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

SPRYCEL 20 mg film-coated tablets

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

Excipient with known effect

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

SPRYCEL 50 mg film-coated tablets

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

Excipient with known effect

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

SPRYCEL 70 mg film-coated tablets

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

Excipient with known effect

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

SPRYCEL 80 mg film-coated tablets

Each film-coated tablet contains 80 mg dasatinib (as monohydrate).

Excipient with known effect

Each film-coated tablet contains 108 mg of lactose monohydrate.

SPRYCEL 100 mg film-coated tablets

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

Excipient with known effect

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

SPRYCEL 140 mg film-coated tablets

Each film-coated tablet contains 140 mg dasatinib (as monohydrate).

Excipient with known effect

Each film-coated tablet contains 189 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

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 80 mg film-coated tablets

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

SPRYCEL 100 mg film-coated tablets

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

SPRYCEL 140 mg film-coated tablets

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

SPRYCEL is indicated for the treatment of adult patients with:

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

▪ chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib.

▪ Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.

SPRYCEL is indicated for the treatment of paediatric patients with:

▪ newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib.

▪ newly diagnosed Ph+ ALL in combination with chemotherapy.

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

Posology

Adult patients

The recommended starting dose for chronic phase CML is 100 mg dasatinib once daily.

The recommended starting dose for accelerated, myeloid or lymphoid blast phase (advanced phase) CML or Ph+ ALL is 140 mg once daily (see section 4.4).

Paediatric population (Ph+ CML-CP and Ph+ ALL)

Dosing for children and adolescents is on the basis of body weight (see Table 1). Dasatinib is administered orally once daily in the form of either SPRYCEL film-coated tablets or SPRYCEL powder for oral suspension (see Summary of Product Characteristics for SPRYCEL powder for oral suspension). The dose should be recalculated every 3 months based on changes in body weight, or more often if necessary. The tablet is not recommended for patients weighing less than 10 kg; the powder for oral suspension should be used for these patients. Dose increase or reduction is recommended based on individual patient response and tolerability. There is no experience with SPRYCEL treatment in children under 1 year of age.

SPRYCEL film-coated tablets and SPRYCEL powder for oral suspension are not bioequivalent. Patients who are able to swallow tablets and who desire to switch from SPRYCEL powder for oral suspension to SPRYCEL tablets or patients who are not able to swallow tablets and who desire to switch from tablets to oral suspension, may do so, provided that the correct dosing recommendations for the dosage form are followed.

The recommended starting daily dosage of SPRYCEL tablets in paediatric patients is shown in Table 1.

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

Treatment duration

In clinical studies, treatment with SPRYCEL in adults with Ph+ CML-CP, accelerated, myeloid or lymphoid blast phase (advanced phase) CML, or Ph+ ALL and paediatric patients with Ph+ CML-CP was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic or molecular response [including complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5] has not been investigated.

In clinical studies, treatment with SPRYCEL in paediatric patients with Ph+ ALL was administered continuously, added to successive blocks of backbone chemotherapy, for a maximum duration of two years. In patients that receive a subsequent stem cell transplantation, SPRYCEL can be administered for an additional year post-transplantation.

To achieve the recommended dose, SPRYCEL is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mg and 140 mg film-coated tablets and powder for oral suspension (10 mg/mL suspension upon constitution). Dose increase or reduction is recommended based on patient response and tolerability.

Dose escalation

In clinical studies in adult CML and Ph+ ALL patients, dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML or Ph+ ALL) was allowed in patients who did not achieve a haematologic or cytogenetic response at the recommended starting dose.

The following dose escalations shown in Table 2 are recommended in paediatric patients with Ph+ CML-CP who do not achieve a haematologic, cytogenetic and molecular response at the recommended time points, per current treatment guidelines, and who tolerate the treatment.

Dose escalation is not recommended for paediatric patients with Ph+ ALL, as SPRYCEL is administered in combination with chemotherapy in these patients.

Dose adjustment for adverse reactions

Myelosuppression

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

Guidelines for dose modifications in adults are summarised in Table 3 and in paediatric patients with Ph+ CML-CP in Table 4. Guidelines for paediatric patients with Ph+ ALL treated in combination with chemotherapy are in a separate paragraph following the tables.

ANC: absolute neutrophil count

ANC: absolute neutrophil count

*lower tablet dose not available

For paediatric patients with Ph+ CML-CP, if Grade ≥3 neutropaenia or thrombocytopaenia recurs during complete haematologic response (CHR), SPRYCEL should be interrupted, and may be subsequently resumed at a reduced dose. Temporary dose reductions for intermediate degrees of cytopaenia and disease response should be implemented as needed.

