Sprycel 20mg, 50mg, 70mg, 80mg and 100mg Film-Coated Tablets

Under the sub-heading Effects on growth and development in paediatric patients, the below text has been added

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

Due to change to the SmPC, date of revision of PIL has been updated

PSUR 18 (28 Jun 2020 to 27 Jun 2021) - to update SPRYCEL PI with addition of the adverse reaction “chylothorax” with a frequency “uncommon” to section 4 of the PIL

PSUR 18 (28 Jun 2020 to 27 Jun 2021) - to update SPRYCEL PI with addition of the adverse reaction “chylothorax” with a frequency “uncommon” to section 4.8 of the SmPC, update of section 4.4 of the SmPC to reflect the cases of chylothorax that have also been reported in patients presenting with pleural effusion

Minor editorial changes throughout SPC, and update to the date of revision due to changes impacting the PIL (LENC).

Manufacturer Legal entity name change FROM 'Swords Laboratories T/A Lawrence Laboratories' TO  'Swords Laboratories Unlimited Company T/A Lawrence Laboratories'

Section 5.1 update ATC code from L01XE06 to L01EA02 and revision date update

After the manufacturer details the list of Local Representative was removed from section 6 and the date of revision has been updated

SmPC Section 4.4 (Special warnings and precautions for use)
Addition of paragraph ‘Effects on growth and development in paediatric patients’ 
[...] Growth retardation has been observed in paediatric patients treated with SPRYCEL in clinical trials (see section 4.8). Monitoring of bone growth and development in paediatric patients is recommended.
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Date of Revision of Text: 25 February 2021
 

SmPC Section 4.4 (Special warnings and precautions for use)
Addition of paragraph ‘Effects on growth and development in paediatric patients’ 
[...] Growth retardation has been observed in paediatric patients treated with SPRYCEL in clinical trials (see section 4.8). Monitoring of bone growth and development in paediatric patients is recommended.
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Date of Revision of Text: 25 February 2021
 

SmPC Section 4.4 (Special warnings and precautions for use)
Addition of paragraph ‘Effects on growth and development in paediatric patients’ 
[...] Growth retardation has been observed in paediatric patients treated with SPRYCEL in clinical trials (see section 4.8). Monitoring of bone growth and development in paediatric patients is recommended.
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Date of Revision of Text: 25 February 2021
 

Updates:

1) SmPC Section 4.4 (Special warnings and precautions for use)
Addition of paragraph ‘Effects on growth and development in paediatric patients’ 
[...] Growth retardation has been observed in paediatric patients treated with SPRYCEL in clinical trials (see section 4.8). Monitoring of bone growth and development in paediatric patients is recommended.
​
2) Date of Revision of Text: 25 February 2021
 

To change the name/address of the BMS-Anagni manufacturer to CATALENT - the SmPC date of revision has been updated to align with the patient leaflet date of revision (01 April 2020)

To change the name/address of the BMS-Anagni manufacturer to CATALENT - the SmPC date of revision has been updated to align with the patient leaflet date of revision (01 April 2020)

Existing/new pharmacokinetics (PK) analyses together with a review of literature data on the dasatinib PK profile in fasted conditions. The following sections of the SmPC are updated (changes marked in blue):

·         SmPC Section 4.2 - Method of administration […] SPRYCEL can be taken with or without a meal and should be taken consistently either in the morning or in the evening (see section 5.2). […]

·         SmPC Section 5.2 - Pharmacokinetic properties - Absorption
[…] Dasatinib exposure variability is higher under fasted conditions (47% CV) compared to light-fat meal (39% CV) and high-fat meal (32% CV) conditions.
Based on the patient population PK analysis, variability in dasatinib exposure was estimated to be mainly due to inter-occasion variability in bioavailability (44% CV) and, to a lesser extent, due to inter-individual variability in bioavailability and inter-individual variability in clearance (30% and 32% CV, respectively). The random inter-occasion variability in exposure is not expected to affect the cumulative exposure and efficacy or safety. […]

·         Update of SmPC section 4.4 and 4.8 to include Thrombotic Microangiopathy (TMA)

·         Update of SmPC section 4.8 to add a footnote at ‘musculoskeletal pain’ to indicate “musculoskeletal pain reported during or after discontinuing treatment”

SmPC Update:

• The extension indication for the treatment of paediatric patients with newly diagnosed Philadelphia chromosome positive (Ph⁺) acute lymphoblastic leukaemia (ALL) in combination with chemotherapy
• MAH Address change (UK to Ireland)

Extend the indication to the treatment of children with Chronic Phase Philadelphia-Chromosome positive Chronic Myelogenous Leukaemia
Include information on risk of cytomegalovirus (CMV) reactivation

4.8     Undesirable effects

        Table 2:           Tabulated summary of adverse reactions

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

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^g    Gravitational oedema, localised oedema, oedema peripheral.

