ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
SPRYCEL 20 mg film-coated
tablets
2.
Each film-coated tablet contains 20 mg dasatinib (as monohydrate).
Excipients
Each tablet contains 27 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated
tablet (tablet)
White to off-white, biconvex, round tablet with "BMS" debossed on one side and "527" on the other
side.
4.
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 mesilate.
Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or
intolerance to prior therapy.
Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with
leukaemia.
Posology
The recommended starting dose for chronic phase CML is 100 mg dasatinib once daily, administered
orally.
The recommended starting dose for accelerated, myeloid or lymphoid blast phase (advanced phase)
CML or Ph+ ALL is 140 mg once daily, administered orally (see section 4.4).
Treatment duration
In clinical studies, treatment with SPRYCEL was continued until disease progression or until no
longer tolerated by the patient. The effect of stopping treatment after the achievement of a complete
cytogenetic response (CCyR) has not been investigated.
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. Dose increase or reduction is recommended based on patient response
and tolerability.
2
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.
Dose adjustment for undesirable effects
Myelosuppression
In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or
discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate.
Haematopoietic growth factor has been used in patients with resistant myelosuppression.
Guidelines for dose modifications are summarized in Table 1.
Table 1: Dose adjustments for neutropenia and thrombocytopenia
1 Stop treatment until ANC ≥ 1.0 x 10
9
/l
and platelets ≥ 50 x 10
9
/l.
2 Resume treatment at the original
starting dose.
Chronic Phase CML
(starting dose 100 mg once
daily)
ANC < 0.5 x 10
9
/l
and/or
Platelets < 50 x 10
9
/l
3 If platelets < 25 x 10
9
/l and/or
recurrence of ANC < 0.5 x 10
9
/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).
1 Check if cytopenia is related to
leukaemia (marrow aspirate or biopsy).
Accelerated and Blast Phase
CML and Ph+ ALL
(starting dose 140 mg once
daily)
2 If cytopenia is unrelated to leukaemia,
stop treatment until ANC ≥ 1.0 x 10
9
/l
and platelets ≥ 20 x 10
9
/l and resume at
the original starting dose.
ANC < 0.5 x 10
9
/l
and/or
Platelets < 10 x 10
9
/l
3 If recurrence of cytopenia, 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 cytopenia is related to leukaemia,
consider dose escalation to 180 mg
once daily.
ANC: absolute neutrophil count
Non-haematological adverse reactions
If a moderate, grade 2, non-haematological adverse reaction develops with dasatinib, interrupt treatment
until the event has resolved or returned to baseline. Resume at the same dose if this is the first occurrence
and at a reduced dose if this is a recurrent event. If a severe grade 3 or 4, non-haematological adverse
reaction develops with dasatinib, treatment must be withheld until the event has resolved. Thereafter,
treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the
3
event. 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.
Pleural effusion:
if a pleural effusion is diagnosed, interrupt dasatinib until patient is asymptomatic or
has returned to baseline. If the episode does not improve within approximately one week, consider a
course of diuretics or corticosteroids or both concurrently (see sections 4.4 and 4.8). Following
resolution of the first episode, consider reintroduction of dasatinib at the same dose level. Following
resolution of a subsequent episode, reintroduce dasatinib at one dose level reduction. 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 event.
Paediatric population
The safety and efficacy of SPRYCEL in children and adolescents below 18 years of age have not yet
been established. No data are available (see section 5.1).
Elderly population
No clinically relevant age-related pharmacokinetic differences have been observed in these patients. No
specific dose recommendation is necessary in the 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
sections 4.4 and 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.
Tablets must not be crushed or cut in order to minimize the risk of dermal exposure, they must be
swallowed whole. They can be taken with or without a meal and should be taken consistently either in
the morning or in the evening.
Hypersensitivity to the active substance or to any of the excipients.
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
metabolized primarily by or modulate the activity of CYP3A4 (see section 4.5).
Concomitant use of dasatinib and medicinal products that potently inhibit CYP3A4 (e.g. ketoconazole,
itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin) may increase exposure to dasatinib.
Therefore, in patients receiving dasatinib, coadministration of a potent CYP3A4 inhibitor is not
recommended (see section 4.5).
4
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 (H
2
) antagonist (e.g. famotidine), proton pump
inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure
to dasatinib. Thus, H
2
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 sections 4.2 and 5.2). Due
to the limitations of this clinical study, caution is recommended when administering dasatinib to
patients with hepatic impairment (see section 4.2).
Important adverse reactions
Myelosuppression
Treatment with dasatinib is associated with anaemia, neutropenia and thrombocytopenia. Their
occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase
CML
.
Complete blood counts should be performed weekly for the first 2 months, and then monthly
thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed
by withholding dasatinib temporarily or by dose reduction (see sections 4.2 and 4.8).
In a Phase III dose-optimisation study in patients with chronic phase CML with resistance or
intolerance to prior imatinib therapy, grade 3 or 4 myelosuppression was reported more frequently in
patients treated with 70 mg twice daily than in patients treated with 100 mg once daily.
Bleeding
In the Phase III study in patients with newly diagnosed chronic phase CML, 1 patient (< 1%) receiving
dasatinib compared to 2 patients (1%) receiving imatinib had grade 3 or 4 haemorrhage. In clinical
studies in patients with resistance or intolerance to prior imatinib therapy, severe central nervous
system (CNS) haemorrhage occurred in < 1% of patients. Eight cases were fatal and 6 of them were
associated with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia. Grade 3 or 4
gastrointestinal haemorrhage occurred in 4% of patients with resistance or intolerance to prior imatinib
therapy and generally required treatment interruptions and transfusions. Other grade 3 or 4
haemorrhage occurred in 2% of patients with resistance or intolerance to prior imatinib therapy. Most
bleeding related events in these patients were typically associated with grade 3 or 4 thrombocytopenia
(see section 4.8). Additionally,
in vitro
and
in vivo
platelet assays suggest that SPRYCEL treatment
reversibly affects platelet activation.
Patients were excluded from participation in initial SPRYCEL clinical studies if they took medicinal
products that inhibit platelet function or anticoagulants. In subsequent studies, the use of
anticoagulants, acetylsalicylic acid, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed
concurrently with SPRYCEL if the platelet count was > 50,000-75,000/mm
3
. Caution should be
exercised if patients are required to take medicinal products that inhibit platelet function or
anticoagulants.
5
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 2 patients (1%) in each of
the dasatinib and the imatinib-treatment groups (see section 4.8). In clinical studies in patients with
resistance or intolerance to prior imatinib therapy, grade 3 or 4 fluid retention was reported in 10% of
patients, including grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients,
respectively. In these studies, grade 3 or 4 ascites and generalised oedema were each reported in < 1%
of patients, and grade 3 or 4 pulmonary oedema was reported in 1% of patients.
Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should
be evaluated by chest X-ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygen
therapy. Fluid retention events were typically managed by supportive care measures that include
diuretics and short courses of steroids (see sections 4.2 and 4.8). While the safety profile of SPRYCEL
in the elderly population was similar to that in the younger population, patients aged 65 years and
older are more likely to experience fluid retention events and dyspnoea and should be monitored
closely. Fluid retention was reported less frequently in patients treated with once daily schedule
compared to twice daily in two Phase III dose-optimisation studies (see section 4.8).
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 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 trials, 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, 14 (< 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 trial of 519 patients with newly diagnosed CML in chronic
phase which included patients with prior cardiac disease. The cardiac adverse reactions of congestive
heart failure/cardiac dysfunction and fatal myocardial infarction were reported in patients taking
dasatinib. Adverse cardiac events were more frequent in patients with risk factors or a history of
cardiac disease. Patients with risk factors (e.g. hypertension, hyperlipidemia, 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. 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 events
(≤ grade 2) and resumed at a dose level reduction for severe events (≥ 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.
6
Lactose
This medicinal product contains 135 mg of lactose monohydrate in a 100 mg daily dose and 189 mg of
lactose monohydrate in a 140 mg daily dose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
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 which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin,
clarithromycin, ritonavir, telithromycin) may increase exposure to dasatinib. Therefore, in patients
receiving dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended.
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. dexamethazone, 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.
Histamine-2 antagonists and proton pump inhibitors
Long-term suppression of gastric acid secretion by H
2
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 C
max
of dasatinib by 42%. The use of antacids should be considered in place
of H
2
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 C
max
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 C
max
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.
7
Pregnancy
There are no adequate data from the use of dasatinib in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
SPRYCEL should not be used during pregnancy unless clearly necessary. If it is used during
pregnancy, the patient must be informed of the potential risk to the foetus.
Breastfeeding
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
The effect of dasatinib on sperm is unknown, therefore both sexually active men and women should
use effective methods of contraception during treatment.
No studies on the effects on the ability to drive and use machines have been performed. Patients
should be advised that they may experience undesirable effects such as dizziness or blurred vision
during treatment with dasatinib. Therefore, caution should be recommended when driving a car or
operating machines.
a. Summary of the safety profile
The data described below reflect exposure to SPRYCEL in 2,440 patients in clinical studies, including
258 patients with newly diagnosed chronic phase CML with a minimum of 12 months follow-up
(starting dose 100 mg once daily) and 2,182 patients with imatinib resistant or intolerant CML or
Ph+ ALL with a minimum of 24 months follow-up (starting dose 100 mg once daily, 140 mg once
daily, 50 mg twice daily, or 70 mg twice daily). The median duration of therapy in this patient
population was 15 months (range 0.03 - 36 months).
Of the 2,440 patients treated, 23% were ≥ 65 years of age, while 5% were ≥ 75 years of age.
In the Phase III study in patients with newly diagnosed chronic phase CML the median duration of
therapy was 14 months (range 0.03-24 months) for SPRYCEL and 14 months (range 0.3-26 months)
for imatinib; the median average daily dose was 99 mg and 400 mg, respectively.
The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Most
reactions were of mild-to-moderate grade.