For paediatric patients with Ph+ ALL, no dose modification is recommended in cases of haematologic Grade 1 to 4 toxicities. If neutropaenia and/or thrombocytopaenia result in delay of the next block of treatment by more than 14 days, SPRYCEL should be interrupted and resumed at the same dose level once the next block of treatment is started. If neutropaenia and/or thrombocytopaenia persist and the next block of treatment is delayed another 7 days, a bone marrow assessment should be performed to assess cellularity and percentage of blasts. If marrow cellularity is <10%, treatment with SPRYCEL should be interrupted until ANC >500/μL (0.5 x 109/L), at which time treatment may be resumed at full dose. If marrow cellularity is >10%, resumption of treatment with SPRYCEL may be considered.

Non-haematologic adverse reactions

If a moderate, grade 2, non-haematologic adverse reaction develops with dasatinib, treatment should be interrupted until the adverse reaction has resolved or returned to baseline. The same dose should be resumed if this is the first occurrence and the dose should be reduced if this is a recurrent adverse reaction. If a severe grade 3 or 4, non-haematologic adverse reaction develops with dasatinib, treatment must be withheld until the adverse reaction has resolved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction. For patients with chronic phase CML who received 100 mg once daily, dose reduction to 80 mg once daily with further reduction from 80 mg once daily to 50 mg once daily, if needed, is recommended. For patients with advanced phase CML or Ph+ ALL who received 140 mg once daily, dose reduction to 100 mg once daily with further reduction from 100 mg once daily to 50 mg once daily, if needed, is recommended. In CML-CP paediatric patients with non-haematologic adverse reactions, the dose reduction recommendations for haematologic adverse reactions that are described above should be followed. In Ph+ ALL paediatric patients with non-haematologic adverse reactions, if needed, one level of dose reduction should be followed, according to the dose reduction recommendations for haematologic adverse reactions that are described above.

Pleural effusion

If a pleural effusion is diagnosed, dasatinib should be interrupted until patient is examined, asymptomatic or has returned to baseline. If the episode does not improve within approximately one week, a course of diuretics or corticosteroids or both concurrently should be considered (see sections 4.4 and 4.8). Following resolution of the first episode, reintroduction of dasatinib at the same dose level should be considered. Following resolution of a subsequent episode, dasatinib at one dose level reduction should be reintroduced. Following resolution of a severe (grade 3 or 4) episode, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the adverse reaction.

Dose reduction for concomitant use of strong CYP3A4 inhibitors

The concomitant use of strong CYP3A4 inhibitors and grapefruit juice with SPRYCEL should be avoided (see section 4.5). If possible, an alternative concomitant medication with no or minimal enzyme inhibition potential should be selected. If SPRYCEL must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to:

• 40 mg daily for patients taking SPRYCEL 140 mg tablet daily.

• 20 mg daily for patients taking SPRYCEL 100 mg tablet daily.

• 20 mg daily for patients taking SPRYCEL 70 mg tablet daily.

For patients taking SPRYCEL 60 mg or 40 mg daily, consider interrupting the dose of SPRYCEL until the CYP3A4 inhibitor is discontinued, or switching to a lower dose with the powder for oral suspension formulation (see Summary of Product Characteristics for SPRYCEL powder for oral suspension). Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating SPRYCEL.

These reduced doses of SPRYCEL are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors; however, clinical data are not available with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If SPRYCEL is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt SPRYCEL until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the SPRYCEL dose is increased.

Special populations

Elderly

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

Hepatic impairment

Patients with mild, moderate or severe hepatic impairment may receive the recommended starting dose. However, SPRYCEL should be used with caution in patients with hepatic impairment (see section 5.2).

Renal impairment

No clinical studies were conducted with SPRYCEL in patients with decreased renal function (the study in patients with newly diagnosed chronic phase CML excluded patients with serum creatinine concentration > 3 times the upper limit of the normal range, and studies in patients with chronic phase CML with resistance or intolerance to prior imatinib therapy excluded patients with serum creatinine concentration > 1.5 times the upper limit of the normal range). Since the renal clearance of dasatinib and its metabolites is < 4%, a decrease in total body clearance is not expected in patients with renal insufficiency.

Method of administration

SPRYCEL must be administered orally.

The film-coated tablets must not be crushed, cut or chewed in order to maintain dosing consistency and minimise the risk of dermal exposure; they must be swallowed whole. Film-coated tablets should not be dispersed as the exposure in patients receiving a dispersed tablet is lower than in those swallowing a whole tablet. SPRYCEL powder for oral suspension is also available for paediatric Ph+ CML-CP and Ph+ ALL patients, and adult CML-CP patients, who cannot swallow tablets.

SPRYCEL can be taken with or without a meal and should be taken consistently either in the morning or in the evening (see section 5.2). SPRYCEL should not be taken with grapefruit or grapefruit juice (see section 4.5).

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 metabolised primarily by or modulate the activity of CYP3A4 (see section 4.5).

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

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

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

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

Special populations

Based on the findings from a single-dose pharmacokinetic study, patients with mild, moderate or severe hepatic impairment may receive the recommend