Bristol-Myers Squibb Pharmaceutical Limited

SPRYCEL^® 20 mg film-coated tablets

SPRYCEL^® 50 mg film-coated tablets

SPRYCEL^® 70 mg film-coated tablets

SPRYCEL^® 80 mg film-coated tablets

SPRYCEL^® 100 mg film-coated tablets

SPRYCEL^® 140 mg film-coated tablets

Each film-coated tablet contains 20 mg, 50 mg, 70 mg, 80 mg, 100 mg or 140 mg dasatinib (as monohydrate).

Excipients with known effect

Each 20 mg tablet contains 27 mg of lactose monohydrate.

Each 50 mg tablet contains 67.5 mg of lactose monohydrate.

Each 70 mg tablet contains 94.5 mg of lactose monohydrate.

Each 80 mg tablet contains 108 mg of lactose monohydrate.

Each 100 mg tablet contains 135.0 mg of lactose monohydrate.

Each 140 mg tablet contains 189 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

20 mg: White to off-white, biconvex, round tablet with “BMS” debossed on one side and “527” on the other side.

50 mg: White to off-white, biconvex, oval tablet with “BMS” debossed on one side and “528” on the other side.

70 mg: White to off-white, biconvex, round tablet with “BMS” debossed on one side and “524” on the other side.

80 mg: White to off-white, biconvex, triangular tablet with "BMS 80" debossed on one side and "855" on the other side.

100 mg: White to off-white, biconvex, oval tablet with “BMS 100” debossed on one side and “852” on the other side.

140 mg: White to off-white, biconvex, round tablet with "BMS 140" debossed on one side and "857" on the other side.

SPRYCEL is indicated for the treatment of adult patients with:

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

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

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 adverse reactions

Myelosuppression

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

Guidelines for dose modifications are summarized in Table 1.

Table 1: Dose adjustments for neutropenia and thrombocytopenia

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 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 listed in section 6.1.

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).

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

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

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

Special populations

Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose (see 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. In imatinib resistant or intolerant patients, complete blood counts should be performed weekly for the first 2 months, and then monthly thereafter, or as clinically indicated. In patients with newly diagnosed chronic phase CML, complete blood counts should be performed every 2 weeks for the first 6 weeks, every 3 months for 2 years and then every 6 months thereafter. Myelosuppression was generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction (see sections 4.2 and 4.8).

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/mm³. Caution should be exercised if patients are required to take medicinal products that inhibit platelet function or anticoagulants.

Fluid retention

Dasatinib is associated with fluid retention. In the Phase III clinical study in patients with newly diagnosed chronic phase CML, grade 3 or 4 fluid retention was reported in 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 11% of patients, including grade 3 or 4 pleural and pericardial effusion reported in 7% and 2% 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).

Pulmonary arterial hypertension (PAH)

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

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib therapy. An echocardiography should be performed at treatment initiation in every patient presenting symptoms of cardiac disease and considered in patients with risk factors for cardiac or pulmonary disease. Patients who develop dyspnoea and fatigue after initiation of therapy should be evaluated for common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. In accordance with recommendations for management of non-haematologic adverse reactions (see section 4.2) the dose of dasatinib should be reduced or therapy interrupted during this evaluation. If no explanation is found, or if there is no improvement with dose reduction or interruption, the diagnosis of PAH should be considered. The diagnostic approach should follow standard practice guidelines. If PAH is confirmed, dasatinib should be permanently discontinued. Follow up should be performed according to standard practice guidelines. Improvements in haemodynamic and clinical parameters have been observed in dasatinib-treated patients with PAH following cessation of dasatinib therapy.

QT Prolongation

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT Interval) (see section 5.3). In 258 dasatinib-treated patients and 258 imatinib-treated patients 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, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one of these patients (1%) experienced a QTcF > 500 msec.

