method (QTcF) were 4 - 6 msec; the upper 95% confidence 
intervals 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 in 
clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one of these 
patients (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 which 
lead to QT prolongation, and cumulative high dose anthracycline therapy. Hypokalaemia or 
hypomagnesaemia 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 in 
chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of 
congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QT 
prolongation and myocardial infarction (including fatal) were reported in patients taking dasatinib. 
Cardiac adverse reactions were more frequent in patients with risk factors or a history of cardiac 
disease. Patients with risk factors (e.g. hypertension, hyperlipidaemia, diabetes) or a history of cardiac 
disease (e.g. prior percutaneous coronary intervention, documented coronary artery disease) should be 
monitored carefully for clinical signs or symptoms consistent with cardiac dysfunction such as chest 
pain, shortness of breath, and diaphoresis. 
 
If these clinical signs or symptoms develop, physicians are advised to interrupt dasatinib 
administration and consider the need for alternative CML-specific treatment. After resolution, a 
functional assessment should be performed prior to resuming treatment with dasatinib. Dasatinib may 
be resumed at the original dose for mild/moderate adverse reactions (≤ grade 2) and resumed at a dose 
level reduction for severe adverse reactions (≥ grade 3) (see section 4.2). Patients continuing treatment 
should be monitored periodically. 
 
Patients with uncontrolled or significant cardiovascular disease were not included in the clinical 
studies. 
 



 46

Thrombotic microangiopathy (TMA) 
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 findings 
associated with TMA occur in a patient receiving SPRYCEL, treatment with SPRYCEL should be 
discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-
ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated 
in conjunction with low ADAMTS13 activity, treatment with SPRYCEL should not be resumed. 
 
Hepatitis B reactivation 
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these 
patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or 
fulminant hepatitis leading to liver transplantation or a fatal outcome.  
Patients should be tested for HBV infection before initiating treatment with SPRYCEL. Experts in 
liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in 
patients with positive hepatitis B serology (including those with active disease) and for patients who 
test 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 throughout 
therapy 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 and 
treatment-naive Ph+ CML-CP paediatric patients after at least 2 years of treatment, treatment-related 
adverse events associated with bone growth and development were reported in 6 (4.6%) patients, one 
of which was severe in intensity (Growth Retardation Grade 3). These 6 cases included cases of 
epiphyses delayed fusion, osteopaenia, growth retardation, and gynecomastia (see section 5.1). These 
results are difficult to interpret in the context of chronic diseases such as CML, and require long-term 
follow-up. 
 
In paediatric trials of SPRYCEL in combination with chemotherapy in newly diagnosed Ph+ ALL 
paediatric patients after a maximum of 2 years of treatment, treatment-related adverse events 
associated with bone growth and development were reported in 1 (0.6%) patient. This case was a 
Grade 1 osteopenia. 
 
Excipients 
Sodium 
This medicinal product contains 2.1 mg sodium per mL of SPRYCEL oral suspension. At the 
maximum daily dose of 16 mL oral suspension, this is equivalent to 1.7% of the WHO recommended 
maximum daily dietary intake of 2 g sodium for an adult. 
 
Sucrose 
SPRYCEL powder for oral suspension contains approximately 0.29 g/mL of sucrose upon constitution 
with water. For the recommended paediatric dosage, SPRYCEL oral suspension contains 1.17 grams 
sucrose per 40 mg dasatinib and 4.37 grams sucrose per 150 mg dasatinib. This should be taken into 
account in patients with diabetes mellitus.  
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or 
sucrase-isomaltase insufficiency should not take this medicinal product. 
May be harmful to the teeth. 
 
Benzoic acid and benzoates 
SPRYCEL contains 0.25 mg benzoic acid in each mL of oral suspension and 0.25 mg sodium 
benzoate in each mL of oral suspension. 
Benzoic acid/Benzoate salt may increase jaundice (yellowing of the skin and eyes) in newborn babies 
(up to 4 weeks old). 
 
Benzyl alcohol 
SPRYCEL contains 0.017 mg benzyl alcohol in each mL of oral suspension.  
Benzyl alcohol may cause allergic reactions. 



 47

 
Monitor patients less than 3 years of age for respiratory symptoms. 
 
SPRYCEL should not be used during pregnancy unless the clinical condition of the woman requires 
treatment with dasatinib (see section 4.6). Advise patients who are or may become pregnant of the 
potential risk to the foetus from dasatinib and the excipient benzyl alcohol, which may accumulate 
over time and cause metabolic acidosis. 
 
Use with caution in patients with hepatic or renal impairment, as benzyl alcohol may accumulate over 
time and cause metabolic acidosis. 
 
Sulphur dioxide (E220) 
May rarely cause severe hypersensitivity reactions and bronchospasm. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Active substances that may increase dasatinib plasma concentrations 
In vitro studies indicate that dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and 
medicinal products or substances which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, 
erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to 
dasatinib. Therefore, in patients receiving dasatinib, systemic administration of a potent CYP3A4 
inhibitor is not recommended (see section 4.2). 
 
At clinically relevant concentrations, binding of dasatinib to plasma proteins is approximately 96% on 
the basis of in vitro experiments. No studies have been performed to evaluate dasatinib interaction 
with other protein-bound medicinal products. The potential for displacement and its clinical relevance 
are unknown. 
 
Active substances that may decrease dasatinib plasma concentrations 
When dasatinib was administered following 8 daily evening administrations of 600 mg rifampicin, a 
potent CYP3A4 inducer, the AUC of dasatinib was decreased by 82%. Other medicinal products that 
induce CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, phenobarbital or herbal 
preparations containing Hypericum perforatum, also known as St. John´s Wort) may also increase 
metabolism 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 potential 
should be used. Concomitant use of dexamethasone, a weak CYP3A4 inducer, with dasatinib is 
allowed; dasatinib AUC is predicted to decrease approximately 25% with concomitant use of 
dexamethasone, 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 healthy 
subjects, the administration of famotidine 10 hours prior to a single dose of SPRYCEL reduced 
dasatinib exposure by 61%. In a study of 14 healthy subjects, administration of a single 100-mg dose 
of SPRYCEL 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC of 
dasatinib by 43% and the Cmax of dasatinib by 42%. The use of antacids should be considered in place 
of 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, the 
concomitant 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 were 
administered 2 hours prior to a single dose of SPRYCEL, no relevant changes in dasatinib 
concentration or exposure were observed. Thus, antacids may be administered up to 2 hours prior to or 
2 hours following SPRYCEL (see section 4.4). 
 



 48

Active substances that may have their plasma concentrations altered by dasatinib 
Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 
substrate. In a study in healthy subjects, a single 100 mg dose of dasatinib increased AUC and Cmax 
exposure to simvastatin, a known CYP3A4 substrate, by 20 and 37% respectively. It cannot be 
excluded that the effect is larger after multiple doses of dasatinib. Therefore, CYP3A4 substrates 
known to have a narrow therapeutic index (e.g. astemizole, terfenadine, cisapride, pimozide, 
quinidine, bepridil or ergot alkaloids [ergotamine, dihydroergotamine]) should be administered with 
caution in patients receiving dasatinib (see section 4.4). 
In vitro data indicate a potential risk for interaction with CYP2C8 substrates, such as glitazones. 
 
Paediatric population 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/contraception in males and females 
Both sexually active men and women of childbearing potential should use effective methods of 
contraception during treatment. 
 
Pregnancy 
Based on human experience, dasatinib is suspected to cause congenital malformations including neural 
tube 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 requires 
treatment with dasatinib. If SPRYCEL is used during pregnancy, the patient must be informed of the 
potential risk to the foetus. 
 
Breast-feeding 
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 in 
breast milk and a risk to the suckling child cannot be excluded. 
Breast-feeding should be stopped during treatment with SPRYCEL. 
 
Pregnant or breast-feeding women should avoid exposure to SPRYCEL powder for oral suspension. 
 
Fertility 
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 of 
appropriate age about possible effects of SPRYCEL on fertility, and this counseling may include 
consideration of semen deposition. 
 
4.7 Effects on ability to drive and use machines 
 
SPRYCEL has minor influence on the ability to drive and use machines. Patients should be advised 
that they may experience adverse reactions such as dizziness or blurred vision during treatment with 
dasatinib. Therefore, caution should be recommended when driving a car or operating machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The data described below reflect the exposure to SPRYCEL as single-agent therapy at all doses tested 
in 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, the 
median duration of therapy was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients 



 49

with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 
months. The median duration of therapy in 1,618 adult patients with chronic phase CML was 
29 months (range 0 to 92.9 months). The median duration of therapy in 1,094 adult patients with 
advanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). Among 188 patients in 
paediatric studies, the median duration of therapy was 26.3 months (range 0 to 99.6 months). In the 
subset of 130 chronic phase CML SPRYCEL-treated paediatric patients, the median duration of 
therapy 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 overall 
population of 2,712 SPRYCEL-treated adult subjects, 520 (19%) experienced adverse reactions 
leading to treatment discontinuation. 
 
The overall safety profile of SPRYCEL in the paediatric Ph+ CML-CP population was similar to that 
of the adult population, regardless of formulation, with the exception of no reported pericardial 
effusion, 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 adverse 
reactions leading to treatment discontinuation. 
 
Tabulated list of adverse reactions 
The following adverse reactions, excluding laboratory abnormalities, were reported in patients treated 
with 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 are 
defined 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 

Infections and infestations 
Very common infection (including bacterial, viral, fungal, non-specified) 
Common pneumonia (including bacterial, viral, and fungal), upper respiratory tract 

infection/inflammation, herpes virus infection (including cytomegalovirus - CMV), 
enterocolitis infection, sepsis (including uncommon cases with fatal outcomes) 

Not known hepatitis B reactivation 
Blood and lymphatic system disorders 
Very Common myelosuppression (including anaemia, neutropaenia, thrombocytopaenia) 
Common febrile neutropaenia 
Uncommon lymphadenopathy, lymphopaenia
Rare aplasia pure red cell 
Immune system disorders 
Uncommon hypersensitivity (including erythema nodosum) 
Rare anaphylactic shock 
Endocrine disorders 
Uncommon hypothyroidism 
Rare hyperthyroidism, thyroiditis 
Metabolism and nutrition disorders 
Common appetite disturbancesa, hyperuricaemia 
Uncommon tumour lysis syndrome, dehydration, hypoalbuminemia, hypercholesterolemia 
Rare diabetes mellitus 
Psychiatric disorders 
Common depression, insomnia 
Uncommon anxiety, confusional state, affect lability, libido decreased 
Nervous system disorders 
Very common headache 
Common neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence 
Uncommon CNS bleeding*b, syncope, tremor, amnesia, balance disorder 



 50

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

Eye disorders 
Common visual disorder (including visual disturbance, vision blurred, and visual acuity 

reduced), dry eye 
Uncommon visual impairment, conjunctivitis, photophobia, lacrimation increased 
Ear and labyrinth disorders 
Common tinnitus 
Uncommon hearing loss, vertigo 
Cardiac disorders 
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), angina 
pectoris, 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 
Vascular disorders 
Very common haemorrhage*d 
Common hypertension, flushing 
Uncommon hypotension, thrombophlebitis, thrombosis 
Rare deep vein thrombosis, embolism, livedo reticularis 
Not known thrombotic microangiopathy 
Respiratory, thoracic and mediastinal disorders 
Very common pleural effusion*, dyspnoea 
Common pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis, cough 
Uncommon pulmonary arterial hypertension, bronchospasm, asthma 
Rare pulmonary embolism, acute respiratory distress syndrome 
Not known interstitial lung disease 
Gastrointestinal disorders 
Very common diarrhoea, vomiting, nausea, abdominal pain 
Common gastrointestinal bleeding*, colitis (including neutropaenic colitis), gastritis, mucosal 

inflammation (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* 
Hepatobiliary disorders  
Uncommon hepatitis, cholecystitis, cholestasis 
Skin and subcutaneous tissue disorders 
Very common skin rashe 
Common alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria, 

hyperhidrosis 
Uncommon neutrophilic dermatosis, photosensitivity, pigmentation disorder, panniculitis, skin 

ulcer, bullous conditions, nail disorder, palmar-plantar erythrodysesthesia syndrome, 
hair disorder 

Rare leukocytoclastic vasculitis, skin fibrosis 
Not known Stevens-Johnson syndromef 
Musculoskeletal and connective tissue disorders 
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 



 51

Renal and urinary disorders 
Uncommon renal impairment (including renal failure), urinary frequency, proteinuria 
Not known nephrotic syndrome 
Pregnancy, puerperium and perinatal conditions
Rare abortion 
Reproductive system and breast disorders 
Uncommon gynecomastia, menstrual disorder 
General disorders and administration site conditions 
Very common peripheral oedema,i fatigue, pyrexia, face oedemaj  
Common asthenia, pain, chest pain, generalised oedema*k, chills 
Uncommon malaise, other superficial oedemal  
Rare gait disturbance 
Investigations 
Common weight decreased, weight increased 
Uncommon blood creatine phosphokinase increased, gamma-glutamyltransferase increased 
Injury, poisoning, and procedural complications 
Common contusion 

a 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 subdural 
haemorrhage. 

c Includes brain natriuretic peptide increased, ventricular dysfunction, left ventricular dysfunction, right ventricular 
dysfunction, cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive, cardiomyopathy, 
congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased and ventricular failure, left ventricular 
failure, right ventricular failure, and ventricular hypokinesia. 

d Excludes gastrointestinal bleeding and CNS bleeding; these adverse reactions are reported under the gastrointestinal 
disorders system organ class and the nervous system disorders system organ class, respectively. 

e Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalised erythema, genital rash, 
heat rash, milia, miliaria, pustular psoriaisis, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash 
maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation, toxic skin 
eruption, urticaria vesiculosa, and vasculitic rash. 

f In the post-marketing setting, individual cases of Stevens-Johnson syndrome have been reported. It could not be 
determined whether these mucocutaneous adverse reactions were directly related to SPRYCEL or to concomitant 
medicinal 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, oedema 

mouth, orbital oedema, periorbital oedema, swelling face. 
k Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, peripheral swelling, oedema, oedema due to 

cardiac 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" 
 
Description of selected adverse reactions 
Myelosuppression 
Treatment with SPRYCEL is associated with anaemia, neutropaenia and thrombocytopaenia. Their 
occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in 
chronic phase CML (see section 4.4).  
 