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^h    Conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, lip oedema, macular oedema, oedema mouth, orbital oedema, periorbital o edema, swelling face.

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9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

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           Date of first authorisation: 20 November 2006

           Date of latest renewal: 1520 JulyNovember 20161

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10.     DATE OF REVISION OF THE TEXT

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           09 June 2017

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1.         NAME OF THE MEDICINAL PRODUCT

SPRYCEL 20 mg film-coated tablets

SPRYCEL 50 mg film-coated tablets

SPRYCEL 70 mg film-coated tablets

SPRYCEL 100 mg film-coated tablets

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

SPRYCEL 20 mg film-coated tablets

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

Excipients Excipient with known effect

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

SPRYCEL 50 mg film-coated tablets

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

Excipient with known effect

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

SPRYCEL 70 mg film-coated tablets

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

Excipient with known effect

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

SPRYCEL 100 mg film-coated tablets

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

Excipient with known effect

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

For the full list of excipients, see section 6.1.

3.       PHARMACEUTICAL form

Film-coated tablet (tablet).

SPRYCEL 20 mg film-coated tablets

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

SPRYCEL 50 mg film-coated tablets

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

SPRYCEL 70 mg film-coated tablets

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

SPRYCEL 100 mg film-coated tablets

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

4.       Clinical particulars

4.2     Posology and method of administration

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

Posology

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 on long-term disease outcome after the achievement of a cytogenetic or molecular response [including complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5] has not been investigated.

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 summarised in Table 1.

ANC: absolute neutrophil count

Non-haematological adverse reactions

If a moderate, grade 2, non-haematological adverse reaction develops with dasatinib, interrupt treatment should be interrupted until the event adverse reaction has resolved or returned to baseline. Resume at the The same dose should be resumed if this is the first occurrence and at a the dose should be reduced dose if this is a recurrent eventadverse reaction. If a severe grade 3 or 4, non-haematological adverse reaction develops with dasatinib, treatment must be withheld until the event adverse reaction has resolved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the eventadverse reaction. For patients with chronic phase CML who received 100 mg once daily, dose reduction to 80 mg once daily with further reduction from 80 mg once daily to 50 mg once daily, if needed, is recommended. For patients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to 100 mg once daily with further reduction from 100 mg once daily to 50 mg once daily, if needed, is recommended.

Pleural effusion

Pleural effusion: if If a pleural effusion is diagnosed, interrupt dasatinib should be interrupted 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 should be considered (see sections 4.4 and 4.8). Following resolution of the first episode, consider reintroduction of dasatinib at the same dose level should be considered. Following resolution of a subsequent episode, reintroduce dasatinib at one dose level reduction should be reintroduced. Following resolution of a severe (grade 3 or 4) episode, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the eventadverse reaction.

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).

Older people

Elderly

No clinically relevant age-related pharmacokinetic differences have been observed in these patients. No specific dose recommendation is necessary in older peopleelderly.

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.

Film-coated The film-coated 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.

4.4     Special warnings and precautions for use

Clinically relevant interactions

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

Concomitant use of dasatinib and medicinal products or substances that potently inhibit CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, grapefruit juice) may increase exposure to dasatinib. Therefore, in patients receiving dasatinib, coadministration of a potent CYP3A4 inhibitor is not recommended (see section 4.5).

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

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

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

Special populations

Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose (see 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 thrombocytopenianeutropaenia and thrombocytopaenia. Their occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In patients with advanced phase CML or Ph+ ALL, complete blood counts should be performed weekly for the first 2 months, and then monthly thereafter, or as clinically indicated. In patients with chronic phase CML, complete blood counts should be performed every 2 weeks for 12 weeks, then every 3 months thereafter or as clinically indicated. Myelosuppression is generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction (see sections 4.2 and 4.8).