Dasatinib should be administered with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalaemia or hypomagnesaemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicinal products or other medicinal products which lead to QT prolongation, and cumulative high dose anthracycline therapy. Hypokalaemia or hypomagnesaemia should be corrected prior to dasatinib administration.

Cardiac adverse reactions

Dasatinib was studied in a randomised 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.

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

Antacids

Non-clinical data demonstrate that the solubility of dasatinib is pH-dependent. In healthy subjects, the concomitant use of aluminium hydroxide/magnesium hydroxide antacids with SPRYCEL reduced the AUC of a single dose of SPRYCEL by 55% and the 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.

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.

Breast-feeding

There is insufficient/limited information on the excretion of dasatinib in human or animal breast milk. Physico-chemical and available pharmacodynamic/toxicological data on dasatinib point to excretion in breast milk and a risk to the suckling child cannot be excluded.

Breast-feeding should be stopped during treatment with SPRYCEL.

Fertility

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 adverse reactions such as dizziness or blurred vision during treatment with dasatinib. Therefore, caution should be recommended when driving a car or operating machines.

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 and 2,182 patients with imatinib resistant or intolerant CML or Ph+ ALL. In the newly diagnosed study, patients had a minimum of 12 months follow-up (starting dose 100 mg once daily) and in the imatinib resistant or intolerant CML or Ph+ ALL studies, 1,520 patients had a minimum of 24 months follow-up and 662 patients with chronic phase CML had a mininum of 60 months follow-up (starting dose 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily).

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 median duration of therapy in 2,182 patients with CML or Ph+ ALL resistant or intolerant to imatinib was 15 months (range 0 - 65.6 months). In patients with resistant or intolerant chronic phase CML, the median duration of treatment for patients still on therapy (n=205) was 59 months (range 28-66 months).

Of the 2,440 patients treated, 23% were 65 years of age, while 5% were 75 years of age.

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 at 2 years were 15% in chronic phase CML for all dosages, 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 with a minimimum of 60 months follow-up, the rate of discontinuation for adverse reactions was 18% for patients treated with 100 mg once daily.

The majority of imatinib-intolerant patients with chronic phase CML were able to tolerate treatment with SPRYCEL. In clinical studies with 24 months follow-up in chronic phase CML, 10 of the 215 imatinib-intolerant patients had the 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.

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, adverse reactions are presented in order of decreasing seriousness.

Table 2: Tabulated summary of adverse reactions

^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, both feet oedema, both lower limb swelling, conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, genital swelling, gravitational oedema, incision site oedema, lip oedema, localised oedema, macular oedema, oedema genital, oedema mouth, oedema peripheral, orbital oedema, penile oedema, periorbital oedema, pitting oedema, scrotal oedema, skin swelling, swelling face and tongue oedema

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

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 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 11% of patients with resistance or intolerance to prior imatinib therapy. Grade 3 or 4 pleural and pericardial effusion were reported in 7% and 2% of patients, respectively. Of patients reporting a grade 3 or 4 pleural effusion, 87% reported improvement to grade 0-2. 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.

Pulmonary arterial hypertension (PAH)

PAH (pre-capillary pulmonary arterial hypertension confirmed by right heart catheterization) has been reported in association with dasatinib exposure in post-marketing reports. In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment. Patients with PAH reported during dasatinib treatment were often taking concomitant medications or had co-morbidities in addition to the underlying malignancy. Improvements in haemodynamic and clinical parameters have been observed in patients with PAH following discontinuation of dasatinib.

QT Prolongation

In the Phase III study in patients with newly diagnosed chronic phase CML, one patient (< 1%) of the SPRYCEL-treated patients had a QTcF > 500 msec (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, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one patients (1%) experienced a QTcF > 500 msec (see section 4.4).

Cardiac adverse reactions

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

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).

Table 3a: Selected adverse reactions reported in phase III dose-optimisation study: Chronic Phase CML (minimum of 24 months follow-up)

^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.

