Bristol-Myers Squibb Pharmaceutical Limited

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. CompleteIn 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).

Section 4.4 the following text has been added:

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.

Section 4.8: The following text highlighted has been added

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.

 Secion 5.3 revised as follows:

No carcinogenesis studies were conducted with dasatinib.

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.

 Please note that the SPC is the same as the one submitted for eMC apart from this not containing Black Triangle in the first section.

Sections 1, 2 and 3, 6.5 and 8:  Information about two additional strengths of 80mg and 140mg included.

Section 4.1, 4.2, 4.4, 4.8, 5.1:  Updated with regards to New indication of First Line CML. 

Indications are as follows:

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.

Section 10: Revision Date changed to 6 December 2010

Section 4.2: 
The sentence "Tablets must not be crushed or cut, they must be swallowed whole. SPRYCEL can be taken with or without a meal and should be taken consistently either in the morning or in the evening" moved to the end of the section
Paediatric patients:  revised as follows:  "The safety and efficacy of SPRYCEL in children and adolescents below 18 years of age have not been established. No data are available (see section 5.1)."

Section 4.5 revised to include the following statement:
"In a study of 14 healthy subjects, administration of a single 100‑mg dose of SPRYCEL 22 hours following a 4-day, 40-mg omeprazole dose at steady state reduced the AUC of dasatinib by 43% and the Cmax of dasatinib by 42%."

Section 5.1:  The statement  "Safety and efficacy of dasatinib have not yet been studied in paediatric patients"  was moved to the end of the Section with the addition of the paragraph below:

 "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)."

Section 4.4: Special warnings and precautions for use

Update on incidence of bleeding: “Eight cases were fatal and 6 of them were

associated with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia.”

Addition of dyspnoea to the section on fluid retention: “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.”

Section 4.8. Undesirable effects

Update on incidences and addition of rare, uncommon and post-marketing reports of

adverse reactions.

Section 5.1. Pharmacodynamic properties

Addition of: “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.”

Section 6.5. Nature and contents of container and Section 8. marketing

Authorisation Numbers

Removal of 56 tablet calendar packs for the 20mg, 50mg and 70mg doses, which are

no longer marketed. These doses remain available in packs of 60 tablets.

Sections 4.2, 4.4 and 5.2:

Updated with outcome of Hepatic Impairment study, which assessed the effects of moderate to severe hepatic impairment on the single oral dose PK of dasatinib.

Sections 4.8:

Side effects profile reformatted to 'Tabulated Summary of Adverse Reactions';

addition of 'Fluid retention' as a very common side effect under General disorders and administration site conditions.

Section 6.5 and 8
Addition of 60s pack sizes.

Sections 4.2, 4.4, 4.8, 5.1 and 5.2 - To update the information following approval of posology for the advanced phase CML and Ph+ ALL patients, from 70 mg twice daily to 140 once daily. 

Section 5.1 - updated information regarding the new posology and MMR data updated

Section 5.3 -  updated information regarding reproductive toxicity and phototoxicity

Section 6.3 - Shelf life changed from 24 months to 36 months (20, 50 and 70mg only)

Section 4.2: Revised re new recommended starting dose 100mg once-daily for Chronic Phase CML patients resistant or intolerant to imatinib.

Please note:  the starting dose for Advanced Phase CML patients resistent or intolerant to imatinib remains unchanged at 70 mg twice-daily.

Section 4.4: 

Added:  In a Phase III dose-optimisation study in patients with chronic phase CML, grade 3 or 4 myelosuppression was reported more frequently in patients treated with 70 mg twice daily than in patients treated with 100 mg once daily; fluid retention was also reported more frequently in patients treated with twice daily schedule compared to once daily (see section 4.8).

Therefore, the starting dose of 100 mg once daily is the recommended initial dosage for patients with chronic phase CML.

Section 4.8: Revised in line with Dose change re Chronic Phase CML.  Also revised according to MedDRA Version 8.2.

Section 4.9:
Revised to:

Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. The highest reported dosage ingested was 280 mg per day for one week with no associated clinical symptoms. Since SPRYCEL is associated with severe myelosuppression (see section 4.4), patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and appropriate supportive treatment given.

Section 5.1: 

Added Information re following:

Phase III Clinical Trials
Two randomised, open-label studies were conducted to evaluate the efficacy of SPRYCEL administered once daily compared with SPRYCEL administered twice daily:

Date of Revision changed to 22 August 2007