In the Phase III study in patients with newly diagnosed chronic phase CML, treatment was
discontinued for adverse reactions in 5% of SPRYCEL-treated patients and 4% of imatinib-treated
patients. Among patients with resistance or intolerance to prior imatinib therapy, the rates of
discontinuation for adverse reactions were 15% in chronic phase CML, 16% in accelerated phase
CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML and 8% in Ph+ ALL. In
the Phase III dose-optimisation study in patients with chronic phase CML, the rate of discontinuation
for adverse reactions was lower for patients treated with 100 mg once daily than for those treated with
70 mg twice daily (10% and 16%, respectively); the rates of dose interruption and reduction were also
lower for patients treated with 100 mg once daily than for those treated with 70 mg twice daily. Less
frequent dose reductions and interruptions were also reported for patients with advanced phase CML
and Ph+ ALL treated with 140 mg once daily than for those treated with 70 mg twice daily.
The majority of imatinib-intolerant patients with chronic phase CML were able to tolerate treatment with
SPRYCEL. In clinical studies in chronic phase CML, 10 of the 215 imatinib-intolerant patients had the
8
same grade 3 or 4 non-hematologic toxicity with SPRYCEL as they did with prior imatinib; 8 of these
10 patients were managed with dose reduction and were able to continue SPRYCEL treatment.
The most frequently reported adverse reactions reported in SPRYCEL-treated patients with newly
diagnosed chronic phase CML were fluid retention (including pleural effusion) (19%), diarrhoea
(17%), headache (12%), rash (11%), musculoskeletal pain (11%), nausea (8%), fatigue (8%), myalgia
(6%), vomiting (5%), and muscle inflammation (4%). The most frequently reported adverse reactions
reported in SPRYCEL-treated patients with resistance or intolerance to prior imatinib therapy were
fluid retention (including pleural effusion), diarrhoea, headache, nausea, skin rash, dyspnoea,
haemorrhage, fatigue, musculoskeletal pain, infection, vomiting, cough, abdominal pain and pyrexia.
Drug-related febrile neutropenia was reported in 5% of SPRYCEL-treated patients with resistance or
intolerance to prior imatinib therapy.
In clinical studies with patients with resistance or intolerance to prior imatinib therapy, it was
recommended that treatment with imatinib be discontinued at least 7 days before starting treatment
with SPRYCEL.
b. Tabulated summary of adverse reactions
The following adverse reactions, excluding laboratory abnormalities, were reported in patients in
SPRYCEL clinical studies and post-marketing experience (Table 2). 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, undesirable effects are presented in order of decreasing seriousness.
Table 2: 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, enterocolitis infection
Uncommon
sepsis (including fatal outcome)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon
tumour lysis syndrome
Blood and lymphatic system disorders
Common
febrile neutropenia, pancytopenia
Rare
aplasia pure red cell
Immune system disorders
Uncommon
hypersensitivity (including erythema nodosum)
Metabolism and nutrition disorders
Common
anorexia, appetite disturbances
Uncommon
hyperuricaemia, hypoalbuminemia
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*
a
, syncope, tremor, amnesia
Rare
cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis
Eye disorders
Common
visual disorder (including visual disturbance, vision blurred, and visual acuity
reduced), dry eye
Uncommon
conjunctivitis
9
Ear and labyrinth disorders
Common
tinnitus
Uncommon
vertigo
Cardiac disorders
Common
congestive heart failure/cardiac dysfunction*
b
, pericardial effusion*, arrhythmia
(including tachycardia), palpitations
Uncommon
myocardial infarction (including fatal outcome)*, electrocardiogram QT prolonged*,
pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina
pectoris, cardiomegaly
Rare
cor pulmonale, myocarditis, acute coronary syndrome
Not known
atrial fibrillation/atrial flutter
Vascular disorders
Very common
haemorrhage
*c
Common
hypertension, flushing
Uncommon
hypotension, thrombophlebitis
Rare
livedo reticularis
Not known
thrombosis/embolism (including pulmonary embolism, deep vein thrombosis)
Respiratory, thoracic and mediastinal disorders
Very common
pleural effusion*, dyspnoea
Common
cough, pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis
Uncommon
bronchospasm, asthma
Rare
acute respiratory distress syndrome
Not known
interstitial lung disease
Gastrointestinal disorders
Very common
diarrhoea, vomiting, nausea, abdominal pain
Common
gastrointestinal bleeding*, colitis (including neutropenic colitis), gastritis, mucosal
inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension,
constipation, oral soft tissue disorder
Uncommon
pancreatitis, upper gastrointestinal ulcer, oesophagitis, ascites*, anal fissure,
dysphagia
Rare
protein-losing gastroenteropathy
Not known
fatal gastrointestinal haemorrhage*
Hepatobiliary disorders
Uncommon
hepatitis, cholecystitis, cholestasis
Skin and subcutaneous tissue disorders
Very common
skin rash
d
Common
alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria,
hyperhidrosis
Uncommon
acute febrile neutrophilic dermatosis, photosensitivity, pigmentation disorder,
panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar
erythrodysesthesia syndrome
Musculoskeletal and connective tissue disorders
Very common
musculoskeletal pain
Common
arthralgia, myalgia, muscle inflammation, muscular weakness
Uncommon
musculoskeletal stiffness, rhabdomyolysis
Rare
tendonitis
Renal and urinary disorders
Uncommon
renal failure, urinary frequency, proteinuria
Reproductive system and breast disorders
Uncommon
gynecomastia, irregular menstruation
General disorders and administration site conditions
Very common
fluid retention*, fatigue, superficial oedema*
e
, pyrexia
Common
asthenia, pain, chest pain, generalised oedema*, chills
Uncommon
malaise, temperature intolerance
10
Investigations
Common
weight decreased, weight increased
Uncommon
blood creatine phosphokinase increased
Injury, poisoning, and procedural complications
Common
contusion
a
Includes cerebral haematoma, cerebral haemorrhage, extradural haematoma, haemorrhage intracranial, haemorrhagic
stroke, subarachnoid haemorrhage, subdural haematoma, and subdural haemorrhage.
b
Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,
diastolic dysfunction, ejection fraction decreased and ventricular failure.
c
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.
d
Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalised erythema, genital rash,
heat rash, milia, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular,
rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation and urticaria vesiculosa
.
e
Includes auricular swelling, conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, genital
swelling, gravitational oedema, lip oedema, localised oedema, macular oedema, oedema genital, oedema mouth, oedema
peripheral, orbital oedema, penile oedema, periorbital oedema, pitting oedema, scrotal oedema, swelling face and tongue
oedema.
* For additional details, see section c.
c. Description of selected adverse reactions
Myelosuppression
Treatment with SPRYCEL is associated with anaemia, neutropenia and thrombocytopenia. Their
occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase
CML (see section 4.4).
Bleeding
Bleeding drug-related events, 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). In the
Phase III study in patients with newly diagnosed chronic phase CML, 1 patient (< 1%) receiving
SPRYCEL had grade 3 haemorrhage. In clinical studies in patients with resistance or intolerance to
prior imatinib therapy, severe CNS haemorrhage occurred in < 1% of patients. Eight cases were fatal
and 6 of them were associated with CTC grade 4 thrombocytopenia. Grade 3 or 4 gastrointestinal
haemorrhage occurred in 4% of patients with resistance or intolerance to prior imatinib therapy and
generally required treatment interruption and transfusions. Other grade 3 or 4 haemorrhage occurred in
2% of patients with resistance or intolerance to prior imatinib therapy. Most bleeding related events in
these patients were typically associated with grade 3 or 4 thrombocytopenia. Additionally,
in vitro
and
in vivo
platelet assays suggest that SPRYCEL treatment reversibly affects platelet activation (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, grade 1 and 2 pleural effusion were reported in 26 patients
(10%) receiving SPRYCEL. The median time to onset was 28 weeks (range 4-88 weeks). The median
duration of pleural effusion was 50 days (range 5-585 days). This reaction 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 pleural effusion, 73% had a
dose interruption for a median of 15 days (6-56 days). Thirty one percent had a dose reduction.
Additionally, 46% received concomitant diuretics (median duration 64 days) and 27% received
concomitant corticosteroids (median duration 29 days). A single patient underwent a therapeutic
thoracentesis. With appropriate medical care, 23 patients (88% of those with pleural effusion) were
able to continue on SPRYCEL and efficacy was not affected (92% achieved a complete cytogenetic
11
response). Other fluid retention adverse reactions reported in patients taking SPRYCEL were
superficial localised oedema (9%), and generalised oedema (2%). Congestive heart failure/cardiac
dysfunction, pericardial effusions, pulmonary hypertension and pulmonary oedema were also reported
in < 2% of patients.
The use of SPRYCEL is associated with fluid
retention with grade 3 or 4 cases in 10% of patients with
resistance or intolerance to prior imatinib therapy. Grade 3 or 4 pleural and pericardial effusion were
reported in 7% and 1% of patients, respectively. Grade 3 or 4 ascites and generalised oedema were
each reported in < 1%. One percent of patients experienced grade 3 or 4 pulmonary oedema. Fluid
retention events were typically managed by supportive care measures that include diuretics or short
courses of steroids.
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 (see section 4.4).
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, 14 (< 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).
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 23 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 (Table 3a).
Myelosuppression was also reported less frequently with the 100 mg once daily (see Laboratory test
abnormalities below).
12
Table 3a: Selected adverse reactions reported in phase III dose-optimisation study: Chronic Phase
CML
100 mg once daily
n = 165
140 mg once daily
a
n = 163
50 mg twice daily
a
n = 167
70 mg twice daily
a
n = 167
All
grades
Grade
3/4
All
grades
Grade
3/4
All
grades
Grade
3/4
All
grades
Grade
3/4
Percent (%) of patients
Preferred term
Diarrhoea
27
2
30
4
31
2
27
4
Fluid retention
34
4
40
7
37
5
40
10
Superficial oedema
18
0
17
1
19
0
19
1
Pleural effusion
18
2
26
5
24
4
24
5
Generalised
oedema
3
0
5
0
0
0
2
0
Congestive heart
failure/cardiac
dysfunction
b
0
0
4
1
1
1
5
3
Pericardial effusion
2
1
6
2
5
2
2
1
Pulmonary oedema
0
0
0
0
1
1
3
1
Pulmonary
hypertension
0
0
1
0
1
0
1
1
Haemorrhage
11
1
14
1
10
4
16
2
Gastrointestinal
bleeding
2
1
2
0
5
3
4
2
a
Not a recommended starting dose of SPRYCEL for chronic phase CML (see section 4.2).
b
Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,
diastolic dysfunction, ejection fraction decreased, and ventricular failure.