With a minimum follow-up of 60 months, long-term cumulative safety data are available for the 100 mg once daily dose. Due to the allowance of switching to the 100 mg once daily dosing in the other three arms of the trial, safety results of these treatment groups are similar to the 100 mg once daily dose. Among patients treated with a starting dose of 100 mg once daily, the cumulative rates of many adverse drug reactions (all grades) were identical at 2 and 5 years including congestive heart failure/cardiac dysfunction, pericardial effusion, pulmonary oedema, pulmonary hypertension, gastrointestinal bleeding (see Table 3a for adverse reactions data) or very similar for diarrhoea (27% vs. 28%), and generalised oedema (3% vs. 4%). Adverse drug reactions (all grades) that continued to occur in patients treated on the 100 mg once daily schedule at 2 and 5 years included: overall fluid retention (34% vs. 42%), pleural effusion (18% vs. 24%), and superficial oedema (18% vs. 21%). Grade 3 or 4 pleural effusion among patients treated with 100 mg once daily at 2 and 5 years was 2% vs. 4%, respectively.

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

^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.

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

CTC grades: neutropenia (Grade 3 0.5– < 1.0 × 10⁹/l, Grade 4 < 0.5 × 10⁹/l); thrombocytopenia (Grade 3 25 – < 50 × 10⁹/l, Grade 4 < 25 × 10⁹/l); anaemia (haemoglobin Grade 3 65 – < 80 g/l, Grade 4 < 65 g/l).

Cumulative grade 3 or 4 cytopenias among patients treated with 100 mg once daily were similar at 2 and 5 years including: neutropenia (35% vs. 36%), thrombocytopenia (23% vs. 24%) and anaemia (13% vs. 13%).

In patients who experienced grade 3 or 4 myelosuppression, recovery generally occurred following brief dose interruptions and/or reductions and permanent discontinuation of treatment occurred in 5% of patients. Most patients continued treatment without further evidence of myelosuppression.

Biochemistry (2 year follow-up)

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.

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.

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).

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

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 efficacy and safety

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

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

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

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

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

A total of 2,440 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. The study is ongoing.

A total of 519 patients were randomised to a treatment group: 259 to SPRYCEL and 260 to imatinib. Baseline characteristics were well balanced between the two treatment groups with respect to age (median age was 46 years for the SPRYCEL group and 49 years for the imatinib group with 10% and 11% of patients 65 years of age or older, respectively), gender (women 44% and 37%, respectively), and race (Caucasian 51% and 55%; Asian 42% and 37%, respectively). At baseline, the distribution of Hasford Scores was similar in the SPRYCEL and imatinib treatment groups (low risk: 33% and 34%; intermediate risk 48% and 47%; high risk: 19% and 19%, respectively).

With a minimum of 12 months follow-up, 85% of patients randomised to the SPRYCEL group and 81% of patients randomised to the imatinib group were still receiving first-line treatment. Discontinuation within 12 months due to disease progression occurred in 3% of SPRYCEL-treated patients and 5% of imatinib-treated patients.

With a minimum of 24 months follow-up, 77% of patients randomised to the SPRYCEL group and 75% of patients randomised to the imatinib group were still receiving first-line treatment. Discontinuation within 24 months due to disease progression occurred in 5% of SPRYCEL-treated patients and 7% 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.

Table 5: Efficacy results in newly diagnosed patients with Chronic Phase CML

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

^b Complete cytogenetic response (CCyR) is based on a single bone marrow cytogenetic evaluation.

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

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

CI = confidence interval

After 24 months of follow-up, median time to cCCyR was 3.1 months in the SPRYCEL group and 5.7 months in the imatinib group in patients with a confirmed CCyR. Median time to MMR after 24 months of follow-up was 8.8 months in the SPRYCEL group and 12.1 months in the imatinib group in patients with a MMR. These results are consistent with those seen at 12 months.