Bleeding 
Bleeding drug-related adverse reactions, ranging from petechiae and epistaxis to 
grade 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 pericardial 
effusion with or without superficial oedema may be collectively described as “fluid retention”. In the 
newly diagnosed chronic phase CML study after a minimum of 60 months follow-up, dasatinib-related 
fluid retention adverse reactions included pleural effusion (28%), superficial oedema (14%), 



 52

pulmonary hypertension (5%), generalised oedema (4%), and pericardial effusion (4%). Congestive 
heart 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 of 46 
dasatinib-treated patients had recurrent pleural effusions. Seventeen patients had 2 separate adverse 
reactions, 6 had 3 adverse reactions, 18 had 4 to 8 adverse reactions and 5 had > 8 episodes of pleural 
effusions. 
 
The median time to first dasatinib-related grade 1 or 2 pleural effusion was 114 weeks (range: 4 to 
299 weeks). Less than 10% of patients with pleural effusion had severe (grade 3 or 4) dasatinib-related 
pleural effusions. The median time to first occurrence of grade ≥ 3 dasatinib-related pleural effusion 
was 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 using 
diuretics or other appropriate supportive care measures (see sections 4.2 and 4.4). Among 
dasatinib-treated patients with drug-related pleural effusion (n=73), 45 (62%) had dose interruptions 
and 30 (41%) had dose reductions. Additionally, 34 (47%) received diuretics, 23 (32%) received 
corticosteroids, and 20 (27%) received both corticosteroids and diuretics. Nine (12%) patients 
underwent 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-treated 
patients 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 CML 
or Ph+ ALL. 
 
Pulmonary arterial hypertension (PAH) 
PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been 
reported in association with dasatinib exposure. In these cases, PAH was reported after initiation of 
dasatinib therapy, including after more than one year of treatment. Patients with PAH reported during 
dasatinib treatment were often taking concomitant medicinal products or had co-morbidities in 
addition to the underlying malignancy. Improvements in haemodynamic and clinical parameters have 
been 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 (see 
section 4.4). No additional patients were reported to have QTcF > 500 msec after a minimum of 
60 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 centrally 
for 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 QTcF 
interval were 4 - 6 msec, with associated upper 95% confidence intervals < 7 msec. Of the 
2,182 patients with resistance or intolerance to prior imatinib therapy who received SPRYCEL in 
clinical 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 or 
symptoms consistent with cardiac dysfunction and should be evaluated and treated appropriately (see 
section 4.4).  
 
Hepatitis B reactivation 
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in 
acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see 
section 4.4). 



 53

 
In the Phase III dose-optimisation study in patients with chronic phase CML with resistance or 
intolerance to prior imatinib therapy (median duration of treatment of 30 months), the incidence of 
pleural 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 group 
was 37 months (range 1-91 months). Cumulative rates of selected adverse reactions that were reported 
in 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 (imatinib 

intolerant or resistant chronic phase CML)a 

 Minimum of 2 years follow up 
Minimum of 5 years 

follow up 
Minimum of 7 years 

follow up 
 All 

grades 
Grade 

3/4 
All 

grades 
Grade 

3/4 
All 

grades 
Grade 

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 
 Pulmonary 

hypertension 0 0 0 0 2 1 

Haemorrhage 11 1 11 1 12 1 
 Gastrointestinal 

bleeding 2 1 2 1 2 1 
a 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, the 
median 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 that 
were reported in the recommended starting dose of 140 mg once daily are shown in Table 6b. A 70 mg 
twice daily regimen was also studied. The 140 mg once daily regimen showed a comparable efficacy 
profile to the 70 mg twice daily regimen but a more favourable safety profile. 
 



 54

Table 6b: Selected adverse reactions reported in phase III dose-optimisation study: 
Advanced phase CML and Ph+ ALLa

 140 mg once daily 
n = 304

 All grades Grade 3/4 
 
Preferred term Percent (%) of patients 

Diarrhoea 28 3 
Fluid retention 33 7 
 Superficial oedema 15 < 1 
 Pleural effusion 20 6 
 Generalised oedema 2 0 
 Congestive heart failure 
 /cardiac dysfunctionb 

1 0 

 Pericardial effusion 2 1 
 Pulmonary oedema 1 1 
Haemorrhage 23 8 
 Gastrointestinal bleeding 8 6 

a 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 paediatric 
patients received SPRYCEL in combination with chemotherapy on a continuous dosing regimen. In a 
supportive study, of 55 paediatric patients, 35 received SPRYCEL in combination with chemotherapy 
on a discontinuous dosing regimen (two weeks on treatment followed by one to two weeks off) and 
20 received SPRYCEL in combination with chemotherapy on a continuous dosing regimen. Among 
the 126 Ph+ ALL paediatric patients treated with SPRYCEL on a continuous dosing regimen, the 
median 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%) experienced 
adverse reactions leading to treatment discontinuation. Adverse reactions reported in these two 
paediatric 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 not 
included in the table. 
 

Table 7: Adverse reactions reported in ≥10% of paediatric patients with Ph+ ALL treated 
with 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 0 

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



 55

 
Laboratory test abnormalities 
Haematology  
In the Phase III newly diagnosed chronic phase CML study, the following grade 3 or 4 laboratory 
abnormalities 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 months 
follow-up, the cumulative rates of neutropaenia, thrombocytopaenia, and anaemia were 29%, 22% and 
13%, respectively. 
 
In SPRYCEL-treated patients with newly diagnosed chronic phase CML who experienced 
grade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/or 
reductions and permanent discontinuation of treatment occurred in 1.6% of patients after a minimum 
of 12 months follow-up. After a minimum of 60 months follow-up the cumulative rate of permanent 
discontinuation 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 occurrence 
of cytopaenias was also clearly dependent on the stage of the disease. The frequency of 
grade 3 and 4 haematological abnormalities is presented in Table 8.  
 
Table 8: CTC grades 3/4 haematological laboratory abnormalities in clinical studies in 

patients with resistance or intolerance to prior imatinib therapya 
 

Chronic phase
(n= 165)b 

Accelerated 
phase 

(n= 157)c 

Myeloid 
blast phase

(n= 74)c 

Lymphoid blast 
phase and 
Ph+ ALL 
(n= 168)c 

 Percent (%) of patients 
Haematology parameters     
 Neutropaenia 36 58 77 76 
 Thrombocytopaenia 23 63 78 74 
 Anaemia 13 47 74 44 

a 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 at 2 
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 following 
brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 5% 
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 reported in 
4% of SPRYCEL-treated patients, and grade 3 or 4 elevations of transaminases, creatinine, and 
bilirubin were reported in ≤ 1% of patients after a minimum of 12 months follow-up. After a minimum 
of 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 transaminases 
remained 1%. There were no discontinuations of SPRYCEL therapy due to these biochemical 
laboratory parameters. 
 
2 year follow-up 
Grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% of patients with chronic 
phase CML (resistant or intolerant to imatinib), but elevations were reported with an increased 
frequency of 1 to 7% of patients with advanced phase CML and Ph+ ALL. It was usually managed 
with dose reduction or interruption. In the Phase III dose-optimisation study in chronic phase CML, 



 56

grade 3 or 4 elevations of transaminases or bilirubin were reported in ≤ 1% of patients with similar 
low 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% of 
patients across treatment groups. 
 
Approximately 5% of the SPRYCEL-treated patients who had normal baseline levels experienced 
grade 3 or 4 transient hypocalcaemia at some time during the course of the study. In general, there was 
no association of decreased calcium with clinical symptoms. Patients developing 
grade 3 or 4 hypocalcaemia often had recovery with oral calcium supplementation. 
Grade 3 or 4 hypocalcaemia, hypokalaemia, and hypophosphataemia were reported in patients with all 
phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid 
blast phase CML and Ph+ ALL. Grade 3 or 4 elevations in creatinine were reported in < 1% of 
patients with chronic phase CML and were reported with an increased frequency of 1 to 4% of patients 
with advanced phase CML. 
 
Paediatric population 
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 SPRYCEL administered in combination with chemotherapy in paediatric patients 
with Ph+ ALL was consistent with the known safety profile of SPRYCEL in adults and the expected 
effects of chemotherapy, with the 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 known 
profile for laboratory parameters in adults. 
 
In the paediatric ALL studies, the rates of laboratory abnormalities were consistent with the known 
profile for laboratory parameters in adults, within the context of an acute leukaemia patient receiving a 
background chemotherapy regimen. 
 
Special population 
While the safety profile of SPRYCEL in elderly was similar to that in the younger population, patients 
aged 65 years and older are more likely to experience the commonly reported adverse reactions such 
as fatigue, pleural effusion, dyspnoea, cough, lower gastrointestinal haemorrhage, and appetite 
disturbance and more likely to experience less frequently reported adverse reactions such as 
abdominal distention, dizziness, pericardial effusion, congestive heart failure, and weight decrease and 
should be monitored closely (see section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. The highest 
overdose of 280 mg per day for one week was reported in two patients and both developed a 
significant decrease in platelet counts. Since dasatinib is associated with 
grade 3 or 4 myelosuppression (see section 4.4), patients who ingest more than the recommended dose 
should be closely monitored for myelosuppression and given appropriate supportive treatment. 
 
 



 57

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE06 
 
Pharmacodynamics 
Dasatinib inhibits the activity of the BCR-ABL kinase and SRC family kinases along with a number of 
other selected oncogenic kinases including c-KIT, ephrin (EPH) receptor kinases, and PDGFβ 
receptor. Dasatinib is a potent, subnanomolar inhibitor of the BCR-ABL kinase with potency at 
concentration of 0.6-0.8 nM. It binds to both the inactive and active conformations of the BCR-ABL 
enzyme. 
 
Mechanism of action 
In vitro, dasatinib is active in leukaemic cell lines representing variants of imatinib-sensitive and 
resistant disease. These non-clinical studies show that dasatinib can overcome imatinib resistance 
resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate 
signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene 
overexpression. Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations. 
 
In vivo, in separate experiments using murine models of CML, dasatinib prevented the progression of 
chronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell lines 
grown at various sites, including the central nervous system. 
 
Clinical efficacy and safety 
In the Phase I study, haematologic and cytogenetic responses were observed in all phases of CML and 
in Ph+ ALL in the first 84 patients treated and followed for up to 27 months. Responses were durable 
across all phases of CML and Ph+ ALL.  
 
Four single-arm, uncontrolled, open-label Phase II clinical studies were conducted to determine the 
safety 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 was 
conducted in chronic phase patients who failed initial treatment with 400 or 600 mg imatinib. The 
starting dose was 70 mg dasatinib twice daily. Dose modifications were allowed for improving activity 
or management of toxicity (see section 4.2). 
Two randomised, open-label Phase III studies were conducted to evaluate the efficacy of dasatinib 
administered once daily compared with dasatinib administered twice daily. In addition, one 
open-label, randomised, comparative Phase III study was conducted in adult patients with newly 
diagnosed chronic phase CML. 
 
The efficacy of dasatinib is based on haematological and cytogenetic response rates. 
Durability of response and estimated survival rates provide additional evidence of dasatinib clinical 
benefit. 
 
A total of 2,712 patients were evaluated in clinical studies; of these 23% were ≥ 65 years of age and 
5% were ≥ 75 years of age.  
 
Chronic phase CML - Newly diagnosed 
An international open-label, multicentre, randomised, comparative Phase III study was conducted in 
adult 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 of 
confirmed complete cytogenetic response (cCCyR) within 12 months. Secondary endpoints included 
time in cCCyR (measure of durability of response), time to cCCyR, major molecular response (MMR) 
rate, time to MMR, progression free survival (PFS) and overall survival (OS). Other relevant efficacy 
results included CCyR and complete molecular response (CMR) rates. The study is ongoing. 
 