In the Phase III dose-optimisation study in patients with advanced phase CML and Ph+ ALL (median
duration of treatment of 14 months for accelerated phase CML, 3 months for myeloid blast CML,
4 months for lymphoid blast CML and 3 months for Ph+ ALL), fluid retention (pleural effusion and
pericardial effusion) was reported less frequently in patients treated with SPRYCEL 140 mg once
daily than in those treated with 70 mg twice daily (Table 3b).
Table 3b: Selected adverse reactions reported in phase III dose-optimisation study: Advanced Phase
CML and Ph+ ALL
All grades
140 mg once daily
n = 304
All grades
70 mg twice daily
a
n = 305
Grade 3/4
Grade 3/4
Preferred term
Percent (%) of patients
Diarrhoea
28
3
29
4
Fluid retention
33
7
43
11
Superficial oedema
15
< 1
19
1
Pleural effusion
20
6
34
7
Generalised oedema
2
0
3
1
Congestive heart failure/
cardiac dysfunction
b
1
0
2
1
Pericardial effusion
2
1
6
2
Pulmonary oedema
1
1
3
1
Ascites
0
0
1
0
Pulmonary hypertension
0
0
1
< 1
Haemorrhage
23
8
27
7
Gastrointestinal bleeding
8
6
12
6
a
Not a recommended starting dose of SPRYCEL for advanced phase CML and Ph+ ALL (see section 4.2).
b
Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,
diastolic dysfunction, ejection fraction decreased, and ventricular failure.
13
Laboratory test abnormalities:
Haematology
In the Phase III newly diagnosed chronic phase CML study, the following grade 3 or 4 laboratory
abnormalities were reported in patients taking SPRYCEL: neutropenia (21%), thrombocytopenia
(19%), and anaemia (10%).
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.
In patients with CML with resistance or intolerance to prior imatinib therapy, cytopenias
(thrombocytopenia, neutropenia, and anaemia) were a consistent finding. However, the occurrence of
cytopenias was also clearly dependent on the stage of the disease. The frequency of grade 3 and 4
haematological abnormalities is presented in Table 4.
Table 4:
CTC grades 3/4 haematological laboratory abnormalities in
clinical studies in patients with resistance or intolerance to prior
imatinib therapy
Chronic Phase
(n= 1,150)
Accelerated Phase
(n= 502)
Myeloid Blast
Phase
(n= 280)
Lymphoid
Blast Phase
and
Ph+ ALL
(n= 250)
Percent (%) of Patients
Haematology parameters
Neutropenia
47
69
80
79
Thrombocytopenia
41
72
82
78
Anaemia
19
55
75
46
CTC grades: neutropenia (Grade 3 ≥ 0.5– < 1.0 × 10
9
/l, Grade 4 < 0.5 × 10
9
/l); thrombocytopenia (Grade 3 ≥ 25 –
< 50 × 10
9
/l, Grade 4 < 25 × 10
9
/l); anaemia (haemoglobin Grade 3
≥ 65 – < 80 g/l, Grade 4 < 65 g/l).
In the Phase III dose-optimisation study in patients with chronic phase CML, the frequency of
neutropenia, thrombocytopenia and anaemia was lower in the SPRYCEL 100 mg once daily than in
the SPRYCEL 70 mg twice daily group.
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 hypophosphatemia 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. There were no discontinuations of SPRYCEL therapy due to these
biochemical laboratory parameters.
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
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 4% of
patients across treatment groups.
14
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 hypophosphatemia 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.
d. Other special population
While the safety profile of SPRYCEL in the elderly population was similar to that in the younger
population, patients aged 65 years and older are more likely to experience fluid retention events and
dyspnoea and should be monitored closely (see section 4.4).
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 ingested more than the recommended dose should be closely monitored for
myelosuppression and given appropriate supportive treatment.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE06
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.
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 studies
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).
15
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 2,440 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, multicenter, 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.
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 due to disease progression occurred in 3% of SPRYCEL-treated patients and 5% of
imatinib-treated patients.
Efficacy results are presented in Table 5. 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.
16
Table 5:
Efficacy results in newly diagnosed patients with Chronic Phase CML
(12-month data)
SPRYCEL
n= 259
imatinib
n= 260
p-value
Response rate (95% CI)
Cytogenetic response
within 12 months
cCCyR
a
76.8% (71.2–81.8)
66.2% (60.1–71.9)
p< 0.007*
CCyR
b
85.3% (80.4-89.4)
73.5% (67.7-78.7)
⎯
Major Molecular Response
c
52.1% (45.9–58.3)
33.8% (28.1–39.9)
p< 0.00003*
Hazard Ratio (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
a
Confirmed complete cytogenetic response (cCCyR) is defined as a response noted on two consecutive
occasions (at least 28 days apart).
b
Cytogenetic response (CCyR) is based on a single bone marrow cytogenetic evaluation.
c
Major molecular response (at any time) was defined as BCR-ABL ratios ≤ 0.1% by RQ-PCR in peripheral
blood samples standardized on the International scale.
*Adjusted for Hasford Score and indicated statistical significance at a pre-defined nominal level of significance.
CI = confidence interval
Median time to cCCyR was 3.1 months in the SPRYCEL group and 5.6 months in the imatinib group
in patients with a confirmed CCyR. Median time to MMR was 6.3 months in the SPRYCEL group and
9.2 months in the imatinib group in patients with a MMR. The rates of cCCyR in the SPRYCEL and
imatinib treatment groups, respectively, within 3 months (54% and 30%), 6 months (70% and 56%),
and 9 months (75% and 63%) 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%), and 12 months (46% and 28%) were also consistent with the
primary endpoint. The rate of CMR (i.e. at least 4.5-log reduction from a standardised baseline value
BCR-ABL ratio ≤ 0.0032%) at any time was 8.5% versus 4.2% in the SPRYCEL and imatinib
treatment groups, respectively.
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 12-month PFS rate was 96.4% (CI: 94.1% - 98.7%) and 96.7% (CI: 94.4% - 99.0%) for the
dasatinib and imatinib treatment groups, respectively. Transformation to accelerated or blast phase
occurred less frequently with dasatinib (n = 5; 1.9%) than with imatinib-treated patients (n = 9; 3.5%).
The estimated 12-month survival rates for dasatinib and imatinib-treated subjects were 97.2% (CI:
95.2% - 99.3%) and 98.8% (CI: 97.4% - 100%), respectively.
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).
1- An open-label, randomised, non-comparative multicenter 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
17
imatinib group. All subjects were extensively pretreated. Prior complete haematologic response (CHR)
to imatinib was achieved in 93% of the overall patient population. A prior MCyR to imatinib was
achieved in 28% and 29% of the patients in the dasatinib and imatinib arms, respectively.
Median duration of treatment was 23 months for dasatinib (with 44% of patients treated for
> 24 months to date) and 3 months for imatinib (with 10% of patients treated for > 24 months to date).
Ninety-three percent 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.
2- An open-label, single-arm, multicenter 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 6. 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
whether patients had any baseline BCR-ABL mutation, P-loop mutation, or no mutation (63%, 61%
and 62%, respectively).
18
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, multicenter 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 6.
Myeloid Blast Phase CML
An open-label, single-arm, multicenter 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 6.
Lymphoid Blast Phase CML and Ph+ ALL
An open-label, single-arm, multicenter 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 6. 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).
19
Table 6:
Efficacy in phase II SPRYCEL
single-arm clinical studies
a
Chronic
(n= 387)
Accelerated
(n= 174)
Myeloid
Blast
(n= 109)
Lymphoid
Blast
(n= 48)
Ph+ ALL
(n= 46)
Haematologic response rate
b
(%)
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 response
c
(%)
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
91% (88-94)
64% (57-72)
35% (25-45)
14% (3-25)
21% (9-34)
1 Year
2 Year
80% (75-84)
46% (38-54)
20% (11-29)
5% (0-13)
12% (2-23)
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/mm
3
, 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/mm
3
, platelets ≥ 100,000/mm
3
, 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/mm
3
and < 1,000/mm
3
, or platelets ≥ 20,000/mm
3
and
≤ 100,000/mm
3
.
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.
97% (95-99)
83% (77-89)
48% (38-59)
30% (14-47)
1 Year
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 24 months follow-up after the start of dasatinib therapy.
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. Median duration of treatment
was 22 months (range < 1-31 months).
20
Overall
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%]). The main
secondary endpoint of the study also showed comparable efficacy (non-inferiority) between the
100 mg total daily dose and the 140 mg total daily dose (difference in MCyR -0.2%; 95% confidence
interval [-8.9% - 8.5%]). Efficacy results are presented in Table 7.