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

The rates of cCCyR in the SPRYCEL and imatinib treatment groups, respectively, within 3 months (54% and 30%), 6 months (70% and 56%), 9 months (75% and 63%), and 24 months (80% and 74%) were consistent with the primary endpoint. The rates of MMR in the SPRYCEL and imatinib treatment groups, respectively, within 3 months (8% and 0.4%), 6 months (27% and 8%), 9 months (39% and 18%), 12 months (46% and 28%), and 24 months (64% and 46%) were also consistent with the primary endpoint. Of the patients achieving an MMR at 12 months, 97% in the SPRYCEL group and 92.4% in the imatinib group maintained their MMR at 24 months.

The proportion of patients achieving BCR-ABL ratio of 0.01% (4-log reduction) at any time was higher in the SPRYCEL group compared to the imatinib group (29.7% versus 19.2%). The proportion of patients achieving BCR-ABL ratio of 0.0032% (4.5-log reduction) at any time was higher in the SPRYCEL group compared to the imatinib group (18.1% versus 8.8%).

The rate of MMR at any time in each risk group determined by Hasford score was higher in the SPRYCEL group compared with the imatinib group (low risk: 73% and 56%; intermediate risk: 61% and 50%; high risk: 57% and 38%, 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 24-month PFS rate was 93.7% (CI: 90.6% - 96.8%) and 92.1% (CI: 88.6% - 95.6%) for the dasatinib and imatinib treatment groups, respectively. At 24 months, transformation to accelerated or blast phase occurred in less than half the number of dasatinib-treated patients (n=6; 2.3%) compared with imatinib-treated patients (n=13; 5%). The estimated 24-month survival rates for dasatinib and imatinib-treated patients were 95.3% (CI: 92.7% - 97.9%) and 95.2% (CI: 92.6% - 97.9%), respectively.

The safety of dasatinib in newly diagnosed chronic phase CML patients with a minimum of 24-months follow-up was consistent with the known safety profile (see sections 4.4 and 4.8).

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 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).

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).

Table 6: Efficacy in phase II SPRYCEL single-arm clinical studies^a

Data described in this table are from studies using a starting dose of 70 mg twice daily. See section 4.2 for the recommended starting dose.

^a Numbers in bold font are the results of primary endpoints.

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

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

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

NEL: same criteria as for CHR but ANC 500/mm³ and < 1,000/mm³, or platelets 20,000/mm³ and 100,000/mm³.

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

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

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

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

Two randomised, open-label studies were conducted to evaluate the efficacy of dasatinib administered once daily compared with dasatinib administered twice daily. Results described below are based on a minimum of 24 months and 60 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 29 months (range < 1-66 months). In patients with resistant or intolerant chronic phase CML, the median duration of treatment for patients still on therapy (n=205) was 59 months (range 28-66 months).

Efficacy was achieved across all dasatinib treatment groups with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% confidence interval [-6.8% - 10.6%]). 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 and 8.

Table 7: Efficacy of SPRYCEL in phase III dose-optimisation study: Chronic Phase CML (2-year results)

^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/mm³, no blasts or promyelocytes in peripheral blood, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.

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

^d Major molecular response criteria: Defined as BCR-ABL/control transcripts 0.1% by RQ-PCR in peripheral blood samples. Molecular response was evaluated in a subset of assessed patients who had a CCyR.

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

Table 8: Efficacy of SPRYCEL in phase III dose-optimisation study: Chronic Phase CML (5-year results)

^a Not a recommended starting dose of SPRYCEL for chronic phase CML (see section 4.2).

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

Based on the Kaplan-Meier estimates, the proportion of patients treated with dasatinib 100 mg once daily who maintained MCyR for 18 months was 93% (95% CI: [88%-98%]) and 88% (95% CI: [81%-95%]) for patients treated with 70 mg of dasatinib twice daily.

In patients resistant to imatinib who received 100 mg once daily, major molecular response (MMR) in all patients assessed for MMR was achieved in 35% within 2 years and 42% within 5 years.