 58

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% and 
11% of patients 65 years of age or older, respectively), gender (women 44% and 37%, respectively), 
and race (Caucasian 51% and 55%; Asian 42% and 37%, respectively). At baseline, the distribution of 
Hasford Scores was similar in the SPRYCEL 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 and 
81% 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-treated 
patients and 5% of imatinib-treated patients. 
 
With a minimum of 60 months follow-up, 60% of patients randomised to the SPRYCEL group and 
63% 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-treated 
patients and 14% of imatinib-treated patients. 
 
Efficacy results are presented in Table 9. A statistically significantly greater proportion of patients in 
the SPRYCEL group achieved a cCCyR compared with patients in the imatinib group within the first 
12 months of treatment. Efficacy of SPRYCEL was consistently demonstrated across different 
subgroups, including age, gender, and baseline Hasford score.  



 59

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

 SPRYCEL 
n= 259 

imatinib 
n= 260 

p-value 

 Response rate (95% CI)  
Cytogenetic response    

within 12 months    
 cCCyRa  76.8% (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 months    
cCCyRa 80.3% 74.2%  
CCyRb 87.3% 82.3%  

within 36 months    
cCCyRa 82.6% 77.3%  
CCyRb 88.0% 83.5%  

within 48 months    
cCCyRa 82.6% 78.5%  
CCyRb 87.6% 83.8%  

within 60 months    
cCCyRa 83.0% 78.5%  
CCyRb 88.0% 83.8%  

Major molecular responsec    
12 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< 0.035 
 within 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=0.1983 
a Confirmed complete cytogenetic response (cCCyR) is defined as a response noted on two consecutive occasions (at least 

28 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 samples 

standardised on the International scale. These are cumulative rates representing minimum follow up for the timeframe 
specified. 

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



 60

After 60 months of follow-up, median time to cCCyR was 3.1 months in the SPRYCEL group and 
5.8 months in the imatinib group in patients with a confirmed CCyR. Median time to MMR after 
60 months of follow-up was 9.3 months in the SPRYCEL group and 15.0 months in the imatinib 
group 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 in 
dasatinib-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 consistent 
with 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 were 
consistently higher in dasatinib-treated patients compared with imatinib-treated patients. 
 

PR
O

PO
R

TI
O

N
 R

ES
PO

N
D

ER
S 



 61

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

 
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 was 
higher in the SPRYCEL group compared to the imatinib group (54.1% versus 45%). The proportion of 
patients 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 were 
consistently higher in dasatinib-treated patients compared with imatinib-treated patients. 
 

%
 w

ith
 M

M
R

 

By 1 year 
46%, p<.0001 

By 2 years 
64%, p<.0001 

By 3 years 
67%, p<.0055 

By 4 years 
73%, p<.0021 

By 5 years 
76%, p<.0022 



 62

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

 
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 of 
progression-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 

Dasatinib N = 235 
Patients with BCR-ABL 

≤ 10% at 3 months 
Patients with BCR-ABL > 

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 consistently 
higher in dasatinib treated patients who achieved BCR-ABL level ≤ 10% at 3 months than those who 
did not. 
 

%
 w

ith
 M

R
4.

5 

By 5 years 
42%, p<.0251 

By 1 year 
5%, p<.2394 

By 2 years 
19%, p<.0008 

By 3 years 
24%, p<.0013 

By 4 years 
34%, p<.0055 



 63

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 chronic 
phase 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 therapeutic 
management, loss of CHR, partial CyR or CCyR, progression to accelerated phase or blast phase, or 
death. The estimated 60-month PFS rate was 88.9% (CI: 84% - 92.4%) for both the dasatinib and 
imatinib treatment groups. At 60 months, transformation to accelerated or blast phase occurred in 
fewer dasatinib-treated patients (n=8; 3%) compared with imatinib-treated patients (n=15; 5.8%). The 
estimated 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 (HR 
1.01, 95% CI: 0.58-1.73, p= 0.9800) and PFS (HR 1.00, 95% CI: 0.58-1.72, p = 0.9998) between 
dasatinib and imatinib. 
 
In patients who report disease progression or discontinue dasatinib or imatinib therapy, BCR-ABL 
sequencing was performed on blood samples from patients where these are available. Similar rates of 
mutation were observed in both the treatment arms. The mutations detected among the 
dasatinib-treated patients were T315I, F317I/L and V299L. A different spectrum of mutation was 
detected 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 efficacy 
endpoint in these studies was Major Cytogenetic Response (MCyR).  
 
Study 1 
An open-label, randomised, non-comparative multicentre study was conducted in patients who failed 
initial treatment with 400 or 600 mg imatinib. They were randomised (2:1) to either dasatinib (70 mg 
twice daily) or imatinib (400 mg twice daily). Crossover to the alternative treatment arm was allowed 
if patients showed evidence of disease progression or intolerance that could not be managed by dose 
modification. The primary endpoint was MCyR at 12 weeks. Results are available for 150 patients: 
101 were randomised to dasatinib and 49 to imatinib (all imatinib-resistant). The median time from 
diagnosis to randomisation was 64 months in the dasatinib group and 52 months in the imatinib group. 
All patients were extensively pretreated. Prior complete haematologic response (CHR) to imatinib was 

PR
O

PO
R

TI
O

N
 A

LI
V

E 



 64

achieved in 93% of the overall patient population. A prior MCyR to imatinib was achieved in 28% and 
29% of the patients in the dasatinib and imatinib arms, respectively. 
Median duration of treatment was 23 months for dasatinib (with 44% of patients treated for 
> 24 months to date) and 3 months for imatinib (with 10% of patients treated for > 24 months to date). 
Ninety-three percent of patients in the dasatinib arm and 82% of patients in the imatinib arm achieved 
a 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 while 
only 8% achieved a CCyR in the imatinib arm. With longer treatment and follow-up (median of 
24 months), MCyR was achieved in 53% of the dasatinib-treated patients (CCyR in 44%) and 33% of 
the imatinib-treated patients (CCyR in 18%) prior to crossover. Among patients who had received 
imatinib 400 mg prior to study entry, MCyR was achieved in 61% of patients in the dasatinib arm and 
50% in the imatinib arm. 
Based on the Kaplan-Meier estimates, the proportion of patients who maintained MCyR for 1 year was 
92% (95% CI: [85%-100%]) for dasatinib (CCyR 97%, 95% CI: [92%-100%]) and 74% (95% CI: 
[49%-100%]) for imatinib (CCyR 100%). The proportion of patients who maintained MCyR for 
18 months was 90% (95% CI: [82%-98%]) for 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%]) for 
imatinib. The proportion of patients who had PFS at 2 years was 86% (95% CI: [78%-93%]) for 
dasatinib 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 of 
study medicinal product, etc.). 
 
The rate of major molecular response (defined as BCR-ABL/control transcripts ≤ 0.1% by RQ-PCR in 
peripheral blood samples) prior to crossover was 29% for dasatinib and 12% for imatinib. 
 
Study 2 
An open-label, single-arm, multicentre study was conducted in patients resistant or intolerant to 
imatinib (i.e. patients who experienced significant toxicity during treatment with imatinib that 
precluded further treatment). 
A total of 387 patients received dasatinib 70 mg twice daily (288 resistant and 99 intolerant). The 
median time from diagnosis to start of treatment was 61 months. The majority of the patients (53%) 
had received prior imatinib treatment for more than 3 years. Most resistant patients (72%) had 
received > 600 mg imatinib. In addition to imatinib, 35% of patients had received prior cytotoxic 
chemotherapy, 65% had received prior interferon, and 10% had received a prior stem cell transplant. 
Thirty-eight percent of patients had baseline mutations known to confer imatinib resistance. Median 
duration of treatment on 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 patients 
and 82% of imatinib-intolerant patients. With a minimum of 24 months follow-up, 21 of the 
240 patients who had achieved a MCyR had progressed and the median duration of MCyR had not 
been reached. 
 
Based on the Kaplan-Meier estimates, 95% (95% CI: [92%-98%]) of the patients maintained MCyR 
for 1 year and 88% (95% CI: [83%-93%]) maintained MCyR for 2 years. The proportion of patients 
who maintained CCyR for 1 year was 97% (95% CI: [94%-99%]) and for 2 years was 90% (95% CI: 
[86%-95%]). 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. Complete 
haematologic response or MCyR was achieved in patients harbouring a variety of BCR-ABL 
mutations associated with imatinib resistance except T315I. The rates of MCyR at 2 years were similar 



 65

whether patients had any baseline BCR-ABL mutation, P-loop mutation, or no mutation (63%, 61% 
and 62%, respectively). 
 
Among imatinib-resistant patients, the estimated rate of PFS was 88% (95% CI: [84%-92%]) at 1 year 
and 75% (95% CI: [69%-81%]) at 2 years. Among imatinib-intolerant patients, the estimated rate of 
PFS was 98% (95% CI: [95%-100%]) at 1 year and 94% (95% CI: [88%-99%]) at 2 years. 
 
The rate of major molecular response at 24 months was 45% (35% for imatinib-resistant patients and 
74% for imatinib-intolerant patients). 
 
Accelerated phase CML 
An open-label, single-arm, multicentre study was conducted in patients intolerant or resistant to 
imatinib. A total of 174 patients received dasatinib 70 mg twice daily (161 resistant and 13 intolerant 
to imatinib). The median time from diagnosis to start of treatment was 82 months. Median duration of 
treatment on dasatinib was 14 months with 31% of patients treated for > 24 months to date. The rate of 
major molecular response (assessed in 41 patients with a CCyR) was 46% at 24 months. Further 
efficacy results are reported in Table 11. 
 
Myeloid blast phase CML 
An open-label, single-arm, multicentre study was conducted in patients intolerant or resistant to 
imatinib. A total of 109 patients received dasatinib 70 mg twice daily (99 resistant and 10 intolerant to 
imatinib). The median time from diagnosis to start of treatment was 48 months. Median duration of 
treatment on dasatinib was 3.5 months with 12% of patients treated for > 24 months to date. The rate 
of major molecular response (assessed in 19 patients with a CCyR) was 68% at 24 months. Further 
efficacy 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 patients 
with lymphoid blast CML received dasatinib 70 mg twice daily (42 resistant and 6 intolerant to 
imatinib). The median time from diagnosis to start of treatment was 28 months. Median duration of 
treatment on dasatinib was 3 months with 2% treated for > 24 months to date. The rate of major 
molecular response (all 22 treated patients with a CCyR) was 50% at 24 months. In addition, 
46 patients with Ph+ ALL received dasatinib 70 mg twice daily (44 resistant and 2 intolerant to 
imatinib). The median time from diagnosis to start of treatment was 18 months. Median duration of 
treatment on dasatinib was 3 months with 7% of patients treated for > 24 months to date. The rate of 
major molecular response (all 25 treated patients with a CCyR) was 52% at 24 months. Further 
efficacy results are reported in Table 11. Of note, major haematologic responses (MaHR) were 
achieved quickly (most within 35 days of first dasatinib administration for patients with lymphoid 
blast CML, and within 55 days for patients with Ph+ ALL). 
 



 66

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

 Chronic 
(n= 387) 

Accelerated
(n= 174) 

Myeloid 
blast 

(n= 109) 

Lymphoid 
blast 

(n= 48) 
Ph+ ALL 
(n= 46) 

Haematologic response rateb (%) 
MaHR (95% CI) n/a 64% (57-72) 33% (24-43) 35% (22-51) 41% (27-57) 
 CHR (95% CI) 91% (88-94) 50% (42-58) 26% (18-35) 29% (17-44) 35% (21-50) 
 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 (%) 
MCyR (95% CI) 62% (57-67) 40% (33-48) 34% (25-44) 52% (37-67) 57% (41-71) 
 CCyR (95% CI) 54% (48-59) 33% (26-41) 27% (19-36) 46% (31-61) 54% (39-69) 
Survival (%; Kaplan-Meier estimates) 
Progression-Free  
 1 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) 
Overall  
 1 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 recommended 
starting 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) = complete 

haematologic response (CHR) + no evidence of leukaemia (NEL).  
CHR (chronic CML): WBC ≤ institutional ULN, platelets < 450,000/mm3, no blasts or promyelocytes in peripheral 
blood, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no 
extramedullary involvement. 
CHR (advanced CML/Ph+ ALL): WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts 
or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral 
blood, basophils in peripheral blood < 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 both 
complete 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 fully 
evaluated. 
 
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 administered 
once daily compared with dasatinib administered twice daily. Results described below are based on a 
minimum 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 of 
670 patients, of whom 497 were imatinib-resistant, were randomised to the dasatinib 100 mg once 
daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. The median duration of 
treatment for all patients still on therapy with a minimum of 5 years of follow-up (n=205) was 
59 months (range 28-66 months). Median duration of treatment for all patients at 7 years of follow-up 
was 29.8 months (range < 1-92.9 months).  
 
Efficacy was achieved across all dasatinib treatment groups with the once daily schedule 
demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary 
efficacy endpoint (difference in MCyR 1.9%; 95% confidence interval [-6.8% - 10.6%]); however, the 



 67

100 mg once daily regimen demonstrated improved safety and tolerability. Efficacy results are 
presented in Tables 12 and 13. 
 