Table 7:
Efficacy of SPRYCEL in phase III dose-optimisation study: Chronic Phase CML
100 mg once daily
50 mg twice daily
a
140 mg once daily
a
70 mg twice daily
a
All patients
n = 167
n = 168
n = 167
n = 168
Imatinib-resistant patients
n = 124
n = 124
n = 123
n = 126
Haematologic response rate
b
(%) (95% CI)
CHR
92% (86-95)
92% (87-96)
87% (81-92)
88% (82-93)
Cytogenetic response
c
(%) (95% CI)
MCyR
All patients
63% (56-71)
61% (54-69)
63% (55-70)
61% (54-69)
Imatinib-resistant patients
59% (50-68)
56% (47-65)
58% (49-67)
57% (48-66)
CCyR
All patients
50% (42-58)
50% (42-58)
50% (42-58)
54% (46-61)
Imatinib-resistant patients
44% (35-53)
42% (33-52)
42% (33-52)
48% (39-57)
Major Molecular Response
d
(%) (95% CI)
All patients
69% (58-79)
70% (59-80)
72% (60-82)
66% (54-76)
Imatinib-resistant patients
72% (58-83)
69% (54-81)
63% (48-76)
64% (50-76)
Survival (% [95% CI]; Kaplan-Meier estimates)
Progression-Free
1 Year
All patients
90% (86-95)
86% (81-92)
88% (82-93)
87% (82-93)
Imatinib-resistant patients
88% (82-94)
84% (77-91)
86% (80-93)
85% (78-91)
2 Year
All patients
80% (73-87)
76% (68-83)
75% (67-82)
76% (68-83)
Imatinib-resistant patients
77% (68-85)
73% (64-82)
68% (59-78)
72% (63-81)
Overall Survival
1 Year
All patients
96% (93-99)
96% (93-99)
96% (93-99)
94% (90-98)
Imatinib-resistant patients
94% (90-98)
95% (91-99)
97% (93-100)
92% (87-97)
2 Year
All patients
91% (86-96)
90% (86-95)
94% (90-97)
88% (82-93)
Imatinib-resistant patients
89% (84-95)
89% (83-94)
94% (89-98)
84% (78-91)
a
Not a recommended starting dose of SPRYCEL for chronic phase CML (see section 4.2).
b
Haematologic response criteria (all responses confirmed after 4 weeks):
CHR (chronic CML): WBC ≤ institutional ULN, platelets < 450,000/mm
3
, no blasts or promyelocytes in peripheral blood, < 5%
myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.
c
Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (> 0%-35%). MCyR (0%-35%) combines both complete and
partial responses.
d
Major molecular response criteria: Defined as BCR-ABL/control transcripts ≤ 0.1% by RQ-PCR in peripheral blood samples.
Molecular response was evaluated in a subset of assessed patients who had a CCyR.
CI = confidence interval; ULN = upper limit of normal range.
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%]) and 88% (95% CI: [81%-
95%]) for patients treated with 70 mg of dasatinib twice daily.
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%, CCyR in 67%, and major molecular
response in 64%. Based on the Kaplan-Meier estimates, all imatinib-intolerant patients (100%)
maintained MCyR for 1 year and 92% (95% CI: [80%-100%]) maintained MCyR for 18 months. The
estimated rate of PFS in this population was 97% (95% CI: [92%-100%]) at 1 year and 87% (95% CI:
[76%-99%]) at 2 years. The estimated rate of overall survival was 100% at 1 year and 95% (95% CI:
[88%-100%]) at 2 years.
21
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%]). Response rates are presented in Table 8.
Table 8: Efficacy of SPRYCEL in phase III dose-optimisation study: Advanced Phase CML and Ph+
ALL
140 mg once daily
70 mg twice daily
a
Accelerated
(n= 158)
Myeloid
Blast
(n= 75)
Lymphoid
Blast
(n= 33)
Ph+ALL
(n= 40)
Accelerated
(n= 159)
Myeloid
Blast
(n= 74)
Lymphoid
Blast
(n= 28)
Ph+ALL
(n= 44)
MaHR
b
(95% CI)
66%
(59-74)
28%
(18-40)
42%
(26-61)
38%
(23-54)
68%
(60-75)
28%
(19-40)
32%
(16-52)
32%
(19-48)
CHR
b
(95% CI)
47%
(40-56)
17%
(10-28)
21%
(9-39)
33%
(19-49)
52%
(44-60)
18%
(10-28)
14%
(4-33)
25%
(13-40)
NEL
b
(95% CI)
19%
(13-26)
11%
(5-20)
21%
(9-39)
5%
(1-17)
16%
(11-23)
11%
(5-20)
18%
(6-37)
7%
(1-19)
MCyR
c
(95% CI)
39%
(31-47)
28%
(18-40)
52%
(34-69)
70%
(54-83)
43%
(35–51)
30%
(20-42)
46%
(28-66)
52%
(37-68)
CCyR
(95% CI)
32%
(25-40)
17%
(10-28)
39%
(23-58)
50%
(34-66)
33%
(26-41)
23%
(14-34)
43%
(25-63)
39%
(24-55)
a
Not a recommended starting dose of SPRYCEL for advanced phase CML and Ph+ ALL (see section 4.2).
b
Hematologic response criteria (all responses confirmed after 4 weeks): Major hematologic response (MaHR) = complete
hematologic response (CHR) + no evidence of leukaemia (NEL).
CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm
3
, platelets ≥ 100,000/mm
3
, 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/mm
3
and < 1,000/mm
3
, or platelets ≥ 20,000/mm
3
and ≤ 100,000/mm
3
.
c
MCyR combines both complete (0% Ph+ metaphases) and partial (> 0%-35%) responses.
CI = confidence interval; ULN = upper limit of normal range.
The median duration of MaHR in patients with accelerated phase CML was not reached for either
group; the median PFS was 25 months and 26 months for the 140 mg once daily group and the 70 mg
twice daily group, respectively; and the median overall survival was not reached for the 140 mg once
daily group and 31 months for the 70 mg twice daily group.
In patients with myeloid blast phase CML, the median duration of MaHR was 8 months and 9 months
for the 140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was
4 months for both groups; and the median overall survival was 8 months for both groups. In patients
with lymphoid blast phase CML, the median duration of MaHR was 5 months and 8 months for the
140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was 5 months
for both groups, and the median overall survival was 11 months and 9 months, respectively.
In patients with Ph+ ALL, the median duration of MaHR was 5 months and 12 months for the 140 mg
once daily group and the 70 mg twice daily group, respectively; the median PFS was 4 months and
3 months, respectively, and the median overall survival was 7 months and 9 months, respectively.
Paediatric population
Safety and efficacy of dasatinib have not yet been studied in paediatric patients.
The European Medicines Agency has deferred the obligation to submit the results of studies with
SPRYCEL in one or more subsets of the paediatric population in Philadelphia chromosome (BCR-
22
ABL translocation)-positive chronic myeloid leukaemia and Philadelphia chromosome (BCR-ABL
translocation)-positive acute lymphoblastic leukaemia (see section 4.2 for information on paediatric
use).
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 (AUC
τ
) 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.
Distribution
In patients, dasatinib has a large apparent volume of distribution (2,505 l) 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 [
14
C]-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
Elimination is predominantly in the faeces, mostly as metabolites. Following a single oral dose of
[
14
C]-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 C
max
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 C
max
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.
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.
23
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.
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).
No carcinogenesis studies were conducted with dasatinib.
6.
6.1 List of excipients
Tablet core
Lactose monohydrate
Cellulose, microcrystalline
Croscarmellose sodium
Hydroxypropyl cellulose
Magnesium stearate
Film-coating
Hypromellose
Titanium dioxide
Macrogol 400
24
6.2 Incompatibilities
Not applicable.
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
Alu/Alu blisters (calendar blisters and unit dose blisters) and high-density polyethylene (HDPE) bottle
with child resistant closure of polypropylene.
Cartons containing 56 film-coated tablets in 4 blisters of 14 film-coated tablets each.
Cartons containing 60 film-coated tablets in perforated unit dose blisters.
Cartons containing one bottle with 60 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The tablets consist of a core tablet, surrounded by a film coating to prevent exposure of health care
professionals to the active substance. However, if the tablets are unintentionally crushed or broken,
health care professionals should wear disposable chemotherapy gloves for appropriate disposal in
order to minimise the risk of dermal exposure.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
8.
EU/1/06/363/004
EU/1/06/363/007
EU/1/06/363/001
9.
20 November 2006
25
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
26
1.
SPRYCEL 50 mg film-coated
tablets
2.
Each film-coated tablet contains 50 mg dasatinib (as monohydrate).
Excipients
Each tablet contains 67.5 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated
tablet (tablet)
White to off-white, biconvex, oval tablet with "BMS" debossed on one side and "528" on the other
side.
4.
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 mesilate.
Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or
intolerance to prior therapy.
Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with
leukaemia.
Posology
The recommended starting dose for chronic phase CML is 100 mg dasatinib once daily, administered
orally.
The recommended starting dose for accelerated, myeloid or lymphoid blast phase (advanced phase)
CML or Ph+ ALL is 140 mg once daily, administered orally (see section 4.4).
Treatment duration
In clinical studies, treatment with SPRYCEL was continued until disease progression or until no
longer tolerated by the patient. The effect of stopping treatment after the achievement of a complete
cytogenetic response (CCyR) has not been investigated.
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. Dose increase or reduction is recommended based on patient response
and tolerability.
27
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.
Dose adjustment for undesirable effects
Myelosuppression
In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or
discontinuation of study therapy. Platelet transfusion and red cell transfusion were used as appropriate.
Haematopoietic growth factor has been used in patients with resistant myelosuppression.
Guidelines for dose modifications are summarized in Table 1.
Table 1: Dose adjustments for neutropenia and thrombocytopenia
1 Stop treatment until ANC ≥ 1.0 x 10
9
/l
and platelets ≥ 50 x 10
9
/l.
2 Resume treatment at the original
starting dose.
Chronic Phase CML
(starting dose 100 mg once
daily)
ANC < 0.5 x 10
9
/l
and/or
Platelets < 50 x 10
9
/l
3 If platelets < 25 x 10
9
/l and/or
recurrence of ANC < 0.5 x 10
9
/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).
1 Check if cytopenia is related to
leukaemia (marrow aspirate or biopsy).
Accelerated and Blast Phase
CML and Ph+ ALL
(starting dose 140 mg once
daily)
2 If cytopenia is unrelated to leukaemia,
stop treatment until ANC ≥ 1.0 x 10
9
/l
and platelets ≥ 20 x 10
9
/l and resume at
the original starting dose.