Bleeding

In patients with chronic phase CML (n=548), 5 patients (1%) receiving dasatinib had grade 3 or 4 haemorrhage. In clinical studies in patients with advanced phase CML receiving the recommended dose of SPRYCEL (n=304), severe central nervous system (CNS) haemorrhage occurred in 1% of patients. One case was fatal and was associated with Common Toxicity Criteria (CTC) grade 4 thrombocytopeniathrombocytopaenia. Grade 3 or 4 gastrointestinal haemorrhage occurred in 6% of patients with advanced phase CML and generally required treatment interruptions and transfusions. Other grade 3 or 4 haemorrhage occurred in 2% of patients with advanced phase CML. Most bleeding related events adverse reactions in these patients were typically associated with grade 3 or 4 thrombocytopenia thrombocytopaenia (see section 4.8). Additionally, in vitro and in vivo platelet assays suggest that SPRYCEL treatment reversibly affects platelet activation.

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

Fluid retention

Dasatinib is associated with fluid retention. In the Phase III clinical study in patients with newly diagnosed chronic phase CML, grade 3 or 4 fluid retention was reported in 13 patients (5%) in the dasatinib-treatment group and in 2 patients (1%) in the imatinib-treatment group after a minimum of 60 months follow-up (see section 4.8). In all SPRYCEL treated patients with chronic phase CML, severe fluid retention occurred in 32 patients (6%) receiving SPRYCEL at the recommended dose (n=548). In clinical studies in patients with advanced phase CML receiving SPRYCEL at the recommended dose (n=304), grade 3 or 4 fluid retention was reported in 8% of patients, including grade 3 or 4 pleural and pericardial effusion reported in 7% and 1% of patients, respectively. In these patients grade 3 or 4 pulmonary oedema and pulmonary hypertension were each reported in 1% of patients.

Patients who develop symptoms suggestive of pleural effusion such as dyspnoea or dry cough should be evaluated by chest X-ray. Grade 3 or 4 pleural effusion may require thoracocentesis and oxygen therapy. Fluid retention events adverse reactions were typically managed by supportive care measures that include diuretics and short courses of steroids (see sections 4.2 and 4.8). Patients aged 65 years and older are more likely than younger patients to experience pleural effusion, dyspnoea, cough, pericardial effusion and congestive heart failure, and should be monitored closely.

Pulmonary arterial hypertension (PAH)

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

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

QT Prolongation

In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarisation (QT Interval) (see section 5.3). In 258 dasatinib-treated patients and 258 imatinib-treated patients with a minimum of 60 months follow-up in the Phase III study in newly diagnosed chronic phase CML, 1 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 trialsstudies, 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 clinical study of 519 patients with newly diagnosed CML in chronic phase which included patients with prior cardiac disease. The cardiac adverse reactions of congestive heart failure/cardiac dysfunction, pericardial effusion, arrhythmias, palpitations, QT prolongation and myocardial infarction (including fatal) were reported in patients taking dasatinib. Adverse cardiac events Cardiac adverse reactions were more frequent in patients with risk factors or a history of cardiac disease. Patients with risk factors (e.g. hypertension, hyperlipidemiahyperlipidaemia, 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 adverse reactions (≤ grade 2) and resumed at a dose level reduction for severe events adverse reactions (≥ grade 3) (see section 4.2). Patients continuing treatment should be monitored periodically.

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

Hepatitis B reactivation

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

Patients should be tested for HBV infection before initiating treatment with SPRYCEL. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with SPRYCEL should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).

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.

4.6     Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

Women Both sexually active men and women of childbearing potential must be advised to should use effective methods of contraception during treatment.

Pregnancy

Based on human experience, dasatinib is suspected to cause congenital malformations including neural tube defects, and harmful pharmacological effects on the fetus foetus when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3).

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

Breast-feeding

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

Breast-feeding should be stopped during treatment with SPRYCEL.

Fertility

The effect of dasatinib on sperm is unknown, therefore both sexually active men and women should use effective methods of contraception during treatment (see section 5.3).

4.7     Effects on ability to drive and use machines

No studies on the effects SPRYCEL has minor influence 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.