Table 12: Efficacy of SPRYCEL in phase III dose-optimization study: imatinib resistant or 

intolerant 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 extramedullary 
involvement. 

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

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

 
Table 13: Long term efficacy of SPRYCEL in phase 3 dose optimisation study: imatinib resistant 

or intolerant chronic phase CML patientsa 
 Minimum follow-up period 
 1 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 including 
subsequent therapy. 

 
Based on the Kaplan-Meier estimates, the proportion of patients treated with dasatinib 100 mg once 
daily 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 patients 
who received 100 mg once daily, MCyR was achieved in 77% and CCyR in 67%.  
 



 68

Study 2 
In the study in advanced phase CML and Ph+ ALL, the primary endpoint was MaHR. A total of 
611 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 daily 
schedule 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 and 
tolerability. 
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 (n= 158) 
Myeloid blast 

(n= 75) 
Lymphoid blast 

(n= 33) 
Ph+ALL 
(n= 40) 

MaHRb 
(95% CI) 

66%  
(59-74) 

28%  
(18-40) 

42%  
(26-61) 

38% 
(23-54) 

CHRb 
(95% CI) 

47%  
(40-56) 

17%  
(10-28) 

21%  
(9-39) 

33% 
(19-49) 

NELb 
(95% CI) 

19%  
(13-26) 

11%  
(5-20) 

21%  
(9-39) 

5% 
(1-17) 

MCyRc 
(95% CI) 

39%  
(31-47) 

28%  
(18-40) 

52%  
(34-69) 

70% 
(54-83) 

CCyR 
(95% CI) 

32%  
(25-40) 

17%  
(10-28) 

39%  
(23-58) 

50% 
(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) = complete 

haematologic response (CHR) + no evidence of leukaemia (NEL). 
CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, no blasts or promyelocytes in 
peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in 
peripheral blood < 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 median 
duration of MaHR and the median overall survival was not reached and the median PFS was 
25 months. 
 
In patients with myeloid blast phase CML treated with the 140 mg once daily regimen, the median 
duration of MaHR was 8 months, the median PFS was 4 months, and the median overall survival was 
8 months. In patients with lymphoid blast phase CML treated with the 140 mg once daily regimen, the 
median duration of MaHR was 5 months, the median PFS was 5 months, and the median overall 
survival was 11 months. 
 
In patients with Ph+ ALL treated with the 140 mg once daily regimen, the median duration of MaHR 
was 5 months the median PFS was 4 months, and the median overall survival was 7 months. 
 
Paediatric population 
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 previous 
treatment 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. 
 



 69

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 period 
 3 months  6 months 12 months  24 months 

CCyR  
(95% CI)     
Newly diagnosed 
(N = 51)a 
 

43.1% 
(29.3, 57.8) 

66.7% 
(52.1, 79.2) 

96.1% 
(86.5, 99.5) 

96.1% 
(86.5, 99.5) 

Prior imatinib 
(N = 46)b 
 

45.7% 
(30.9, 61.0) 

71.7% 
(56.5, 84.0) 

78.3% 
(63.6, 89.1) 

82.6% 
(68.6, 92.2) 

MCyR  
(95% CI)     
Newly diagnosed 
(N = 51)a 
 

60.8% 
(46.1, 74.2) 

90.2% 
(78.6, 96.7) 

98.0% 
(89.6, 100) 

98.0% 
(89.6, 100) 

Prior imatinib 
(N = 46)b 
 

60.9% 
(45.4, 74.9) 

82.6% 
(68.6, 92.2) 

89.1% 
(76.4, 96.4) 

89.1% 
(76.4, 96.4) 

MMR  
(95% CI) 

    

Newly diagnosed 
(N = 51)a 
 

7.8% 
(2.2, 18.9) 

31.4% 
(19.1, 45.9) 

56.9% 
(42.2, 70.7) 

74.5% 
(60.4, 85.7) 

Prior imatinib 
(N = 46)b 
 

15.2% 
(6.3, 28.9) 

26.1% 
(14.3, 41.1) 

39.1% 
(25.1, 54.6) 

52.2% 
(36.9, 67.1) 

a Patients from Phase II paediatric study of newly diagnosed CML-CP receiving oral tablet formulation 
b Patients from Phase I and Phase II paediatric studies of imatinib-resistant or intolerant CML-CP receiving oral tablet 

formulation 
 
In the Phase I paediatric study, after a minimum of 7 years of follow-up among the 17 patients with 
imatinib-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 PFS 
rate 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 intolerant 
patients progressed to blast phase CML. 
 
There were 33 newly diagnosed paediatric patients with CML-CP who received SPRYCEL powder 
for oral suspension at a dose of 72 mg/m2. This dose represents 30% lower exposure compared to the 
recommended dose (see section 5.2). 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 mutations 
detected at the end of treatment were: T315A, E255K and F317L. However, E255K and F317L were 
also detected prior to treatment. There were no mutations detected in newly diagnosed CML-CP 
patients at the end of treatment. 
 
Paediatric patients with ALL 
The efficacy of SPRYCEL in combination with chemotherapy was evaluated in a pivotal study in 
paediatric patients over one year of age with newly diagnosed Ph+ ALL. 



 70

 
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 to 
24 months, in combination with chemotherapy. Eighty-two patients received dasatinib tablets 
exclusively and 24 patients received dasatinib powder for oral suspension at least once, 8 of whom 
received dasatinib powder for oral suspension exclusively. The backbone chemotherapy regimen was 
the same as used in the AIEOP-BFM ALL 2000 trial (chemotherapeutic standard multi-agent 
chemotherapy protocol). The primary efficacy endpoint was 3-year event-free survival (EFS), which 
was 65.5% (55.5, 73.7).  
 
The minimal residual disease (MRD) negativity rate assessed by Ig/TCR rearrangement was 71.7% by 
the end of consolidation in all treated patients. When this rate was based on the 85 patients with 
evaluable Ig/TCR assessments, the estimate was 89.4%. The MRD negativity rates at the end of 
induction and consolidation as measured by flow cytometry were 66.0% and 84.0%, respectively. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of dasatinib were evaluated in 229 adult healthy subjects and in 84 patients. 
 
Absorption 
Dasatinib is rapidly absorbed in patients following oral administration, with peak concentrations 
between 0.5-3 hours. Following oral administration, the increase in the mean exposure (AUCτ) is 
approximately proportional to the dose increment across doses ranging from 25 mg to 120 mg twice 
daily. 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 a 
high-fat meal indicated a 14% increase in the mean AUC of dasatinib. A low-fat meal 30 minutes prior 
to dasatinib resulted in a 21% increase in the mean AUC of dasatinib. The observed food effects do 
not represent clinically relevant changes in exposure. Dasatinib exposure variability is higher under 
fasted 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 be 
mainly due to inter-occasion variability in bioavailability (44% CV) and, to a lesser extent, due to 
inter-individual variability in bioavailability and inter-individual variability in clearance (30% and 
32% CV, respectively). The random inter-occasion variability in exposure is not expected to affect the 
cumulative exposure and efficacy or safety. 
 
Distribution 
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 extravascular 
space. At clinically relevant concentrations of dasatinib, binding to plasma proteins was approximately 
96% on the basis of in vitro experiments. 
 
Biotransformation 
Dasatinib is extensively metabolised in humans with multiple enzymes involved in the generation of 
the metabolites. In healthy subjects administered 100 mg of [14C]-labelled dasatinib, unchanged 
dasatinib represented 29% of circulating radioactivity in plasma. Plasma concentration and measured 
in vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observed 
pharmacology of the product. CYP3A4 is a major enzyme responsible for the metabolism of dasatinib. 
 
Elimination 
The mean terminal half-life of dasatinib is 3 hours to 5 hours. The mean apparent oral clearance is 
363.8 L/hr (CV% 81.3%). 
 



 71

Elimination is predominantly in the faeces, mostly as metabolites. Following a single oral dose of 
[14C]-labelled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 
85% of the radioactivity recovered in the urine and faeces, respectively. Unchanged dasatinib 
accounted for 0.1% and 19% of the dose in urine and faeces, respectively, with the remainder of the 
dose as metabolites. 
 
Hepatic and renal impairment 
The effect of hepatic impairment on the single-dose pharmacokinetics of dasatinib was assessed in 8 
moderately hepatic-impaired subjects who received a 50 mg dose and 5 severely hepatic-impaired 
subjects who received a 20 mg dose compared to matched healthy subjects who received a 70 mg dose 
of dasatinib. The mean Cmax and AUC of dasatinib adjusted for the 70 mg dose were decreased by 47% 
and 8%, respectively, in subjects with moderate hepatic impairment compared to subjects with normal 
hepatic function. In severely hepatic-impaired subjects, the mean Cmax and AUC adjusted for the 
70 mg dose were decreased by 43% and 28%, respectively, compared to subjects with normal hepatic 
function (see sections 4.2 and 4.4). 
 
Dasatinib and its metabolites are minimally excreted via the kidney. 
 
Paediatric population  
The pharmacokinetics of dasatinib have been evaluated in 104 paediatric patients with leukaemia or 
solid tumours (72 who received the tablet formulation and 32 who received the powder for oral 
suspension). 
 
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. 
 
A bioequivalence study evaluating the powder for oral suspension to the reference tablet formulation 
in 77 adult patients showed that the exposure for the powder for oral suspension was 19% less than 
that of reference tablets. Concentration data in 32 paediatric patients treated with the powder for oral 
suspension dose of 72 mg/m2 was pooled with data from the tablet for a population pharmacokinetic 
(PPK) analysis, which showed that the exposure of the powder for oral suspension (as measured by 
time-averaged concentration at steady state [Cavgss]) at 72 mg/m2 was approximately 30% lower than 
that of the tablet at 60 mg/m2. A PPK model-based simulation predicted that the body weight tiered 
dosing recommendation described for the powder for oral suspension, in section 4.2 of the Summary 
of Product Characteristics for the powder for oral suspension, is expected to provide similar exposure 
to a tablet dose of 60 mg/m2. These data should be considered if patients are to switch from powder for 
oral suspension to tablets or vice versa. 
 
5.3 Preclinical safety data 
 
The non-clinical safety profile of dasatinib was assessed in a battery of in vitro and in vivo studies in 
mice, 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 target 
organ. In rats, minimal to mild decreases in erythrocyte parameters were accompanied by bone 
marrow changes; similar changes occurred in monkeys at a lower incidence. Lymphoid toxicity in rats 
consisted of lymphoid depletion of the lymph nodes, spleen, and thymus, and decreased lymphoid 
organ weights. Changes in the gastrointestinal, haematopoietic and lymphoid systems were reversible 
following cessation of treatment. 
 
Renal changes in monkeys treated for up to 9 months were limited to an increase in background 
kidney mineralisation. Cutaneous haemorrhage was observed in an acute, single-dose oral study in 
monkeys but was not observed in repeat-dose studies in either monkeys or rats. In rats, dasatinib 
inhibited platelet aggregation in vitro and prolonged cuticle bleeding time in vivo, but did not invoke 
spontaneous haemorrhage. 
 



 72

Dasatinib activity in vitro in hERG and Purkinje fiber assays suggested a potential for prolongation of 
cardiac ventricular repolarisation (QT interval). However, in an in vivo single-dose study in conscious 
telemetered 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 an 
in 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 embryonic 
development study, but induced embryolethality at dose levels approximating human clinical 
exposures. In embryofoetal development studies, dasatinib likewise induced embryolethality with 
associated 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 a 
selective reproductive toxicant from implantation through the completion of organogenesis. 
 
In mice, dasatinib induced immunosuppression, which was dose-related and effectively managed by 
dose reduction and/or changes in dosing schedule. Dasatinib had phototoxic potential in an in vitro 
neutral red uptake phototoxicity assay in mouse fibroblasts. Dasatinib was considered to be 
non-phototoxic in vivo after a single oral administration to female hairless mice at exposures up to 
3-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, and 
3 mg/kg/day. The highest dose resulted in a plasma exposure (AUC) level generally equivalent to the 
human exposure at the recommended range of starting doses from 100 mg to 140 mg daily. A 
statistically significant increase in the combined incidence of squamous cell carcinomas and 
papillomas in the uterus and cervix of high-dose females and of prostate adenoma in low-dose males 
was noted. The relevance of the findings from the rat carcinogenicity study for humans is not known. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients  
 
Sucrose 
Carmellose sodium 
Simethicone emulsion  
consisting of:  

simeticone,  
polyethylene glycol sorbitan tristearate,  
polyethoxylate stearate,  
glycerides,  
methylcellulose,  
xanthan gum,  
benzoic acid,  
sorbic acid,  
sulfuric acid. 

Tartaric acid 
Trisodium citrate anhydrous 
Sodium benzoate (E211) 
Silica hydrophobic colloidal 
Mixed berry flavour [containing benzyl alcohol, sulphur dioxide (E220)] 
 
6.2 Incompatibilities 
 
Not applicable. 
 



 73

6.3 Shelf life 
 
Unopened bottle 
2 years. 
 