ANC < 0.5 x 10
9
/l
and/or
Platelets < 10 x 10
9
/l
3 If recurrence of cytopenia, 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 cytopenia is related to leukaemia,
consider dose escalation to 180 mg
once daily.
ANC: absolute neutrophil count
Non-haematological adverse reactions
If a moderate, grade 2, non-haematological adverse reaction develops with dasatinib, interrupt treatment
until the event has resolved or returned to baseline. Resume at the same dose if this is the first occurrence
and at a reduced dose if this is a recurrent event. If a severe grade 3 or 4, non-haematological adverse
reaction develops with dasatinib, treatment must be withheld until the event has resolved. Thereafter,
treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the
28
event. 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.
Pleural effusion:
if a pleural effusion is diagnosed, interrupt dasatinib until patient is asymptomatic or
has returned to baseline. If the episode does not improve within approximately one week, consider a
course of diuretics or corticosteroids or both concurrently (see sections 4.4 and 4.8). Following
resolution of the first episode, consider reintroduction of dasatinib at the same dose level. Following
resolution of a subsequent episode, reintroduce dasatinib at one dose level reduction. 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 event.
Paediatric population
The safety and efficacy of SPRYCEL in children and adolescents below 18 years of age have not yet
been established. No data are available (see section 5.1).
Elderly population
No clinically relevant age-related pharmacokinetic differences have been observed in these patients. No
specific dose recommendation is necessary in the 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
sections 4.4 and 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.
Tablets must not be crushed or cut in order to minimize the risk of dermal exposure, they must be
swallowed whole. They can be taken with or without a meal and should be taken consistently either in
the morning or in the evening.
Hypersensitivity to the active substance or to any of the excipients.
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
metabolized primarily by or modulate the activity of CYP3A4 (see section 4.5).
Concomitant use of dasatinib and medicinal products that potently inhibit CYP3A4 (e.g. ketoconazole,
itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin) may increase exposure to dasatinib.
Therefore, in patients receiving dasatinib, coadministration of a potent CYP3A4 inhibitor is not
recommended (see section 4.5).
29
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 (H
2
) antagonist (e.g. famotidine), proton pump
inhibitor (e.g. omeprazole), or aluminium hydroxide/magnesium hydroxide may reduce the exposure
to dasatinib. Thus, H
2
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 sections 4.2 and 5.2). Due
to the limitations of this clinical study, caution is recommended when administering dasatinib to
patients with hepatic impairment (see section 4.2).
Important adverse reactions
Myelosuppression
Treatment with dasatinib is associated with anaemia, neutropenia and thrombocytopenia. Their
occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase
CML
.
Complete blood counts should be performed weekly for the first 2 months, and then monthly
thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed
by withholding dasatinib temporarily or by dose reduction (see sections 4.2 and 4.8).
In a Phase III dose-optimisation study in patients with chronic phase CML with resistance or
intolerance to prior imatinib therapy, grade 3 or 4 myelosuppression was reported more frequently in
patients treated with 70 mg twice daily than in patients treated with 100 mg once daily.
Bleeding
In the Phase III study in patients with newly diagnosed chronic phase CML, 1 patient (< 1%) receiving
dasatinib compared to 2 patients (1%) receiving imatinib had grade 3 or 4 haemorrhage. In clinical
studies in patients with resistance or intolerance to prior imatinib therapy, severe central nervous
system (CNS) haemorrhage occurred in < 1% of patients. Eight cases were fatal and 6 of them were
associated with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia. Grade 3 or 4
gastrointestinal haemorrhage occurred in 4% of patients with resistance or intolerance to prior imatinib
therapy and generally required treatment interruptions and transfusions. Other grade 3 or 4
haemorrhage occurred in 2% of patients with resistance or intolerance to prior imatinib therapy. Most
bleeding related events in these patients were typically associated with grade 3 or 4 thrombocytopenia
(see section 4.8). Additionally,
in vitro
and
in vivo
platelet assays suggest that SPRYCEL treatment
reversibly affects platelet activation.
Patients were excluded from participation in initial SPRYCEL clinical studies if they took medicinal
products that inhibit platelet function or anticoagulants. In subsequent studies, the use of
anticoagulants, acetylsalicylic acid, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed
concurrently with SPRYCEL if the platelet count was > 50,000-75,000/mm
3
. Caution should be
exercised if patients are required to take medicinal products that inhibit platelet function or
anticoagulants.
30
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 2 patients (1%) in each of
the dasatinib and the imatinib-treatment groups (see section 4.8). In clinical studies in patients with
resistance or intolerance to prior imatinib therapy, grade 3 or 4 fluid retention was reported in 10% of
patients, including grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients,
respectively. In these studies, grade 3 or 4 ascites and generalised oedema were each reported in < 1%
of patients, and grade 3 or 4 pulmonary oedema was reported in 1% of patients.
Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should
be evaluated by chest X-ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygen
therapy. Fluid retention events were typically managed by supportive care measures that include
diuretics and short courses of steroids (see sections 4.2 and 4.8). While the safety profile of SPRYCEL
in the elderly population was similar to that in the younger population, patients aged 65 years and
older are more likely to experience fluid retention events and dyspnoea and should be monitored
closely. Fluid retention was reported less frequently in patients treated with once daily schedule
compared to twice daily in two Phase III dose-optimisation studies (see section 4.8).
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 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 trials, 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, 14 (< 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 trial of 519 patients with newly diagnosed CML in chronic
phase which included patients with prior cardiac disease. The cardiac adverse reactions of congestive
heart failure/cardiac dysfunction and fatal myocardial infarction were reported in patients taking
dasatinib. Adverse cardiac events were more frequent in patients with risk factors or a history of
cardiac disease. Patients with risk factors (e.g. hypertension, hyperlipidemia, 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. 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 events
(≤ grade 2) and resumed at a dose level reduction for severe events (≥ 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.
31
Lactose
This medicinal product contains 135 mg of lactose monohydrate in a 100 mg daily dose and 189 mg of
lactose monohydrate in a 140 mg daily dose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
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 which potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin,
clarithromycin, ritonavir, telithromycin) may increase exposure to dasatinib. Therefore, in patients
receiving dasatinib, systemic administration of a potent CYP3A4 inhibitor is not recommended.
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. dexamethazone, 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.
Histamine-2 antagonists and proton pump inhibitors
Long-term suppression of gastric acid secretion by H
2
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 C
max
of dasatinib by 42%. The use of antacids should be considered in place
of H
2
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 C
max
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 C
max
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.
32
Pregnancy
There are no adequate data from the use of dasatinib in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
SPRYCEL should not be used during pregnancy unless clearly necessary. If it is used during
pregnancy, the patient must be informed of the potential risk to the foetus.
Breastfeeding
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
The effect of dasatinib on sperm is unknown, therefore both sexually active men and women should
use effective methods of contraception during treatment.
No studies on the effects on the ability to drive and use machines have been performed. Patients
should be advised that they may experience undesirable effects such as dizziness or blurred vision
during treatment with dasatinib. Therefore, caution should be recommended when driving a car or
operating machines.
a. Summary of the safety profile
The data described below reflect exposure to SPRYCEL in 2,440 patients in clinical studies, including
258 patients with newly diagnosed chronic phase CML with a minimum of 12 months follow-up
(starting dose 100 mg once daily) and 2,182 patients with imatinib resistant or intolerant CML or
Ph+ ALL with a minimum of 24 months follow-up (starting dose 100 mg once daily, 140 mg once
daily, 50 mg twice daily, or 70 mg twice daily). The median duration of therapy in this patient
population was 15 months (range 0.03 - 36 months).
Of the 2,440 patients treated, 23% were ≥ 65 years of age, while 5% were ≥ 75 years of age.
In the Phase III study in patients with newly diagnosed chronic phase CML the median duration of
therapy was 14 months (range 0.03-24 months) for SPRYCEL and 14 months (range 0.3-26 months)
for imatinib; the median average daily dose was 99 mg and 400 mg, respectively.
The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Most
reactions were of mild-to-moderate grade.
In the Phase III study in patients with newly diagnosed chronic phase CML, treatment was
discontinued for adverse reactions in 5% of SPRYCEL-treated patients and 4% of imatinib-treated
patients. Among patients with resistance or intolerance to prior imatinib therapy, the rates of
discontinuation for adverse reactions were 15% in chronic phase CML, 16% in accelerated phase
CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML and 8% in Ph+ ALL. In
the Phase III dose-optimisation study in patients with chronic phase CML, the rate of discontinuation
for adverse reactions was lower for patients treated with 100 mg once daily than for those treated with
70 mg twice daily (10% and 16%, respectively); the rates of dose interruption and reduction were also
lower for patients treated with 100 mg once daily than for those treated with 70 mg twice daily. Less
frequent dose reductions and interruptions were also reported for patients with advanced phase CML
and Ph+ ALL treated with 140 mg once daily than for those treated with 70 mg twice daily.
The majority of imatinib-intolerant patients with chronic phase CML were able to tolerate treatment with
SPRYCEL. In clinical studies in chronic phase CML, 10 of the 215 imatinib-intolerant patients had the
33
same grade 3 or 4 non-hematologic toxicity with SPRYCEL as they did with prior imatinib; 8 of these
10 patients were managed with dose reduction and were able to continue SPRYCEL treatment.
The most frequently reported adverse reactions reported in SPRYCEL-treated patients with newly
diagnosed chronic phase CML were fluid retention (including pleural effusion) (19%), diarrhoea
(17%), headache (12%), rash (11%), musculoskeletal pain (11%), nausea (8%), fatigue (8%), myalgia
(6%), vomiting (5%), and muscle inflammation (4%). The most frequently reported adverse reactions
reported in SPRYCEL-treated patients with resistance or intolerance to prior imatinib therapy were
fluid retention (including pleural effusion), diarrhoea, headache, nausea, skin rash, dyspnoea,
haemorrhage, fatigue, musculoskeletal pain, infection, vomiting, cough, abdominal pain and pyrexia.