4.8     Undesirable effects

Summary of the safety profile

The data described below reflect exposure to SPRYCEL in 2,712 patients in clinical studies, including 324 patients with newly diagnosed chronic phase CML and 2,388 patients with imatinib resistant or intolerant CML or Ph+ ALL. The median duration of therapy in 2,712 SPRYCEL treated patients was 19.2 months (range 0-93.2 months).

In the Phase III study in patients with newly diagnosed chronic phase CML with a minimum of 5 years of follow up,  the median duration of therapy was approximately 60 months for both SPRYCEL (range 0.03-72.7 months) and for imatinib (range 0.3-74.6 months). The median duration of therapy in 1,618 patients with all chronic phase CML was 29 months (range 0-92.9 months).  In 1,094 patients with advanced phase CML or Ph+ ALL, the median duration of treatment for patients was 6.2 months (range 0-9.32 months).

Of the 2,712 patients treated, 18% were ≥ 65 years of age, while 5% were ≥ 75 years of age.

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the overall population of 2,712 SPRYCEL treated patients, 520 (19%) experienced adverse reactions leading to treatment discontinuation. 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 with a minimum of 12 months follow-up. After a minimum of 60 months follow-up, the cumulative discontinuation rates were 14% and 7%, respectively. Among the 1,618 dasatinib-treated patients with chronic phase CML, adverse reactions leading to discontinuation were reported in 329 (20.3%) patients, and among the 1,094 dasatinib-treated patients with advanced phase disease, adverse reactions leading to discontinuation were reported in 191 (17.5%) patients.

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 non-haematologic 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.

Based on a minimum of 12 months follow-up the most frequently reported adverse reactions 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%). After a minimum of 60 months follow-up the cumulative rates for rash (14%), musculoskeletal pain (14%), headache (13%), fatigue (11%), nausea (10%), myalgia (7%), vomiting (5%), and muscle inflammation or spasms (5%) increased by £ 3%. Cumulative rates of fluid retention and diarrhoea were 39% and 22%, respectively. The most frequently reported adverse reactions 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 neutropaenia 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 list 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.

a    Includes decreased appetite, early satiety, increased appetite.

b      Includes central nervous system haemorrhage, cerebral haematoma, cerebral haemorrhage, extradural haematoma, haemorrhage intracranial, haemorrhagic stroke, subarachnoid haemorrhage, subdural haematoma, and subdural haemorrhage.

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

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

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

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

g     gravitational Gravitational oedema, localised oedema, oedema peripheral.

^h     conjunctival Conjunctival oedema, eye oedema, eye swelling, eyelid oedema, face oedema, lip oedema, macular oedema, oedema mouth, orbital oedema, periorbitalo edema, swelling face.

ⁱ      fluid Fluid overload, fluid retention, gastrointestinal oedema, generalised oedema, oedema, oedema due to cardiac disease, perinephric effusion, post procedural oedema, visceral oedema.

^j    genital Genital swelling, incision site oedema, oedema genital, penile oedema, penile swelling, scrotal oedema, skin swelling, testicular swelling, vulvovaginal swelling.

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

Description of selected adverse reactions

Myelosuppression

Treatment with SPRYCEL is associated with anaemia, neutropenia and thrombocytopenianeutropaenia and thrombocytopaenia. Their occurrence is earlier and more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML (see section 4.4).

Bleeding

Bleeding drug-related eventsadverse reactions, ranging from petechiae and epistaxis to grade 3 or 4 gastrointestinal haemorrhage and CNS bleeding, were reported in patients taking SPRYCEL (see section 4.4).

Fluid retention

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

The cumulative rate of dasatinib-related pleural effusion (all grades) over time was 10% at 12 months, 14% at 24 months, 19% at 36 months, 24% at 48 months and 28% at 60 months. A total of 46 dasatinib-treated patients had recurrent pleural effusions. Seventeen patients had 2 separate eventsadverse reactions, 6 had 3 eventsadverse reactions, 18 had 4 to 8 events adverse reactions and 5 had > 8 episodes of pleural effusions.