After constitution 
The oral suspension is stable for 60 days. Store in a refrigerator (2°C - 8°C). Do not freeze.  
 
Constituted oral suspension mixed with milk, yogurt, apple juice, or applesauce may be stored at or 
below 25°C for up to 1 hour. 
 
6.4 Special precautions for storage 
 
Store below 25°C. 
 
For storage conditions after constitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
120-mL high-density polyethylene bottle with polypropylene child-resistant closure containing 33 g of 
powder for oral suspension. 
 
Pack size: 1 bottle 
 
Each pack also contains a low-density polyethylene press-in-bottle adapter (PIBA) and a 12-mL oral 
dosing syringe (polypropylene syringe barrel with high-density polyethylene syringe plunger rod) in a 
sealed plastic bag. 
 
6.6 Special precautions for disposal and other handling 
 
SPRYCEL powder for oral suspension must be constituted by a pharmacist or qualified healthcare 
professional prior to being dispensed to the patient. The powder for oral suspension consists of powder 
blend with the active substance plus excipients, contained within a bottle for constitution. Once 
constituted, the bottle contains 99 mL of oral suspension, of which 90 mL is intended for dosing and 
administration.  
 
The use of latex or nitrile gloves is recommended when handling any powder that is inadvertently 
spilled from the bottle, for appropriate disposal in order to minimise the risk of dermal exposure. 
 
Instructions for constitution of powder for oral suspension  
 
SPRYCEL powder for oral suspension is to be constituted as follows: 
Note: If you have to constitute more than one bottle, complete one bottle at a time.  
Wash your hands before initiating the constitution. This procedure should be performed on a clean 
surface. 
 
Step 1: Tap bottom of each bottle (containing 33 g SPRYCEL powder for oral suspension) gently to 
loosen the powder. Remove child-resistant closure and foil seal. Add 77.0 mL of purified water all at 
once to the bottle and close tightly with closure. 
Step 2: Immediately invert the bottle and shake vigorously for no less than 60 seconds to obtain a 
uniform suspension. If there are still visible clumps, continue shaking until no clumps are visible. 



 74

Constitution in this way produces 90 mL (deliverable volume) of 10 mg/mL SPRYCEL oral 
suspension. 
Step 3: Remove the closure, insert the press-in bottle adapter (PIBA) into the bottle neck, and close the 
bottle tightly with the child-resistant closure. 
Step 4: Write the date of expiry of the constituted oral suspension on the bottle label (the date of 
expiry of the constituted oral suspension is 60 days from the date of constitution).  
Step 5: Dispense the bottle with inserted PIBA, package leaflet, and oral dosing syringe in the original 
carton to the patient or caregiver. Remind the patient or caregiver to shake the bottle vigorously prior 
to each use. 
 
Instructions for administration to the patient 
 Take SPRYCEL oral suspension on an empty or full stomach.  
 Wash your hands before and after each use. 
 Store the constituted oral suspension in a refrigerator (2°C - 8°C). Do not freeze. 
 Review total prescribed dose and determine number of milliliters (mL) you will need.  
 If the amount needed is greater than 11 mL, it must be split into 2 doses as indicated in Table 16. 
 
Table 16:  How to split a dose of oral suspension that is greater than 11 mL 
 

Total prescribed dose (mL) First dose (mL) Second dose (mL) 
12 6 6 
13 7 6 
14 7 7 
15 8 7 
16 8 8 

 
Before you prepare a dose of SPRYCEL oral suspension for administration to the patient, get the 
following supplies ready: 
 

 Paper towel 
 1 SPRYCEL oral 

suspension bottle 
containing a white 
to yellow opaque 
suspension. 

 12-mL oral syringe 
provided with the 
bottle. 

 A small container 
filled with water to 
use to rinse the 
syringe. 

 

 
 

oral syringe bottle 



 75

Carefully prepare the SPRYCEL oral suspension for administration, measure the dose, and fill the 
syringe, like this: 
 

1. Mix the SPRYCEL oral 
suspension in the closed bottle 
by shaking for 30 seconds. 

 
 Shake well before each 

use. 

 
 

2. Remove the closure from 
the bottle. Make sure the 
adapter provided on the bottle 
for syringe placement is firmly 
pressed into the bottle. 

 
 

3. Look at the measurements 
on the side of the syringe so 
you can see how much to fill it 
before you begin. Note that the 
markings on the syringe are in 
mL. Find the marking that 
matches the dose that was 
prescribed by your doctor. 
Before each use, make sure the 
syringe plunger is pushed to 
the bottom of the syringe 
barrel. 

 
 

Shake  
bottle 
repeatedly 
for 30 
seconds. 

Make 
sure 
bottle 
adapter 
is firmly 
pressed. 



 76

4. With the bottle in an upright 
position, insert the tip of the 
syringe firmly into the bottle 
adapter. 

 
 

5. Holding the syringe tip 
firmly into the bottle, turn the 
bottle with the syringe upside 
down. 

 
 

6. Slowly withdraw the 
amount of SPRYCEL oral 
suspension prescribed by 
pulling the syringe plunger 
until it reaches the marking of 
the dose prescribed. 
 Hold plunger to prevent it 

from moving. There may 
be a vacuum pulling the 
plunger back into barrel. 

 If unable to fill with one 
bottle, use the second 
bottle to complete the full 
prescribed dose. Make 
sure the second bottle is 
shaken before use. 

 
 

 



 77

7. Holding the syringe tip 
firmly in the bottle, turn the 
bottle with the syringe upright 
again. 

 
 

8. Remove the syringe from 
the bottle being careful not to 
depress the plunger. 

 
 

9. With the patient in an 
upright position, place the tip 
of the syringe into the mouth 
between the side of the mouth 
and the tongue. Slowly push 
the plunger down until all of 
the dose has been given. 
 Check to make sure the 

patient has swallowed all 
of the dose. 

 If a second dose is needed 
to complete the total 
prescribed dose, repeat 
steps 3 through 10.  

 Put closure back on the 
bottle and close tightly. 
Store upright. 

 



 78

10. Wash the outside 
and the inside of the 
syringe with water 
and allow to air dry 
after each use to re-
use for the next day.  

 

 Do not wash in a 
dishwasher. 
 

 Do not take the 
syringe apart in 
order to avoid 
damaging it. 

 
 
11. Refer to the 
package leaflet (see 
section 5 ‘How to 
store SPRYCEL’) for 
instructions on 
discarding any 
unused medicine, 
syringe and bottle. 

 
 

Once constituted, the oral suspension should only be administered using the oral dosing syringe 
supplied with each pack. Refer to the package leaflet for more detailed instructions for use. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/363/016 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 November 2006 
Date of latest renewal: 15 July 2016 

DO NOT USE A 
DISHWASHER 

ALLOW TO 
AIR DRY AFTER 

EACH USE 

DO NOT 
TAKE APART 
THE SYRINGE 



 79

 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

  



 80

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



 81

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
SPRYCEL film-coated tablets  
Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc 
Strada Provinciale 12 Casilina, 41 
03012 Anagni (FR) 
Italy 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
SPRYCEL 10 mg/mL powder for oral suspension 
Swords Laboratories T/A Lawrence Laboratories 
Unit 12 & 15, Distribution Centre  
Shannon Industrial Estate  
Shannon, Co. Clare, V14 DD39 
Ireland 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE 

AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
 At the request of the European Medicines Agency, 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached.  



 82

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



 83

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 84

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR BOTTLE PACK 
OUTER CARTON FOR BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 20 mg film-coated tablets 
dasatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 20 mg dasatinib (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: contains lactose monohydrate. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets 
60 x 1 film-coated tablets 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



 85

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/363/004 - 56 film-coated tablets (blisters) 
EU/1/06/363/007 - 60 x 1 film-coated tablets (unit dose blisters) 
EU/1/06/363/001 - 60 film-coated tablets (bottle) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
sprycel 20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Outer Carton: 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Outer Carton: 
PC: 
SN: 
NN: 



 86

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 20 mg tablets 
dasatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
calendar pack: 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday  



 87

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR BOTTLE PACK 
OUTER CARTON FOR BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 50 mg film-coated tablets 
dasatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 50 mg dasatinib (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: contains lactose monohydrate. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets 
60 x 1 film-coated tablets 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



 88

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/363/005 - 56 film-coated tablets (blisters) 
EU/1/06/363/008 - 60 x 1 film-coated tablets (unit dose blisters) 
EU/1/06/363/002 - 60 film-coated tablets (bottle) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
sprycel 50 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Outer Carton: 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Outer Carton: 
PC: 
SN: 
NN: 



 89

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 50 mg tablets 
dasatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
calendar pack: 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 



 90

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR BOTTLE PACK 
OUTER CARTON FOR BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 70 mg film-coated tablets 
dasatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 70 mg dasatinib (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: contains lactose monohydrate. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets 
60 x 1 film-coated tablets 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



 91

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/363/006 - 56 film-coated tablets (blisters) 
EU/1/06/363/009 - 60 x 1 film-coated tablets (unit dose blisters) 
EU/1/06/363/003 - 60 film-coated tablets (bottle) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
sprycel 70 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Outer Carton: 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Outer Carton: 
PC: 
SN: 
NN: 



 92

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 70 mg tablets 
dasatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
calendar pack: 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 



 93

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR BOTTLE PACK 
OUTER CARTON FOR BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 80 mg film-coated tablets 
dasatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 80 mg dasatinib (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: contains lactose monohydrate. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 x 1 film-coated tablets 
30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



 94

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/06/363/013 - 30 x 1 film-coated tablets (unit dose blisters) 
EU/1/06/363/012 - 30 film-coated tablets (bottle) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
sprycel 80 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Outer Carton: 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Outer Carton: 
PC: 
SN: 
NN: 



 95

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 80 mg tablets 
dasatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



 96

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR BOTTLE PACK 
OUTER CARTON FOR BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 100 mg film-coated tablets 
dasatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg dasatinib (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: contains lactose monohydrate. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 x 1 film-coated tablets 
30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



 97

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/06/363/011 - 30 x 1 film-coated tablets (unit dose blisters) 
EU/1/06/363/010 - 30 film-coated tablets (bottle) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
sprycel 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Outer Carton: 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Outer Carton: 
PC: 
SN: 
NN: 



 98

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 100 mg tablets 
dasatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



 99

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR BOTTLE PACK 
OUTER CARTON FOR BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 140 mg film-coated tablets 
dasatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 140 mg dasatinib (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: contains lactose monohydrate. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 x 1 film-coated tablets 
30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



 100

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/06/363/015 - 30 x 1 film-coated tablets (unit dose blisters) 
EU/1/06/363/014 - 30 film-coated tablets (bottle) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
sprycel 140 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Outer Carton: 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Outer Carton: 
PC: 
SN: 
NN: 
 



 101

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 140 mg tablets 
dasatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BRISTOL-MYERS SQUIBB PHARMA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 
  



 102

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR BOTTLE PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SPRYCEL 10 mg/mL powder for oral suspension 
dasatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One bottle of powder for oral suspension contains 990 mg of dasatinib (as monohydrate). 
After constitution, one bottle contains 99 mL of oral suspension. Each mL of oral suspension contains 
10 mg of dasatinib (as monohydrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: contains sucrose, sodium, sodium benzoate, benzoic acid, benzyl alcohol and sulphur 
dioxide (E220). 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for oral suspension 
Outer Carton: 
1 bottle of 33 g powder 
1 bottle adapter 
1 oral syringe 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For oral use after constitution. 
After constitution, shake bottle well before each use. 
Use the oral syringe included in the package. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 



 103

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Powder: Store below 25°C. 
After constitution: Store in a refrigerator. Do not freeze. Discard any unused suspension 60 days after 
constitution. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/06/363/016 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Outer Carton: 
sprycel 10 mg/mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Outer Carton: 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Outer Carton: 
PC:  



 104

SN:  
NN: 
 
 
  



 105

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 106

Package leaflet: Information for the user 
 

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 

dasatinib 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects , talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.  
 
What is in this leaflet 
 
1. What SPRYCEL is and what it is used for 
2. What you need to know before you take SPRYCEL 
3. How to take SPRYCEL 
4. Possible side effects 
5. How to store SPRYCEL 
6. Contents of the pack and other information 
 
 
1. What SPRYCEL is and what it is used for 
 
SPRYCEL contains the active substance dasatinib. This medicine is used to treat chronic myeloid 
leukaemia (CML) in adults, adolescents and children at least 1 year of age. Leukaemia is a cancer of 
white blood cells. These white cells usually help the body to fight infection. In people with CML, 
white cells called granulocytes start growing out of control. SPRYCEL inhibits the growth of these 
leukaemic cells. 
 
SPRYCEL is also used to treat Philadelphia chromosome positive (Ph+) acute lymphoblastic 
leukaemia (ALL) in adults, adolescents and children at least 1 year of age, and lymphoid blast CML in 
adults who are not benefiting from prior therapies. In people with ALL, white cells called lymphocytes 
multiply too quickly and live too long. SPRYCEL inhibits the growth of these leukaemic cells. 
 