Drug-related febrile neutropenia was reported in 5% of SPRYCEL-treated patients with resistance or
intolerance to prior imatinib therapy.
In clinical studies with patients with resistance or intolerance to prior imatinib therapy, it was
recommended that treatment with imatinib be discontinued at least 7 days before starting treatment
with SPRYCEL.
b. Tabulated summary of adverse reactions
The following adverse reactions, excluding laboratory abnormalities, were reported in patients in
SPRYCEL clinical studies and post-marketing experience (Table 2). 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, undesirable effects are presented in order of decreasing seriousness.
Table 2: 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, enterocolitis infection
Uncommon
sepsis (including fatal outcome)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon
tumour lysis syndrome
Blood and lymphatic system disorders
Common
febrile neutropenia, pancytopenia
Rare
aplasia pure red cell
Immune system disorders
Uncommon
hypersensitivity (including erythema nodosum)
Metabolism and nutrition disorders
Common
anorexia, appetite disturbances
Uncommon
hyperuricaemia, hypoalbuminemia
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*
a
, syncope, tremor, amnesia
Rare
cerebrovascular accident, transient ischaemic attack, convulsion, optic neuritis
Eye disorders
Common
visual disorder (including visual disturbance, vision blurred, and visual acuity
reduced), dry eye
Uncommon
conjunctivitis
34
Ear and labyrinth disorders
Common
tinnitus
Uncommon
vertigo
Cardiac disorders
Common
congestive heart failure/cardiac dysfunction*
b
, pericardial effusion*, arrhythmia
(including tachycardia), palpitations
Uncommon
myocardial infarction (including fatal outcome)*, electrocardiogram QT prolonged*,
pericarditis, ventricular arrhythmia (including ventricular tachycardia), angina
pectoris, cardiomegaly
Rare
cor pulmonale, myocarditis, acute coronary syndrome
Not known
atrial fibrillation/atrial flutter
Vascular disorders
Very common
haemorrhage
*c
Common
hypertension, flushing
Uncommon
hypotension, thrombophlebitis
Rare
livedo reticularis
Not known
thrombosis/embolism (including pulmonary embolism, deep vein thrombosis)
Respiratory, thoracic and mediastinal disorders
Very common
pleural effusion*, dyspnoea
Common
cough, pulmonary oedema*, pulmonary hypertension*, lung infiltration, pneumonitis
Uncommon
bronchospasm, asthma
Rare
acute respiratory distress syndrome
Not known
interstitial lung disease
Gastrointestinal disorders
Very common
diarrhoea, vomiting, nausea, abdominal pain
Common
gastrointestinal bleeding*, colitis (including neutropenic colitis), gastritis, mucosal
inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension,
constipation, oral soft tissue disorder
Uncommon
pancreatitis, upper gastrointestinal ulcer, oesophagitis, ascites*, anal fissure,
dysphagia
Rare
protein-losing gastroenteropathy
Not known
fatal gastrointestinal haemorrhage*
Hepatobiliary disorders
Uncommon
hepatitis, cholecystitis, cholestasis
Skin and subcutaneous tissue disorders
Very common
skin rash
d
Common
alopecia, dermatitis (including eczema), pruritus, acne, dry skin, urticaria,
hyperhidrosis
Uncommon
acute febrile neutrophilic dermatosis, photosensitivity, pigmentation disorder,
panniculitis, skin ulcer, bullous conditions, nail disorder, palmar-plantar
erythrodysesthesia syndrome
Musculoskeletal and connective tissue disorders
Very common
musculoskeletal pain
Common
arthralgia, myalgia, muscle inflammation, muscular weakness
Uncommon
musculoskeletal stiffness, rhabdomyolysis
Rare
tendonitis
Renal and urinary disorders
Uncommon
renal failure, urinary frequency, proteinuria
Reproductive system and breast disorders
Uncommon
gynecomastia, irregular menstruation
General disorders and administration site conditions
Very common
fluid retention*, fatigue, superficial oedema*
e
, pyrexia
Common
asthenia, pain, chest pain, generalised oedema*, chills
Uncommon
malaise, temperature intolerance
35
Investigations
Common
weight decreased, weight increased
Uncommon
blood creatine phosphokinase increased
Injury, poisoning, and procedural complications
Common
contusion
a
Includes cerebral haematoma, cerebral haemorrhage, extradural haematoma, haemorrhage intracranial, haemorrhagic
stroke, subarachnoid haemorrhage, subdural haematoma, and subdural haemorrhage.
b
Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,
diastolic dysfunction, ejection fraction decreased and ventricular failure.
c
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.
d
Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalised erythema, genital rash,
heat rash, milia, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular,
rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin irritation and urticaria vesiculosa
.
e
Includes auricular swelling, conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, genital
swelling, gravitational oedema, lip oedema, localised oedema, macular oedema, oedema genital, oedema mouth, oedema
peripheral, orbital oedema, penile oedema, periorbital oedema, pitting oedema, scrotal oedema, swelling face and tongue
oedema.
* For additional details, see section c.
c. Description of selected adverse reactions
Myelosuppression
Treatment with SPRYCEL is associated with anaemia, neutropenia and thrombocytopenia. Their
occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase
CML (see section 4.4).
Bleeding
Bleeding drug-related events, 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). In the
Phase III study in patients with newly diagnosed chronic phase CML, 1 patient (< 1%) receiving
SPRYCEL had grade 3 haemorrhage. In clinical studies in patients with resistance or intolerance to
prior imatinib therapy, severe CNS haemorrhage occurred in < 1% of patients. Eight cases were fatal
and 6 of them were associated with CTC grade 4 thrombocytopenia. Grade 3 or 4 gastrointestinal
haemorrhage occurred in 4% of patients with resistance or intolerance to prior imatinib therapy and
generally required treatment interruption and transfusions. Other grade 3 or 4 haemorrhage occurred in
2% of patients with resistance or intolerance to prior imatinib therapy. Most bleeding related events in
these patients were typically associated with grade 3 or 4 thrombocytopenia. Additionally,
in vitro
and
in vivo
platelet assays suggest that SPRYCEL treatment reversibly affects platelet activation (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, grade 1 and 2 pleural effusion were reported in 26 patients
(10%) receiving SPRYCEL. The median time to onset was 28 weeks (range 4-88 weeks). The median
duration of pleural effusion was 50 days (range 5-585 days). This reaction 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 pleural effusion, 73% had a
dose interruption for a median of 15 days (6-56 days). Thirty one percent had a dose reduction.
Additionally, 46% received concomitant diuretics (median duration 64 days) and 27% received
concomitant corticosteroids (median duration 29 days). A single patient underwent a therapeutic
thoracentesis. With appropriate medical care, 23 patients (88% of those with pleural effusion) were
able to continue on SPRYCEL and efficacy was not affected (92% achieved a complete cytogenetic
36
response). Other fluid retention adverse reactions reported in patients taking SPRYCEL were
superficial localised oedema (9%), and generalised oedema (2%). Congestive heart failure/cardiac
dysfunction, pericardial effusions, pulmonary hypertension and pulmonary oedema were also reported
in < 2% of patients.
The use of SPRYCEL is associated with fluid
retention with grade 3 or 4 cases in 10% of patients with
resistance or intolerance to prior imatinib therapy. Grade 3 or 4 pleural and pericardial effusion were
reported in 7% and 1% of patients, respectively. Grade 3 or 4 ascites and generalised oedema were
each reported in < 1%. One percent of patients experienced grade 3 or 4 pulmonary oedema. Fluid
retention events were typically managed by supportive care measures that include diuretics or short
courses of steroids.
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 (see section 4.4).
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, 14 (< 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).
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 23 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 (Table 3a).
Myelosuppression was also reported less frequently with the 100 mg once daily (see Laboratory test
abnormalities below).
37
Table 3a: Selected adverse reactions reported in phase III dose-optimisation study: Chronic Phase
CML
100 mg once daily
n = 165
140 mg once daily
a
n = 163
50 mg twice daily
a
n = 167
70 mg twice daily
a
n = 167
All
grades
Grade
3/4
All
grades
Grade
3/4
All
grades
Grade
3/4
All
grades
Grade
3/4
Percent (%) of patients
Preferred term
Diarrhoea
27
2
30
4
31
2
27
4
Fluid retention
34
4
40
7
37
5
40
10
Superficial oedema
18
0
17
1
19
0
19
1
Pleural effusion
18
2
26
5
24
4
24
5
Generalised
oedema
3
0
5
0
0
0
2
0
Congestive heart
failure/cardiac
dysfunction
b
0
0
4
1
1
1
5
3
Pericardial effusion
2
1
6
2
5
2
2
1
Pulmonary oedema
0
0
0
0
1
1
3
1
Pulmonary
hypertension
0
0
1
0
1
0
1
1
Haemorrhage
11
1
14
1
10
4
16
2
Gastrointestinal
bleeding
2
1
2
0
5
3
4
2
a
Not a recommended starting dose of SPRYCEL for chronic phase CML (see section 4.2).
b
Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,
diastolic dysfunction, ejection fraction decreased, and ventricular failure.
In the Phase III dose-optimisation study in patients with advanced phase CML and Ph+ ALL (median
duration of treatment of 14 months for accelerated phase CML, 3 months for myeloid blast CML,
4 months for lymphoid blast CML and 3 months for Ph+ ALL), fluid retention (pleural effusion and
pericardial effusion) was reported less frequently in patients treated with SPRYCEL 140 mg once
daily than in those treated with 70 mg twice daily (Table 3b).
Table 3b: Selected adverse reactions reported in phase III dose-optimisation study: Advanced Phase
CML and Ph+ ALL
All grades
140 mg once daily
n = 304
All grades
70 mg twice daily
a
n = 305
Grade 3/4
Grade 3/4
Preferred term
Percent (%) of patients
Diarrhoea
28
3
29
4
Fluid retention
33
7
43
11
Superficial oedema
15
< 1
19
1
Pleural effusion
20
6
34
7
Generalised oedema
2
0
3
1
Congestive heart failure/
cardiac dysfunction
b
1
0
2
1
Pericardial effusion
2
1
6
2
Pulmonary oedema
1
1
3
1
Ascites
0
0
1
0
Pulmonary hypertension
0
0
1
< 1
Haemorrhage
23
8
27
7
Gastrointestinal bleeding
8
6
12
6
a
Not a recommended starting dose of SPRYCEL for advanced phase CML and Ph+ ALL (see section 4.2).
b
Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,
diastolic dysfunction, ejection fraction decreased, and ventricular failure.