Efficacy was also assessed in patients who were intolerant to imatinib. In this population of patients who received 100 mg once daily, MCyR was achieved in 77% and CCyR in 67%. In the intolerant population receiving 100 mg once daily, MMR in all patients assessed for MMR was achieved in 43% within 2 years and 53% within 5 years. Based on the Kaplan-Meier estimates, all imatinib-intolerant patients (100%) maintained MCyR for 1 year and 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 and 56% (95% CI: [37%-76%]) at 5 years. The estimated rate of overall survival was 100% at 1 year and 95% (95% CI: [88%-100%]) at 2 years and 82% (95% CI: [70%-94%]) at 5 years.

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 9.

Table 9: Efficacy of SPRYCEL in phase III dose-optimisation study: Advanced Phase CML and Ph+ ALL

^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/mm³, platelets 100,000/mm³, no blasts or promyelocytes in peripheral blood, bone marrow blasts 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.

NEL: same criteria as for CHR but ANC 500/mm³ and < 1,000/mm³, or platelets 20,000/mm³ and 100,000/mm³.

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

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

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-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).

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 [¹⁴C]-labelled dasatinib, unchanged dasatinib represented 29% of circulating radioactivity in plasma. Plasma concentration and measured in vitro activity indicate that metabolites of dasatinib are unlikely to play a major role in the observed pharmacology of the product. CYP3A4 is a major enzyme responsible for the metabolism of dasatinib.

Elimination

Elimination is predominantly in the faeces, mostly as metabolites. Following a single oral dose of [¹⁴C]-labelled dasatinib, approximately 89% of the dose was eliminated within 10 days, with 4% and 85% of the radioactivity recovered in the urine and faeces, respectively. Unchanged dasatinib accounted for 0.1% and 19% of the dose in urine and faeces, respectively, with the remainder of the dose as metabolites.

Hepatic and renal impairment

The effect of hepatic impairment on the single-dose pharmacokinetics of dasatinib was assessed in 8 moderately hepatic-impaired subjects who received a 50 mg dose and 5 severely hepatic-impaired subjects who received a 20 mg dose compared to matched healthy subjects who received a 70 mg dose of dasatinib. The mean 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.

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

The primary toxicities occurred in the gastrointestinal, haematopoietic, and lymphoid systems. Gastrointestinal toxicity was dose-limiting in rats and monkeys, as the intestine was a consistent target organ. In rats, minimal to mild decreases in erythrocyte parameters were accompanied by bone marrow changes; similar changes occurred in monkeys at a lower incidence. Lymphoid toxicity in rats consisted of lymphoid depletion of the lymph nodes, spleen, and thymus, and decreased lymphoid organ weights. Changes in the gastrointestinal, haematopoietic and lymphoid systems were reversible following cessation of treatment.

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

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).

Dasatinib was not carcinogenic in rats at doses up to 3 mg/kg/day, a dose which gave rise to a dasatinib plasma exposure level close to what is observed clinically.

Tablet core

Lactose monohydrate

Cellulose, microcrystalline

Croscarmellose sodium

Hydroxypropyl cellulose

Magnesium stearate

Film-coating

Hypromellose

Titanium dioxide

Macrogol 400

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

20 mg, 50 mg and 70mg Film-coated tablets:

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

High-density polyethylene (HDPE) bottle with child resistant closure of polypropylene.

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

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

Carton containing one bottle with 60 film-coated tablets.

80 mg, 100 mg and 140 mg Film-coated tablets:

Alu/Alu blisters (unit dose blisters).

High-density polyethylene (HDPE) bottle with child resistant closure of polypropylene.

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

Carton containing one bottle with 30 film-coated tablets

Not all pack sizes may be marketed

The film-coated tablets consist of a core tablet, surrounded by a film coating to prevent exposure 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 medicinal product or waste material should be disposed of in accordance with local requirements.

BRISTOL-MYERS SQUIBB PHARMA EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

Date of first authorisation: 20 November 2006

Date of latest renewal: 20 November 2011

21st February 2012

POM

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.