If you have any questions about how SPRYCEL works or why this medicine has been prescribed for 
you, ask your doctor. 
 
 
2. What you need to know before you take SPRYCEL 
 
Do not take SPRYCEL 
 if you are allergic to dasatinib or any of the other ingredients of this medicine (listed in 

section 6). 
If you could be allergic, ask your doctor for advice. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before using SPRYCEL  
 if you are taking medicines to thin the blood or prevent clots (see "Other medicines and 

SPRYCEL") 



 107

 if you have a liver or heart problem, or used to have one 
 if you start having difficulty breathing, chest pain, or a cough when taking SPRYCEL: this 

may be a sign of fluid retention in the lungs or chest (which can be more common in patients 
aged 65 years and older), or due to changes in the blood vessels supplying the lungs 

 if you have ever had or might now have a hepatitis B infection. This is because SPRYCEL 
could cause hepatitis B to become active again, which can be fatal in some cases. Patients will 
be carefully checked by their doctor for signs of this infection before treatment is started. 

 if you experience bruising, bleeding, fever, fatigue and confusion when taking SPRYCEL, 
contact your doctor. This may be a sign of damage to blood vessels known as thrombotic 
microangiopathy (TMA). 

 
Your doctor will regularly monitor your condition to check whether SPRYCEL is having the desired 
effect. You will also have blood tests regularly while you are taking SPRYCEL. 
 
Children and adolescents 
Do not give this medicine to children younger than one year of age. There is limited experience with 
the use of SPRYCEL in this age group. Bone growth and development will be closely monitored in 
children taking SPRYCEL. 
 
Other medicines and SPRYCEL 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
SPRYCEL is mainly handled by the liver. Certain medicines may interfere with the effect of 
SPRYCEL when taken together. 
 
These medicines are not to be used with SPRYCEL: 
 ketoconazole, itraconazole - these are antifungal medicines 
 erythromycin, clarithromycin, telithromycin - these are antibiotics 
 ritonavir - this is an antiviral medicine 
 phenytoin, carbamazepine, phenobarbital - these are treaments for epilepsy 
 rifampicin - this is a treatment for tuberculosis 
 famotidine, omeprazole - these are medicines that block stomach acids 
 St. John’s wort - a herbal preparation obtained without a prescription, used to treat depression 

and other conditions (also known as Hypericum perforatum) 
 
Do not take medicines that neutralise stomach acids (antacids such as aluminium hydroxide or 
magnesium hydroxide) in the 2 hours before or 2 hours after taking SPRYCEL. 
 
Tell your doctor if you are taking medicines to thin the blood or prevent clots. 
 
SPRYCEL with food and drink 
Do not take SPRYCEL with grapefruit or grapefruit juice. 
 
Pregnancy and breast-feeding 
If you are pregnant or think you may be pregnant, tell your doctor immediately. SPRYCEL is not 
to be used during pregnancy unless clearly necessary. Your doctor will discuss with you the 
potential risk of taking SPRYCEL during pregnancy. 
Both men and women taking SPRYCEL will be advised to use effective contraception during 
treatment. 
 
If you are breast-feeding, tell your doctor. You should stop breast-feeding while you are taking 
SPRYCEL. 
 
Driving and using machines 
Take special care when driving or using machines in case you experience side effects such as dizziness 
and blurred vision. 
 



 108

SPRYCEL contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor 
before taking this medicine. 
 
 
3. How to take SPRYCEL 
 
SPRYCEL will only be prescribed to you by a doctor with experience in treating leukaemia. Always 
take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure. SPRYCEL is prescribed for adults and children at least 1 year of age. 
 
The starting dose recommended for adult patients with chronic phase CML is 100 mg once a 
day. 
 
The starting dose recommended for adult patients with accelerated or blast crisis CML or Ph+ 
ALL is 140 mg once a day. 
 
Dosing for children with chronic phase CML or Ph+ ALL is on the basis of body weight. 
SPRYCEL is administered orally once daily in the form of either SPRYCEL tablets or SPRYCEL 
powder for oral suspension. SPRYCEL tablets are not recommended for patients weighing less than 
10 kg. The powder for oral suspension should be used for patients weighing less than 10 kg and 
patients who cannot swallow tablets. A change in dose may occur when switching between 
formulations (i.e., tablets and powder for oral suspension), so you should not switch from one to the 
other. 
 
Your doctor will decide the right formulation and dose based on your weight, any side effects and 
response to treatment. The starting dose of SPRYCEL for children is calculated by body weight as 
shown below: 
 
Body Weight (kg)a Daily Dose (mg)
10 to less than 20 kg 40 mg 
20 to less than 30 kg 60 mg 
30 to less than 45 kg 70 mg 
at least 45 kg 100 mg 

a The tablet is not recommended for patients weighing less than 10 kg; the powder for oral suspension should be used for these 
patients. 

 
There is no dose recommendation for SPRYCEL with children under 1 year of age.  
 
Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose, or 
even stopping treatment briefly. For higher or lower doses, you may need to take combinations of the 
different tablet strengths. 
 
The tablets may come in packs with calendar blisters. These are blisters showing the days of the 
week. There are arrows to show the next tablet to be taken according to your treatment schedule. 
 
How to take SPRYCEL 
Take your tablets at the same time every day. Swallow the tablets whole. Do not crush, cut or 
chew them. Do not take dispersed tablets. You cannot be sure you will receive the correct dose if you 
crush, cut, chew or disperse the tablets. SPRYCEL tablets can be taken with or without a meal. 
 
Special handling instructions for SPRYCEL 
It is unlikely that the SPRYCEL tablets will get broken. But if they do, persons other than the patient 
should use gloves when handling SPRYCEL. 
 
How long to take SPRYCEL 
Take SPRYCEL daily until your doctor tells you to stop. Make sure you take SPRYCEL for as long as 
it is prescribed. 



 109

 
If you take more SPRYCEL than you should 
If you have accidentally taken too many tablets, talk to your doctor immediately. You may require 
medical attention. 
 
If you forget to take SPRYCEL 
Do not take a double dose to make up for a forgotten tablet. Take the next scheduled dose at the 
regular time. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
 The following can all be signs of serious side effects: 
 if you have chest pain, difficulty breathing, coughing and fainting 
 if you experience unexpected bleeding or bruising without having an injury 
 if you find blood in your vomit, stools or urine, or have black stools 
 if you get signs of infections such as fever, severe chills 
 if you get fever, sore mouth or throat, blistering or peeling of your skin and/or mucous 

membranes 
Contact your doctor immediately if you notice any of the above. 
 
Very common side effects (may affect more than 1 in 10 people) 
 Infections (including bacterial, viral and fungal) 
 Heart and lungs: shortness of breath 
 Digestive problems: diarrhoea, feeling or being sick (nausea, vomiting) 
 Skin, hair, eye, general: skin rash, fever, swelling around the face, hands and feet, headache, 

feeling tired or weak, bleeding 
 Pain: pain in the muscles (during or after discontinuing treatment), tummy (abdominal) pain 
 Tests may show: low blood platelet count, low white blood cells count (neutropaenia), 

anaemia, fluid around the lungs 
 
Common side effects (may affect up to 1 in 10 people) 
 Infections: pneumonia, herpes virus infection (including cytomegalovirus - CMV), upper 

respiratory tract infection, serious infection of the blood or tissues (including uncommon cases 
with fatal outcomes) 

 Heart and lungs: palpitations, irregular heartbeat, congestive heart failure, weak heart muscle, 
high blood pressure, increased blood pressure in the lungs, cough 

 Digestive problems: appetite disturbances, taste disturbance, bloated or distended tummy 
(abdomen), inflammation of the colon, constipation, heartburn, mouth ulceration, weight 
increase, weight decrease, gastritis 

 Skin, hair, eye, general: skin tingling, itching, dry skin, acne, inflammation of the skin, 
persistent noise in ears, hair loss, excessive perspiration, visual disorder (including blurred 
vision and disturbed vision), dry eye, bruise, depression, insomnia, flushing, dizziness, 
contusion (bruising), anorexia, somnolence, generalised oedema 

 Pain: pain in joints, muscular weakness, chest pain, pain around hands and feet, chills, stiffness 
in muscles and joints, muscle spasm 

 Tests may show: fluid around the heart, fluid in the lungs, arrhythmia, febrile neutropaenia, 
gastrointestinal bleeding, high uric acid levels in the blood 

 
Uncommon side effects (may affect up to 1 in 100 people) 
 Heart and lungs: heart attack (including fatal outcome), inflammation of the lining (fibrous 

sack) surrounding the heart, irregular heartbeat, chest pain due to lack of blood supply to the 



 110

heart (angina), low blood pressure, narrowing of airway that may cause breathing difficulties, 
asthma, increased blood pressure in the arteries (blood vessels) of the lungs 

 Digestive problems: inflammation of the pancreas, peptic ulcer, inflammation of the food pipe, 
swollen tummy (abdomen), tear in the skin of the anal canal, difficulty in swallowing, 
inflammation of the gallbladder, blockage of bile ducts, gastro-oesophageal reflux (a condition 
where acid and other stomach contents come back up into the throat) 

 Skin, hair, eye, general: allergic reaction including tender, red lumps on the skin (erythema 
nodosum), anxiety, confusion, mood swings, lower sexual drive, fainting, tremor, inflammation 
of the eye which causes redness or pain, a skin disease characterized by tender, red, 
well-defined blotches with the sudden onset of fever and raised white blood cell count 
(neutrophilic dermatosis), loss of hearing, sensitivity to light, visual impairment, increased eye 
tearing, disturbance in skin colour, inflammation of fatty tissue under the skin, skin ulcer, 
blistering of the skin, nail disorder, hair disorder, hand-foot disorder, renal failure, urinary 
frequency, breast enlargement in men, menstrual disorder, general weakness and discomfort, 
low thyroid function, losing balance while walking, osteonecrosis (a disease of reduced blood 
flow to the bones, which can cause bone loss and bone death), arthritis, skin swelling anywhere 
in the body 

 Pain: inflammation of vein which can cause redness, tenderness and swelling, inflammation of 
the tendon 

 Brain: loss of memory 
 Tests may show: abnormal blood test results and possibly impaired kidney function caused by 

the waste products of the dying tumour (tumour lysis syndrome), low levels of albumin in the 
blood, low levels of lymphocytes (a type of white blood cell) in the blood, high level of 
cholesterol in the blood, swollen lymph nodes, bleeding in the brain, irregularity of the electrical 
activity of the heart, enlarged heart, inflammation of the liver, protein in the urine, raised 
creatine phosphokinase (an enzyme mainly found in the heart, brain and skeletal muscles), 
raised troponin (an enzyme mainly found in the heart and skeletal muscles), raised 
gamma-glutamyltransferase (an enzyme mainly found in the liver) 

 
Rare side effects (may affect up to 1 in 1,000 people) 
 Heart and lungs: enlargement of the right ventricle in the heart, inflammation of the heart 

muscle, collection of conditions resulting from blockage of blood supply to the heart muscle 
(acute coronary syndrome), cardiac arrest (stopping of blood flow from the heart), coronary 
(heart) artery disease, inflammation of the tissue covering the heart and lungs, blood clots, blood 
clots in the lungs 

 Digestive problems: loss of vital nutrients such as protein from your digestive tract, bowel 
obstruction, anal fistula (an abnormal opening from the anus to the skin around the anus), 
impairment of kidney function, diabetes 

 Skin, hair, eye, general: convulsion, inflammation of the optic nerve that may cause a 
complete or partial loss of vision, blue-purple mottling of the skin, abnormally high thyroid 
function, inflammation of the thyroid gland, ataxia (a condition associated with lack of muscular 
coordination), difficulty walking, miscarriage, inflammation of the skin blood vessels, skin 
fibrosis 

 Brain: stroke, temporary episode of neurologic dysfunction caused by loss of blood flow, facial 
nerve paralysis, dementia 

 Immune system: severe allergic reaction 
 Musculoskeletal and connective tissue: delayed fusion of the rounded ends that form joints 

(epiphyses); slower or delayed growth 
 
Other side effects that have been reported with frequency not known (cannot be estimated from 
the available data) 
 Inflammation of the lungs 
 Bleeding in the stomach or bowels that can cause death 
 Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a 

liver infection) 
 A reaction with fever, blisters on the skin, and ulceration of the mucous membranes 



 111

 Disease of the kidneys with symptoms including oedema and abnormal laboratory test results 
such as protein in the urine and low protein level in the blood 

 Damage to blood vessels known as thrombotic microangiopathy (TMA), including decreased 
red blood cell count, decreased platelets, and formation of blood clots 

 
Your doctor will check for some of these effects during your treatment. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store SPRYCEL 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle label, blister or carton after 
EXP. The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What SPRYCEL contains 
 The active substance is dasatinib. Each film-coated tablet contains 20 mg, 50 mg, 70 mg, 80 mg, 

100 mg or 140 mg dasatinib (as monohydrate). 
 The other ingredients are: 

 Tablet core: lactose monohydrate (see section 2 "SPRYCEL contains lactose"); 
microcrystalline cellulose; croscarmellose sodium; hydroxypropylcellulose; magnesium 
stearate 

 Film-coating: hypromellose; titanium dioxide (E171); macrogol 400 
 
What SPRYCEL looks like and contents of the pack 
SPRYCEL 20 mg: the film-coated tablet is white to off-white, biconvex, round with “BMS” debossed 
on one side and “527” on the other side. 
 