38
Laboratory test abnormalities:
Haematology
In the Phase III newly diagnosed chronic phase CML study, the following grade 3 or 4 laboratory
abnormalities were reported in patients taking SPRYCEL: neutropenia (21%), thrombocytopenia
(19%), and anaemia (10%).
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.
In patients with CML with resistance or intolerance to prior imatinib therapy, cytopenias
(thrombocytopenia, neutropenia, and anaemia) were a consistent finding. However, the occurrence of
cytopenias was also clearly dependent on the stage of the disease. The frequency of grade 3 and 4
haematological abnormalities is presented in Table 4.
Table 4:
CTC grades 3/4 haematological laboratory abnormalities in
clinical studies in patients with resistance or intolerance to prior
imatinib therapy
Chronic Phase
(n= 1,150)
Accelerated Phase
(n= 502)
Myeloid Blast
Phase
(n= 280)
Lymphoid
Blast Phase
and
Ph+ ALL
(n= 250)
Percent (%) of Patients
Haematology parameters
Neutropenia
47
69
80
79
Thrombocytopenia
41
72
82
78
Anaemia
19
55
75
46
CTC grades: neutropenia (Grade 3 ≥ 0.5– < 1.0 × 10
9
/l, Grade 4 < 0.5 × 10
9
/l); thrombocytopenia (Grade 3 ≥ 25 –
< 50 × 10
9
/l, Grade 4 < 25 × 10
9
/l); anaemia (haemoglobin Grade 3
≥ 65 – < 80 g/l, Grade 4 < 65 g/l).
In the Phase III dose-optimisation study in patients with chronic phase CML, the frequency of
neutropenia, thrombocytopenia and anaemia was lower in the SPRYCEL 100 mg once daily than in
the SPRYCEL 70 mg twice daily group.
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 hypophosphatemia 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. There were no discontinuations of SPRYCEL therapy due to these
biochemical laboratory parameters.
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
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 4% of
patients across treatment groups.
39
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 hypophosphatemia 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.
d. Other special population
While the safety profile of SPRYCEL in the elderly population was similar to that in the younger
population, patients aged 65 years and older are more likely to experience fluid retention events and
dyspnoea and should be monitored closely (see section 4.4).
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 ingested more than the recommended dose should be closely monitored for
myelosuppression and given appropriate supportive treatment.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE06
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.
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 studies
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).
40
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 2,440 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, multicenter, 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.
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 due to disease progression occurred in 3% of SPRYCEL-treated patients and 5% of
imatinib-treated patients.
Efficacy results are presented in Table 5. 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.
41
Table 5:
Efficacy results in newly diagnosed patients with Chronic Phase CML
(12-month data)
SPRYCEL
n= 259
imatinib
n= 260
p-value
Response rate (95% CI)
Cytogenetic response
within 12 months
cCCyR
a
76.8% (71.2–81.8)
66.2% (60.1–71.9)
p< 0.007*
CCyR
b
85.3% (80.4-89.4)
73.5% (67.7-78.7)
⎯
Major Molecular Response
c
52.1% (45.9–58.3)
33.8% (28.1–39.9)
p< 0.00003*
Hazard Ratio (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
a
Confirmed complete cytogenetic response (cCCyR) is defined as a response noted on two consecutive
occasions (at least 28 days apart).
b
Cytogenetic response (CCyR) is based on a single bone marrow cytogenetic evaluation.
c
Major molecular response (at any time) was defined as BCR-ABL ratios ≤ 0.1% by RQ-PCR in peripheral
blood samples standardized on the International scale.
*Adjusted for Hasford Score and indicated statistical significance at a pre-defined nominal level of significance.
CI = confidence interval
Median time to cCCyR was 3.1 months in the SPRYCEL group and 5.6 months in the imatinib group
in patients with a confirmed CCyR. Median time to MMR was 6.3 months in the SPRYCEL group and
9.2 months in the imatinib group in patients with a MMR. The rates of cCCyR in the SPRYCEL and
imatinib treatment groups, respectively, within 3 months (54% and 30%), 6 months (70% and 56%),
and 9 months (75% and 63%) 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%), and 12 months (46% and 28%) were also consistent with the
primary endpoint. The rate of CMR (i.e. at least 4.5-log reduction from a standardised baseline value
BCR-ABL ratio ≤ 0.0032%) at any time was 8.5% versus 4.2% in the SPRYCEL and imatinib
treatment groups, respectively.
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 12-month PFS rate was 96.4% (CI: 94.1% - 98.7%) and 96.7% (CI: 94.4% - 99.0%) for the
dasatinib and imatinib treatment groups, respectively. Transformation to accelerated or blast phase
occurred less frequently with dasatinib (n = 5; 1.9%) than with imatinib-treated patients (n = 9; 3.5%).
The estimated 12-month survival rates for dasatinib and imatinib-treated subjects were 97.2% (CI:
95.2% - 99.3%) and 98.8% (CI: 97.4% - 100%), respectively.
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).
1- An open-label, randomised, non-comparative multicenter 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
42
imatinib group. All subjects were extensively pretreated. Prior complete haematologic response (CHR)
to imatinib was achieved in 93% of the overall patient population. A prior MCyR to imatinib was
achieved in 28% and 29% of the patients in the dasatinib and imatinib arms, respectively.
Median duration of treatment was 23 months for dasatinib (with 44% of patients treated for
> 24 months to date) and 3 months for imatinib (with 10% of patients treated for > 24 months to date).
Ninety-three percent 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.
2- An open-label, single-arm, multicenter 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 6. 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
whether patients had any baseline BCR-ABL mutation, P-loop mutation, or no mutation (63%, 61%
and 62%, respectively).
43
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, multicenter 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 6.
Myeloid Blast Phase CML
An open-label, single-arm, multicenter 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 6.
Lymphoid Blast Phase CML and Ph+ ALL
An open-label, single-arm, multicenter 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 6. 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).
44
Table 6:
Efficacy in phase II SPRYCEL
single-arm clinical studies
a
Chronic
(n= 387)
Accelerated
(n= 174)
Myeloid
Blast
(n= 109)
Lymphoid
Blast
(n= 48)
Ph+ ALL
(n= 46)
Haematologic response rate
b
(%)
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 response
c
(%)
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
91% (88-94)
64% (57-72)
35% (25-45)
14% (3-25)
21% (9-34)
1 Year
2 Year
80% (75-84)
46% (38-54)
20% (11-29)
5% (0-13)
12% (2-23)
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/mm
3
, 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/mm
3
, platelets ≥ 100,000/mm
3
, 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/mm
3
and < 1,000/mm
3
, or platelets ≥ 20,000/mm
3
and
≤ 100,000/mm
3
.
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.
97% (95-99)
83% (77-89)
48% (38-59)
30% (14-47)
1 Year
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 24 months follow-up after the start of dasatinib therapy.
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. Median duration of treatment
was 22 months (range < 1-31 months).
45
Overall
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%]). The main
secondary endpoint of the study also showed comparable efficacy (non-inferiority) between the
100 mg total daily dose and the 140 mg total daily dose (difference in MCyR -0.2%; 95% confidence
interval [-8.9% - 8.5%]). Efficacy results are presented in Table 7.
Table 7:
Efficacy of SPRYCEL in phase III dose-optimisation study: Chronic Phase CML
100 mg once daily
50 mg twice daily
a
140 mg once daily
a
70 mg twice daily
a
All patients
n = 167
n = 168
n = 167
n = 168
Imatinib-resistant patients
n = 124
n = 124
n = 123
n = 126
Haematologic response rate
b
(%) (95% CI)
CHR
92% (86-95)
92% (87-96)
87% (81-92)
88% (82-93)
Cytogenetic response
c
(%) (95% CI)
MCyR
All patients
63% (56-71)
61% (54-69)
63% (55-70)
61% (54-69)
Imatinib-resistant patients
59% (50-68)
56% (47-65)
58% (49-67)
57% (48-66)
CCyR
All patients
50% (42-58)
50% (42-58)
50% (42-58)
54% (46-61)
Imatinib-resistant patients
44% (35-53)
42% (33-52)
42% (33-52)
48% (39-57)
Major Molecular Response
d
(%) (95% CI)
All patients
69% (58-79)
70% (59-80)
72% (60-82)
66% (54-76)
Imatinib-resistant patients
72% (58-83)
69% (54-81)
63% (48-76)
64% (50-76)
Survival (% [95% CI]; Kaplan-Meier estimates)
Progression-Free
1 Year
All patients
90% (86-95)
86% (81-92)
88% (82-93)
87% (82-93)
Imatinib-resistant patients
88% (82-94)
84% (77-91)
86% (80-93)
85% (78-91)
2 Year
All patients
80% (73-87)
76% (68-83)
75% (67-82)
76% (68-83)
Imatinib-resistant patients
77% (68-85)
73% (64-82)
68% (59-78)
72% (63-81)
Overall Survival
1 Year
All patients
96% (93-99)
96% (93-99)
96% (93-99)
94% (90-98)
Imatinib-resistant patients
94% (90-98)
95% (91-99)
97% (93-100)
92% (87-97)
2 Year
All patients
91% (86-96)
90% (86-95)
94% (90-97)
88% (82-93)
Imatinib-resistant patients
89% (84-95)
89% (83-94)
94% (89-98)
84% (78-91)
a
Not a recommended starting dose of SPRYCEL for chronic phase CML (see section 4.2).
b
Haematologic response criteria (all responses confirmed after 4 weeks):
CHR (chronic CML): WBC ≤ institutional ULN, platelets < 450,000/mm
3
, no blasts or promyelocytes in peripheral blood, < 5%
myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.
c
Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (> 0%-35%). MCyR (0%-35%) combines both complete and
partial responses.
d
Major molecular response criteria: Defined as BCR-ABL/control transcripts ≤ 0.1% by RQ-PCR in peripheral blood samples.