The median time to first dasatinib-related grade 1 or 2 pleural effusion was 114 weeks (range: 4 to 299 weeks). Less than 10% of patients with pleural effusion had severe (grade 3 or 4) dasatinib-related pleural effusions. The median time to first occurrence of grade ≥ 3 dasatinib-related pleural effusion was 175 weeks (range: 114 to 274 weeks). The median duration of dasatinib-related pleural effusion (all grades) was 283 days (~40 weeks).

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

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

Pleural effusion did not impair the ability of patients to obtain a response. Among the dasatinib-treated patients with pleural effusion, 96% achieved a cCCyR, 82% achieved a MMR, and 50% achieved a MR4.5 despite dose interruptions or dose adjustment.

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

Pulmonary arterial hypertension (PAH)

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

QT Prolongation

In the Phase III study in patients with newly diagnosed chronic phase CML, one patient (< 1%) of the SPRYCEL-treated patients had a QTcF > 500 msec after a minimum of 12 months follow-up (see section 4.4). No additional patients were reported to have QTcF > 500 msec after a minimum of 60 months follow-up.

In 5 Phase II clinical studies in patients with resistance or intolerance to prior imatinib therapy, repeated baseline and on-treatment ECGs were obtained at pre-specified time points and read centrally for 865 patients receiving SPRYCEL 70 mg twice daily. QT interval was corrected for heart rate by Fridericia's method. At all post-dose time points on day 8, the mean changes from baseline in QTcF interval were 4 - 6 msec, with associated upper 95% confidence intervals < 7 msec. Of the 2,182 patients with resistance or intolerance to prior imatinib therapy who received SPRYCEL in clinical studies, 15 (1%) had QTc prolongation reported as an adverse reaction. Twenty-one patients (1%) experienced a QTcF > 500 msec (see section 4.4).

Cardiac adverse reactions

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

Hepatitis B reactivation

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

In the Phase III dose-optimisation study in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy (median duration of treatment of 30 months), the incidence of pleural effusion and congestive heart failure/cardiac dysfunction was lower in patients treated with SPRYCEL 100 mg once daily than in those treated with SPRYCEL 70 mg twice daily. Myelosuppression was also reported less frequently in the 100 mg once daily treatment group (see Laboratory test abnormalities below). The median duration of therapy in the 100 mg once daily group was 37 months (range 1-91 months). Cumulative rates of selected adverse reactions that were reported in the 100 mg once daily recommended starting dose are shown in Table 3a.

In the Phase III dose-optimisation study in patients with advanced phase CML and Ph+ ALL, the median duration of treatment was 14 months for accelerated phase CML, 3 months for myeloid blast CML, 4 months for lymphoid blast CML and 3 months for Ph+ ALL. Selected adverse reactions that were reported in the recommended starting dose of 140 mg once daily are shown in Table 3b. A 70 mg twice daily regimen was also studied. The 140 mg once daily regimen showed a comparable efficacy profile to the 70 mg twice daily regimen but a more favorable favourable safety profile.

^a  Phase 3 dose optimisation study results reported at the recommended starting dose of 140 mg once daily (n=304) population at 2 year final study follow up.

b Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure.

Laboratory test abnormalities

Haematology

In the Phase III newly diagnosed chronic phase CML study, the following grade 3 or 4 laboratory abnormalities were reported after a minimum of 12 months follow-up in patients taking SPRYCEL: neutropenia neutropaenia (21%), thrombocytopenia thrombocytopaenia (19%), and anaemia (10%). After a minimum of 60 months follow-up, the cumulative rates of neutropenianeutropaenia, thrombocytopenia thrombocytopaenia, and anaemia were 29%, 22% and 13%, respectively.

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

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

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

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

Biochemistry

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

2 year follow-up

Grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% of patients with chronic phase CML (resistant or intolerant to imatinib), but elevations were reported with an increased frequency of 1 to 7% of patients with advanced phase CML and Ph+ ALL. It was usually managed with dose reduction or interruption. In the Phase III dose-optimisation study in chronic phase CML, grade 3 or 4 elevations of transaminases or bilirubin were reported in ≤ 1% of patients with similar low incidence in the four treatment groups. In the Phase III dose-optimisation study in advanced phase CML and Ph+ALL, grade 3 or 4 elevations of transaminases or bilirubin were reported in 1% to 5% of patients across treatment groups.