SPRYCEL 50 mg: the film-coated tablet is white to off-white, biconvex, oval with “BMS” debossed 
on one side and “528” on the other side. 
 
SPRYCEL 70 mg: the film-coated tablet is white to off-white, biconvex, round with “BMS” debossed 
on one side and “524” on the other side. 
 
SPRYCEL 80 mg: the film-coated tablet is white to off-white, biconvex, triangular with “BMS 80” 
debossed on one side and “855” on the other side. 
 
SPRYCEL 100 mg: the film-coated tablet is white to off-white, biconvex, oval with “BMS 100” 
debossed on one side and “852” on the other side. 
 
SPRYCEL 140 mg: the film-coated tablet is white to off-white, biconvex, round with “BMS 140” 
debossed on one side and “857” on the other side. 
 



 112

SPRYCEL 20 mg, 50 mg or 70 mg film-coated tablets are available in cartons containing 
56 film-coated tablets in 4 calendar blisters of 14 film-coated tablets each, and in cartons containing 
60 x 1 film-coated tablets in perforated unit dose blisters. They are also available in bottles with 
child-resistant closure containing 60 film-coated tablets. Each carton contains one bottle. 
 
SPRYCEL 80 mg, 100 mg or 140 mg film-coated tablets are available in cartons containing 
30 x 1 film-coated tablets in perforated unit dose blisters. They are also available in bottles with 
child-resistant closure containing 30 film-coated tablets. Each carton contains one bottle. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
Manufacturer 
Swords Laboratories T/A Bristol-Myers Squibb Pharmaceutical Operations, External Manufacturing 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc 
Strada Provinciale 12 Casilina, 41 
03012 Anagni (FR) 
Italy 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: +370 52 369140  

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 2 4942 480 
 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel.: + 36 1 9206 550 
 

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
Bristol-Myers Squibb S.r.l.  
Tel: + 356 23976333 
 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: + 0800 0752002 (+49 (0)89 121 42 350) 
 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 
 



 113

Eesti 
Bristol-Myers Squibb Kft. 
Tel: +372 640 1030 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 
 

Ελλάδα 
Bristol-Myers Squibb A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 

España 
Bristol-Myers Squibb, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
Bristol-Myers Squibb Polska Sp. z o.o. 
Tel.: + 48 22 2606400 
 

France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)1 58 83 84 96 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 
 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
TEL: +385 1 2078 508 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: +386 1 2355 100 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 20833 600 
 

Italia 
Bristol-Myers Squibb S.r.l. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 
 

Κύπρος 
Bristol-Myers Squibb A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 
 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: +371 66164750 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 
 

This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site:  
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
  



 114

Package leaflet: Information for the user 
 

SPRYCEL 10 mg/mL powder for oral suspension 
dasatinib 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even 

if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.  
 
What is in this leaflet 
 
1. What SPRYCEL is and what it is used for 
2. What you need to know before you take SPRYCEL 
3. How to take SPRYCEL 
4. Possible side effects 
5. How to store SPRYCEL 
6. Contents of the pack and other information 
 
 
1. What SPRYCEL is and what it is used for 
 
SPRYCEL contains the active substance dasatinib. This medicine is used to treat chronic myeloid 
leukaemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) 
in adolescents and children from at least one year of age. Leukaemia is a cancer of white blood cells. 
These white cells usually help the body to fight infection. In people with CML, white cells called 
granulocytes start growing out of control. SPRYCEL inhibits the growth of these leukaemic cells. 
 
If you have any questions about how SPRYCEL works or why this medicine has been prescribed for 
you or your child, ask your doctor. 
 
 
2. What you need to know before you take SPRYCEL 
 
Do not take SPRYCEL 
 if you are allergic to dasatinib or any of the other ingredients of this medicine (listed in 

section 6). 
If you or your child could be allergic, ask your doctor for advice. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before using SPRYCEL   
 if you are taking medicines to thin the blood or prevent clots (see "Other medicines and 

SPRYCEL") 
 if you have a liver or heart problem, or used to have one 
 if you start having difficulty breathing, chest pain, or a cough when taking SPRYCEL: this 

may be a sign of fluid retention in the lungs or chest (which can be more common in patients 
aged 65 years and older), or due to changes in the blood vessels supplying the lungs 

 if you have ever had or might now have a hepatitis B infection. This is because SPRYCEL could 
cause hepatitis B to become active again, which can be fatal in some cases. Patients will be 
carefully checked by their doctor for signs of this infection before treatment is started. 

 if you experience bruising, bleeding, fever, fatigue and confusion when taking SPRYCEL, 
contact your doctor. This may be a sign of damage to blood vessels known as thrombotic 
microangiopathy (TMA). 



 115

 
Your doctor will regularly monitor your condition to check whether SPRYCEL is having the desired 
effect. You or your child will also have blood tests regularly while taking SPRYCEL. 
 
Children and adolescents 
Do not give this medicine to children younger than one year of age. 
Bone growth and development will be closely monitored in children taking SPRYCEL. 
 
Other medicines and SPRYCEL 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
SPRYCEL is mainly handled by the liver. Certain medicines may interfere with the effect of 
SPRYCEL when taken together. 
 
These medicines are not to be used with SPRYCEL: 
 ketoconazole, itraconazole - these are antifungal medicines 
 erythromycin, clarithromycin, telithromycin - these are antibiotics 
 ritonavir - this is an antiviral medicine 
 phenytoin, carbamazepine, phenobarbital - these are treaments for epilepsy 
 rifampicin - this is a treatment for tuberculosis 
 famotidine, omeprazole - these are medicines that block stomach acids 
 St. John’s wort - a herbal preparation obtained without a prescription, used to treat depression 

and other conditions (also known as Hypericum perforatum) 
 
Do not take medicines that neutralise stomach acids (antacids such as aluminium hydroxide or 
magnesium hydroxide) in the 2 hours before or 2 hours after taking SPRYCEL. 
 
Tell your doctor if you are taking medicines to thin the blood or prevent clots. 
 
SPRYCEL with food and drink 
Do not take SPRYCEL with grapefruit or grapefruit juice. 
 
Pregnancy and breast-feeding 
If you are pregnant or may be pregnant, tell your doctor immediately. SPRYCEL is not to be used 
during pregnancy unless clearly necessary. Your doctor will discuss with you the potential risk of 
taking SPRYCEL during pregnancy. 
Both men and women taking SPRYCEL will be advised to use effective contraception during 
treatment. 
 
If you are breast-feeding, tell your doctor. You should stop breast-feeding while you are taking 
SPRYCEL. 
 
Driving and using machines 
Take special care when driving or using machines in case you experience side effects such as dizziness 
and blurred vision. 
 
SPRYCEL contains sucrose 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine.  
Contains 0.29 g of sucrose per mL of oral suspension. This should be taken into account in patients 
with diabetes mellitus. May be harmful to the teeth. 
 
SPRYCEL contains sodium 
This medicinal product contains 2.1 mg sodium (main component of cooking/table salt) per mL of 
SPRYCEL oral suspension. At the maximum daily dose of 16 mL oral suspension, this is equivalent to 
1.7% of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult. 
 



 116

SPRYCEL contains benzoic acid and sodium benzoate 
SPRYCEL contains 0.25 mg benzoic acid in each mL of oral suspension and 0.25 mg sodium 
benzoate in each mL of oral suspension. 
Benzoic acid/Benzoate salt may increase jaundice (yellowing of the skin and eyes) in newborn babies 
(up to 4 weeks old). 
 
SPRYCEL contains benzyl alcohol 
SPRYCEL contains 0.017 mg benzyl alcohol in each mL of oral suspension. 
Benzyl alcohol may cause allergic reactions. 
 
Use of SPRYCEL is not recommended during pregnancy. Ask your doctor or pharmacist for advice if 
you are pregnant or breast feeding. This is because large amounts of benzyl alcohol can build-up in 
your body and may cause side effects (called “metabolic acidosis”). 
 
Ask your doctor or pharmacist for advice if you have a liver or kidney disease. This is because large 
amounts of benzyl alcohol can build-up in your body and may cause side effects (called “metabolic 
acidosis”). 
 
SPRYCEL contains sulphur dioxide (E220) 
May rarely cause severe hypersensitivity reactions and bronchospasm. 
 
 
3. How to take SPRYCEL 
 
SPRYCEL will only be prescribed by a doctor with experience in treating leukaemia. Always take this 
medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not 
sure. 
 
SPRYCEL oral suspension is taken once daily. Your doctor will decide the right dose based on your 
weight. The starting dose of SPRYCEL is calculated by body weight as shown below: 
 
Body Weight (kg)  Daily Dose, mL (mg) 
5 to less than 10 kg 4 mL (40 mg) 
10 to less than 20 kg 6 mL (60 mg) 
20 to less than 30 kg 9 mL (90 mg) 
30 to less than 45 kg 10.5 mL (105 mg) 
at least 45 kg 12 mL (120 mg) 

 
SPRYCEL is also available as tablets for use in adults and children from one year of age and weighing 
more than 10 kg. The powder for oral suspension should be used for patients weighing less than 10 kg 
and patients who cannot swallow tablets. A change in dose may occur when switching between 
formulations (i.e., tablets and powder for oral suspension), so you should not switch from one to the 
other. Your doctor will decide the right formulation and dose based on your weight, any side effects 
and response to treatment.  
 
There is no dose recommendation for SPRYCEL with children under 1 year of age.  
 
Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose, or 
even stopping treatment briefly. 
  
How to take SPRYCEL 
Your pharmacist or qualified healthcare professional will constitute (mix to form a liquid) 
SPRYCEL powder for oral suspension to form SPRYCEL oral suspension before dispensing to 
you. 
 
SPRYCEL should be taken at the same time every day. SPRYCEL can be taken with or without a 
meal. SPRYCEL oral suspension may be mixed with milk, yogurt, apple juice, or applesauce. 



 117

 
See the "Instructions for administration to the patient" at the end of the package leaflet for how to give 
a dose of SPRYCEL oral suspension. 
 
Special handling instructions for SPRYCEL 
Persons other than the patient should use gloves when handling SPRYCEL. 
Pregnant or breast-feeding women should avoid exposure to SPRYCEL powder for oral suspension. 
 
How long to take SPRYCEL 
Take SPRYCEL daily until your doctor tells you to stop. Make sure you take SPRYCEL for as long as 
it is prescribed. 
 
If you take more SPRYCEL than you should 
If you have accidentally taken too much SPRYCEL, talk to your doctor immediately. You may 
require medical attention. 
 
If you forget to take SPRYCEL 
Do not take a double dose to make up for a forgotten dose. Take the next scheduled dose at the regular 
time. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The following can all be signs of serious side effects: 
 if you have chest pain, difficulty breathing, coughing and fainting 
 if you experience unexpected bleeding or bruising without having an injury 
 if you find blood in your vomit, stools or urine, or have black stools 
 if you get signs of infections such as fever, severe chills 
 if you get fever, sore mouth or throat, blistering or peeling of your skin and/or mucous 

membranes 
Contact your doctor immediately if you notice any of the above. 
 