Molecular response was evaluated in a subset of assessed patients who had a CCyR.
CI = confidence interval; ULN = upper limit of normal range.
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%]) and 88% (95% CI: [81%-
95%]) for patients treated with 70 mg of dasatinib twice daily.
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%, CCyR in 67%, and major molecular
response in 64%. Based on the Kaplan-Meier estimates, all imatinib-intolerant patients (100%)
maintained MCyR for 1 year and 92% (95% CI: [80%-100%]) maintained MCyR for 18 months. The
estimated rate of PFS in this population was 97% (95% CI: [92%-100%]) at 1 year and 87% (95% CI:
[76%-99%]) at 2 years. The estimated rate of overall survival was 100% at 1 year and 95% (95% CI:
[88%-100%]) at 2 years.
46
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%]). Response rates are presented in Table 8.
Table 8: Efficacy of SPRYCEL in phase III dose-optimisation study: Advanced Phase CML and Ph+
ALL
140 mg once daily
70 mg twice daily
a
Accelerated
(n= 158)
Myeloid
Blast
(n= 75)
Lymphoid
Blast
(n= 33)
Ph+ALL
(n= 40)
Accelerated
(n= 159)
Myeloid
Blast
(n= 74)
Lymphoid
Blast
(n= 28)
Ph+ALL
(n= 44)
MaHR
b
(95% CI)
66%
(59-74)
28%
(18-40)
42%
(26-61)
38%
(23-54)
68%
(60-75)
28%
(19-40)
32%
(16-52)
32%
(19-48)
CHR
b
(95% CI)
47%
(40-56)
17%
(10-28)
21%
(9-39)
33%
(19-49)
52%
(44-60)
18%
(10-28)
14%
(4-33)
25%
(13-40)
NEL
b
(95% CI)
19%
(13-26)
11%
(5-20)
21%
(9-39)
5%
(1-17)
16%
(11-23)
11%
(5-20)
18%
(6-37)
7%
(1-19)
MCyR
c
(95% CI)
39%
(31-47)
28%
(18-40)
52%
(34-69)
70%
(54-83)
43%
(35–51)
30%
(20-42)
46%
(28-66)
52%
(37-68)
CCyR
(95% CI)
32%
(25-40)
17%
(10-28)
39%
(23-58)
50%
(34-66)
33%
(26-41)
23%
(14-34)
43%
(25-63)
39%
(24-55)
a
Not a recommended starting dose of SPRYCEL for advanced phase CML and Ph+ ALL (see section 4.2).
b
Hematologic response criteria (all responses confirmed after 4 weeks): Major hematologic response (MaHR) = complete
hematologic response (CHR) + no evidence of leukaemia (NEL).
CHR: WBC ≤ institutional ULN, ANC ≥ 1,000/mm
3
, platelets ≥ 100,000/mm
3
, 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/mm
3
and < 1,000/mm
3
, or platelets ≥ 20,000/mm
3
and ≤ 100,000/mm
3
.
c
MCyR combines both complete (0% Ph+ metaphases) and partial (> 0%-35%) responses.
CI = confidence interval; ULN = upper limit of normal range.
The median duration of MaHR in patients with accelerated phase CML was not reached for either
group; the median PFS was 25 months and 26 months for the 140 mg once daily group and the 70 mg
twice daily group, respectively; and the median overall survival was not reached for the 140 mg once
daily group and 31 months for the 70 mg twice daily group.
In patients with myeloid blast phase CML, the median duration of MaHR was 8 months and 9 months
for the 140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was
4 months for both groups; and the median overall survival was 8 months for both groups. In patients
with lymphoid blast phase CML, the median duration of MaHR was 5 months and 8 months for the
140 mg once daily group and the 70 mg twice daily group, respectively; the median PFS was 5 months
for both groups, and the median overall survival was 11 months and 9 months, respectively.
In patients with Ph+ ALL, the median duration of MaHR was 5 months and 12 months for the 140 mg
once daily group and the 70 mg twice daily group, respectively; the median PFS was 4 months and
3 months, respectively, and the median overall survival was 7 months and 9 months, respectively.
Paediatric population
Safety and efficacy of dasatinib have not yet been studied in paediatric patients.
The European Medicines Agency has deferred the obligation to submit the results of studies with
SPRYCEL in one or more subsets of the paediatric population in Philadelphia chromosome (BCR-
47
ABL translocation)-positive chronic myeloid leukaemia and Philadelphia chromosome (BCR-ABL
translocation)-positive acute lymphoblastic leukaemia (see section 4.2 for information on paediatric
use).
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 (AUC
τ
) 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.
Distribution
In patients, dasatinib has a large apparent volume of distribution (2,505 l) 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 [
14
C]-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
Elimination is predominantly in the faeces, mostly as metabolites. Following a single oral dose of
[
14
C]-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 C
max
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 C
max
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.
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.
48
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.
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).
No carcinogenesis studies were conducted with dasatinib.
6.
6.1 List of excipients
Tablet core
Lactose monohydrate
Cellulose, microcrystalline
Croscarmellose sodium
Hydroxypropyl cellulose
Magnesium stearate
Film-coating
Hypromellose
Titanium dioxide
Macrogol 400
49
6.2 Incompatibilities
Not applicable.
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
Alu/Alu blisters (calendar blisters and unit dose blisters) and high-density polyethylene (HDPE) bottle
with child resistant closure of polypropylene.
Cartons containing 56 film-coated tablets in 4 blisters of 14 film-coated tablets each.
Cartons containing 60 film-coated tablets in perforated unit dose blisters.
Cartons containing one bottle with 60 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The tablets consist of a core tablet, surrounded by a film coating to prevent exposure of health care
professionals to the active substance. However, if the tablets are unintentionally crushed or broken,
health care professionals should wear disposable chemotherapy gloves for appropriate disposal in
order to minimise the risk of dermal exposure.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
8.
EU/1/06/363/005
EU/1/06/363/008
EU/1/06/363/002
9.
20 November 2006
50
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
51
1.
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
76
1.
FURTHER 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; cellulose, microcrystalline; croscarmellose sodium;
hydroxypropyl cellulose; magnesium stearate
Film-coating:
hypromellose; titanium dioxide; 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.
SPRYCEL 20 mg, 50 mg or 70 mg film-coated tablets are available in cartons containing
56 film-coated tablets in 4 blisters of 14 film-coated tablets each, and in cartons containing
60 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 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
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH
United Kingdom
Manufacturer
Bristol-Myers Squibb
Rue du Docteur André Gilles
28230 Epernon
France
Bristol-Myers Squibb S.r.l.
Contrada Fontana del Ceraso
03012 Anagni (FR)
Italy
176
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Belgique/België/Belgien
B
RISTOL
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YERS
S
QUIBB
B
ELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
Luxembourg/Luxemburg
B
RISTOL
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YERS
S
QUIBB
B
ELGIUM
S.A./N.V.
Tél/Tel: + 32 2 352 76 11
България
B
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YERS
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QUIBB
G
YÓGYSZERKERESKEDELMI
K
FT
.
Teл.: + 359 800 12 400
Magyarország
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QUIBB
G
YÓGYSZERKERESKEDELMI
K
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.
Tel.: + 36 1 301 9700
Česká republika
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RISTOL
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Tel: + 420 221 016 111
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S.
R
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L
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Tel: + 39 06 50 39 61
Danmark
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QUIBB
Tlf: + 45 45 93 05 06
Nederland
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S
QUIBB
BV
Tel: + 31 34 857 42 22
Deutschland
B
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YERS
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QUIBB
G
MB
H
&
C
O
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KG
A
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Tel: + 49 89 121 42-0
Norge
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YERS
S
QUIBB
N
ORWAY
L
TD
Tlf: + 47 67 55 53 50
Eesti
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QUIBB
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ESMB
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Tel: + 43 1 60 14 30
Ελλάδα
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YERS
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QUIBB
A.E.
Τηλ: + 30 210 6074300
Polska
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YERS
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P
OLSKA
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Z O
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Tel.: + 48 22 5796666
España
B
RISTOL
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YERS
S
QUIBB
,
S.A.
Tel: + 34 91 456 53 00
Portugal
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F
ARMACÊUTICA
P
ORTUGUESA
, S.A.
Tel: + 351 21 440 70 00
France
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YERS
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QUIBB
S
ARL
Tél: + 33 (0)810 410 500
România
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YÓGYSZERKERESKEDELMI
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Tel: + 40 (0)21 272 16 00
Ireland
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RISTOL
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YERS
S
QUIBB
P
HARMACEUTICALS
L
TD
Tel: + 353 (1 800) 749 749
Slovenija
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YERS
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QUIBB SPOL
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Tel: + 386 1 236 47 00
Ísland
V
ISTOR HF
Sími: + 354 535 7000
Slovenská republika
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QUIBB SPOL
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Tel: + 421 2 59298411
Italia
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YERS
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QUIBB
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L
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Tel: + 39 06 50 39 61
Suomi/Finland
O
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B
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QUIBB
(F
INLAND
)
A
B
Puh/Tel: + 358 9 251 21 230
177
Κύπρος
BRISTOL-MYERS
SQUIBB
A.E
Τηλ: + 357 800 92666
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QUIBB
AB
Tel: + 46 8 704 71 00
Latvija
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YÓGYSZERKERESKEDELMI
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Tel: + 371 67 50 21 85
United Kingdom
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QUIBB
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HARMACEUTICALS
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Tel: + 44 (0800) 731 1736
Lietuva
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YÓGYSZERKERESKEDELMI
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Tel: + 370 5 2790 762
This leaflet was last approved 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
.
178
Source: European Medicines Agency
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