Approximately 5% of the SPRYCEL-treated patients who had normal baseline levels experienced grade 3 or 4 transient hypocalcaemia at some time during the course of the study. In general, there was no association of decreased calcium with clinical symptoms. Patients developing grade 3 or 4 hypocalcaemia often had recovery with oral calcium supplementation. Grade 3 or 4 hypocalcaemia, hypokalaemia, and hypophosphatemia hypophosphataemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL. Grade 3 or 4 elevations in creatinine were reported in < 1% of patients with chronic phase CML and were reported with an increased frequency of 1 to 4% of patients with advanced phase CML.

Other special Special population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agentagents, protein kinase inhibitorinhibitors, 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 2,712 patients were evaluated in clinical studies; of these 23% were ≥ 65 years of age and 5% were ≥ 75 years of age.

Chronic Phase phase CML - Newly Diagnoseddiagnosed

An international open-label, multicentermulticentre, 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 60 months follow-up, 60% of patients randomised to the SPRYCEL group and 63% of patients randomised to the imatinib group were still receiving first-line treatment. Discontinuation within 60 months due to disease progression occurred in 11% of SPRYCEL-treated patients and 14% of imatinib-treated patients.

Efficacy results are presented in Table 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.

After 60 months of follow-up, median time to cCCyR was 3.1 months in the SPRYCEL group and 5.8 months in the imatinib group in patients with a confirmed CCyR. Median time to MMR after 60 months of follow-up was 9.3 months in the SPRYCEL group and 15.0 months in the imatinib group in patients with a MMR. These results are consistent with those seen at 12, 24 and 36 months.

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

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

                                                                                                                                                            MONTHS

     ___ Dasatinib                                                                                                        ------ Imatinib

Censored                                                                                                     Censored

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

DASATINIBDasatinib                                                                           198/259

IMATINIBImatinib                                                                167/260

DASATINIB OVER IMATINIBDasatinib over imatinib                                                                                                                                      1.54 (1.25 - 1.89)

The rates of cCCyR in the SPRYCEL and imatinib treatment groups, respectively, within 3 months (54% and 30%), 6 months (70% and 56%), 9 months (75% and 63%), 24 months (80% and 74%), 36 months (83% and 77%), 48 months (83% and 79%) and 60 months (83% and 79%) were consistent with the primary endpoint. The rates of MMR in the SPRYCEL and imatinib treatment groups, respectively, within 3 months (8% and 0.4%), 6 months (27% and 8%), 9 months (39% and 18%), 12 months (46% and 28%), 24 months (64% and 46%) , 36 months (67% and 55%), 48 months (73% and 60%) and 60 months (76% and 64%)were also consistent with the primary endpoint.

MMR rates by specific timepoint are displayed graphically in Figure 2. Rates of MMR were consistently higher in dasatinib-treated patients compared with imatinib-treated patients.

Figure 2: MMR Rates Over Time - All Randomised Patients in a Phase 3 Study of Newly Diagnosed Patients with Chronic Phase CML)

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

Months Since Randomisationsince randomisation

                                                                        N

     ______ Dasatinib 100 mg once daily 259

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

The proportion of patients achieving BCR-ABL ratio of ≤0.01% (4-log reduction) at any time was higher in the SPRYCEL group compared to the imatinib group (54.1% versus 45%). The proportion of patients achieving BCR-ABL ratio of ≤0.0032% (4.5-log reduction) at any time was higher in the SPRYCEL group compared to the imatinib group (44% versus 34%).

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

Figure 3:         MR4.5 Rates Over Time - All Randomised Patients in a Phase 3 Study of Newly Diagnosed Patients with Chronic Phase CML

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

Months Since Randomisationsince randomisation

                                                                        N

     ______ Dasatinib 100 mg once daily 259

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

The rate of MMR at any time in each risk group determined by Hasford score was higher in the SPRYCEL group compared with the imatinib group (low risk: 90% and 69%; intermediate risk: 71% and 65%; high risk: 67% and 54%, respectively).

In an additional analysis, more dasatinib-treated patients (84%) achieved early molecular response (defined as BCR-ABL levels £ 10% at 3 months) compared with imatinib-treated patients (64%). Patients achieving early molecular response had a lower risk of transformation, higher rate of progression-free survival (PFS) and higher rate of overall survival (OS), as shown in Table 6.

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