Very common side effects (may affect more than 1 in 10 people) 
 Infections (including bacterial, viral and fungal) 
 Heart and lungs: shortness of breath 
 Digestive problems: diarrhoea, feeling or being sick (nausea, vomiting) 
 Skin, hair, eye, general: skin rash, fever, swelling around the face, hands and feet, headache, 

feeling tired or weak, bleeding 
 Pain: pain in the muscles (during or after discontinuing treatment), tummy (abdominal) pain 
 Tests may show: low blood platelet count, low white blood cells count (neutropaenia), 

anaemia, fluid around the lungs 
 
Common side effects (may affect up to 1 in 10 people) 
 Infections: pneumonia, herpes virus infection (including cytomegalovirus - CMV), upper 

respiratory tract infection, serious infection of the blood or tissues (including uncommon cases 
with fatal outcomes) 

 Heart and lungs: palpitations, irregular heartbeat, congestive heart failure, weak heart muscle, 
high blood pressure, increased blood pressure in the lungs, cough 

 Digestive problems: appetite disturbances, taste disturbance, bloated or distended tummy 
(abdomen), inflammation of the colon, constipation, heartburn, mouth ulceration, weight 
increase, weight decrease, gastritis 

 Skin, hair, eye, general: skin tingling, itching, dry skin, acne, inflammation of the skin, 
persistent noise in ears, hair loss, excessive perspiration, visual disorder (including blurred 



 118

vision and disturbed vision), dry eye, bruise, depression, insomnia, flushing, dizziness, 
contusion (bruising), anorexia, somnolence, generalised oedema 

 Pain: pain in joints, muscular weakness, chest pain, pain around hands and feet, chills, stiffness 
in muscles and joints, muscle spasm 

 Tests may show: fluid around the heart, fluid in the lungs, arrhythmia, febrile neutropaenia, 
gastrointestinal bleeding, high uric acid levels in the blood 

 
Uncommon side effects (may affect up to 1 in 100 people) 
 Heart and lungs: heart attack (including fatal outcome), inflammation of the lining (fibrous 

sack) surrounding the heart, irregular heartbeat, chest pain due to lack of blood supply to the 
heart (angina), low blood pressure, narrowing of airway that may cause breathing difficulties, 
asthma, increased blood pressure in the arteries (blood vessels) of the lungs 

 Digestive problems: inflammation of the pancreas, peptic ulcer, inflammation of the food pipe, 
swollen tummy (abdomen), tear in the skin of the anal canal, difficulty in swallowing, 
inflammation of the gallbladder, blockage of bile ducts, gastro-oesophageal reflux (a condition 
where acid and other stomach contents come back up into the throat) 

 Skin, hair, eye, general: allergic reaction including tender, red lumps on the skin (erythema 
nodosum), anxiety, confusion, mood swings, lower sexual drive, fainting, tremor, inflammation 
of the eye which causes redness or pain, a skin disease characterized by tender, red, 
well-defined blotches with the sudden onset of fever and raised white blood cell count 
(neutrophilic dermatosis), loss of hearing, sensitivity to light, visual impairment, increased eye 
tearing, disturbance in skin colour, inflammation of fatty tissue under the skin, skin ulcer, 
blistering of the skin, nail disorder, hair disorder, hand-foot disorder, renal failure, urinary 
frequency, breast enlargement in men, menstrual disorder, general weakness and discomfort, 
low thyroid function, losing balance while walking, osteonecrosis (a disease of reduced blood 
flow to the bones, which can cause bone loss and bone death), arthritis, skin swelling anywhere 
in the body 

 Pain: inflammation of vein which can cause redness, tenderness and swelling, inflammation of 
the tendon 

 Brain: loss of memory 
 Tests may show: abnormal blood test results and possibly impaired kidney function caused by 

the waste products of the dying tumour (tumour lysis syndrome), low levels of albumin in the 
blood, low levels of lymphocytes (a type of white blood cell) in the blood, high level of 
cholesterol in the blood, swollen lymph nodes, bleeding in the brain, irregularity of the electrical 
activity of the heart, enlarged heart, inflammation of the liver, protein in the urine, raised 
creatine phosphokinase (an enzyme mainly found in the heart, brain and skeletal muscles), 
raised troponin (an enzyme mainly found in the heart and skeletal muscles), raised 
gamma-glutamyltransferase (an enzyme mainly found in the liver) 

 
Rare side effects (may affect up to 1 in 1,000 people) 
 Heart and lungs: enlargement of the right ventricle in the heart, inflammation of the heart 

muscle, collection of conditions resulting from blockage of blood supply to the heart muscle 
(acute coronary syndrome), cardiac arrest (stopping of blood flow from the heart), coronary 
(heart) artery disease, inflammation of the tissue covering the heart and lungs, blood clots, blood 
clots in the lungs 

 Digestive problems: loss of vital nutrients such as protein from your digestive tract, bowel 
obstruction, anal fistula (an abnormal opening from the anus to the skin around the anus), 
impairment of kidney function, diabetes 

 Skin, hair, eye, general: convulsion, inflammation of the optic nerve that may cause a complete 
or partial loss of vision, blue-purple mottling of the skin, abnormally high thyroid function, 
inflammation of the thyroid gland, ataxia (a condition associated with lack of muscular 
coordination), difficulty walking, miscarriage, inflammation of the skin blood vessels, skin 
fibrosis 

 Brain: stroke, temporary episode of neurologic dysfunction caused by loss of blood flow, facial 
nerve paralysis, dementia 

 Immune system: severe allergic reaction 



 119

 Musculoskeletal and connective tissue: delayed fusion of the rounded ends that form joints 
(epiphyses); slower or delayed growth 

 
Other side effects that have been reported with frequency not known (cannot be estimated from 
the available data) 
 Inflammation of the lungs 
 Bleeding in the stomach or bowels that can cause death 
 Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a 

liver infection) 
 A reaction with fever, blisters on the skin, and ulceration of the mucous membranes 
 Disease of the kidneys with symptoms including oedema and abnormal laboratory test results 

such as protein in the urine and low protein level in the blood 
 Damage to blood vessels known as thrombotic microangiopathy (TMA), including decreased 

red blood cell count, decreased platelets, and formation of blood clots 
 
Your doctor will check for some of these effects during your treatment. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store SPRYCEL 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle label and carton after EXP. 
The expiry date refers to the last day of that month. 
 
Powder 
Store below 25°C. 
 
After constitution 
Store in a refrigerator (2°C - 8°C). Do not freeze. Discard any unused suspension 60 days after 
constitution.  
 
Constituted oral suspension mixed with milk, yogurt, apple juice, or applesauce may be stored at or 
below 25°C for up to 1 hour. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What SPRYCEL contains 
 The active substance is dasatinib. One bottle of powder for oral suspension contains 990 mg of 

dasatinib (as monohydrate). After constitution, one bottle contains 99 mL of oral suspension. 
Each mL of oral suspension contains 10 mg of dasatinib (as monohydrate). 

 The other ingredients are: sucrose, carmellose sodium, simethicone emulsion (consisting of 
simeticone, polyethylene glycol sorbitan tristearate, polyethoxylate stearate, glycerides, 
methylcellulose, xanthan gum, benzoic acid, sorbic acid, sulfuric acid), tartaric acid, trisodium 
citrate anhydrous, sodium benzoate (E211), silica hydrophobic colloidal, mixed berry flavour 
(containing: benzyl alcohol, sulphur dioxide) (see section 2 "What you need to know before you 
take SPRYCEL"). 



 120

 
What SPRYCEL looks like and contents of the pack 
SPRYCEL is supplied as a white to off-white powder for oral suspension which forms a white to 
yellow opaque suspension after constitution with water.  
 
One 120-mL plastic bottle (with child-resistant closure) contains 33 g of powder for oral suspension. 
 
Once constituted, the bottle contains 99 mL of oral suspension, of which 90 mL is intended for dosing 
and administration.  
 
Each pack also contains a press-in-bottle adapter (PIBA) and a 12-mL oral dosing syringe in a sealed 
plastic bag. 
 
Each carton contains one bottle. 
 
Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
Manufacturer 
Swords Laboratories T/A Lawrence Laboratories 
Unit 12 & 15, Distribution Centre  
Shannon Industrial Estate  
Shannon, Co. Clare, V14 DD39 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: +370 52 369140  

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 2 4942 480 
 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel.: + 36 1 9206 550 
 

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
Bristol-Myers Squibb S.r.l.  
Tel: + 356 23976333 
 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: + 0800 0752002 (+49 (0)89 121 42 350) 
 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 
 

Eesti 
Bristol-Myers Squibb Kft. 
Tel: +372 640 1030 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 
 



 121

Ελλάδα 
Bristol-Myers Squibb A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 

España 
Bristol-Myers Squibb, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
Bristol-Myers Squibb Polska Sp. z o.o. 
Tel.: + 48 22 2606400 
 

France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)1 58 83 84 96 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 
 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
TEL: +385 1 2078 508 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: +386 1 2355 100 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 20833 600 
 

Italia 
Bristol-Myers Squibb S.r.l. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 
 

Κύπρος 
Bristol-Myers Squibb A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 
 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: +371 66164750 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 
 

This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site:  
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
Instructions for administration to the patient 
 
These instructions show you how to give a dose of SPRYCEL oral suspension to the patient. Once 
constituted by your pharmacist or healthcare professional, the oral suspension should only be 
administered using the oral dosing syringe supplied with each pack. Your doctor will decide the right 
dose based on age and weight. Make sure that you read and understand these instructions before using 
the oral suspension.  
 
What you need to know before using this medicine 
 Take SPRYCEL oral suspension on an empty or full stomach.  
 Wash your hands before and after each use. 
 Store the constituted oral suspension in a refrigerator (2°C - 8°C). Do not freeze. 
 Review total prescribed dose and determine number of milliliters (mL) you will need.  
 If the amount needed is greater than 11 mL, it must be split into 2 doses as shown below: 



 122

 

How to split a dose that is greater than 11 mL 
 

Total prescribed dose (mL) First dose (mL) Second dose (mL) 
12 6 6 
13 7 6 
14 7 7 
15 8 7 
16 8 8 

 
Before you prepare a dose of SPRYCEL oral suspension for administration to the patient, get 
the following supplies ready: 
 

 Paper towel 
 1 SPRYCEL oral 

suspension bottle 
containing a white 
to yellow opaque 
suspension. 

 12-mL oral syringe 
provided with the 
bottle. 

 A small container 
filled with water to 
use to rinse the 
syringe. 

 

 
 

Carefully prepare the SPRYCEL oral suspension for administration, measure the dose, and fill 
the syringe, like this: 
 

1. Mix the SPRYCEL oral 
suspension in the closed bottle 
by shaking for 30 seconds. 

 
 Shake well before each 

use. 

 
 

oral syringe bottle 

Shake  
bottle 
repeatedly 
for 30 
seconds. 



 123

2. Remove the closure from 
the bottle. Make sure the 
adapter provided on the bottle 
for syringe placement is firmly 
pressed into the bottle. 

 
 

3. Look at the measurements 
on the side of the syringe so 
you can see how much to fill it 
before you begin. Note that the 
markings on the syringe are in 
mL. Find the marking that 
matches the dose that was 
prescribed by your doctor. 
Before each use, make sure the 
syringe plunger is pushed to 
the bottom of the syringe 
barrel. 

 
 

4. With the bottle in an upright 
position, insert the tip of the 
syringe firmly into the bottle 
adapter. 

 
 

Make 
sure 
bottle 
adapter 
is firmly 
pressed. 



 124

5. Holding the syringe tip 
firmly into the bottle, turn the 
bottle with the syringe upside 
down. 

 
 

6. Slowly withdraw the 
amount of SPRYCEL oral 
suspension prescribed by 
pulling the syringe plunger 
until it reaches the marking of 
the dose prescribed. 
 Hold plunger to prevent it 

from moving. There may 
be a vacuum pulling the 
plunger back into barrel. 

 If unable to fill with one 
bottle, use the second 
bottle to complete the full 
prescribed dose. Make 
sure the second bottle is 
shaken before use.  

7. Holding the syringe tip 
firmly in the bottle, turn the 
bottle with the syringe upright 
again. 

 
 



 125

8. Remove the syringe from 
the bottle being careful not to 
depress the plunger. 

 
 

9. With the patient in an 
upright position, place the tip 
of the syringe into the mouth 
between the side of the mouth 
and the tongue. Slowly push 
the plunger down until all of 
the dose has been given. 
 Check to make sure the 

patient has swallowed all 
of the dose. 

 If a second dose is needed 
to complete the total 
prescribed dose, repeat 
steps 3 through 10.  

 Put closure back on the 
bottle and close tightly. 
Store upright. 

 



 126

10. Wash the outside 
and the inside of the 
syringe with water 
and allow to air dry 
after each use to re-
use for the next day.  

 

 Do not wash in a 
dishwasher. 
 

 Do not take the 
syringe apart in 
order to avoid 
damaging it. 

 
 
11. Refer to the 
package leaflet (see 
section 5 ‘How to 
store SPRYCEL’) for 
instructions on 
discarding any 
unused medicine, 
syringe and bottle. 

 
 

If you have any questions on how to prepare or give a dose of SPRYCEL oral suspension, talk to your 
doctor, pharmacist or nurse. 
 
--------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only: 
 
Instructions for constitution of powder for oral suspension  
 
SPRYCEL powder for oral suspension is to be constituted as follows: 
Note: If you have to constitute more than one bottle, complete one bottle at a time.  
Wash your hands before initiating the constitution. This procedure should be performed on a clean 
surface. 
 
Step 1: Tap bottom of each bottle (containing 33 g SPRYCEL powder for oral suspension) gently to 
loosen the powder. Remove child-resistant closure and foil seal. Add 77.0 mL of purified water all at 
once to the bottle and close tightly with closure. 
Step 2: Immediately invert the bottle and shake vigorously for no less than 60 seconds to obtain a 
uniform suspension. If there are still visible clumps, continue shaking until no clumps are visible. 

DO NOT USE A 
DISHWASHER 

ALLOW TO AIR 
DRY AFTER EACH 

USE 

DO NOT TAKE 
APART THE 

SYRINGE 



 127

Constitution in this way produces 90 mL (deliverable volume) of 10 mg/mL SPRYCEL oral 
suspension. 
Step 3: Remove the closure, insert the press-in bottle adapter (PIBA) into the bottle neck, and close the 
bottle tightly with the child-resistant closure. 
Step 4: Write the date of expiry of the constituted oral suspension on the bottle label (the date of 
expiry of the constituted oral suspension is 60 days from the date of constitution). 
Step 5: Dispense the bottle with inserted PIBA, package leaflet, and oral dosing syringe in the original 
carton to the patient or caregiver. Remind the patient or caregiver to shake the bottle vigorously prior 
to each use. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFEAND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET