Posology : מינונים

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.

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).

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 and 100 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 summarised in Table 1.

Table 1:      Dose adjustments for neutropaenia and thrombocytopaenia in adults 
1 Stop treatment until ANC ≥ 1.0 x 109/L and platelets ≥ 50 x 109/ L.

2 Resume treatment at the original starting dose.
3 If platelets < 25 x 109/L and/or
Adults with chronic phase recurrence of ANC < 0.5 x 109/L for
CML                              ANC < 0.5 x 109/Land/or
> 7 days, repeat step 1 and resume
(starting dose 100 mg once       platelets < 50 x 109/L treatment at a reduced dose of 80 mg daily) once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue (for patients resistant or intolerant to prior therapy including imatinib).

1 Check if cytopaenia is related to leukaemia (marrow aspirate or biopsy).

2 If cytopaenia is unrelated to leukaemia,
stop treatment until ANC ≥ 1.0 x 109/L and platelets ≥ 20 x 109/L and resume at the original starting dose.
Adults with accelerated and blast phase CML and              ANC < 0.5 x 109/L
3 If recurrence of cytopaenia, repeat step
Ph+ ALL                          and/or
1 and resume treatment at a reduced
(starting dose 140 mg once       platelets < 10 x 109/L dose of 100 mg once daily (second daily) episode) or 80 mg once daily (third episode).
4 If cytopaenia is related to leukaemia,
consider dose escalation to 180 mg once daily.

ANC: absolute neutrophil count


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-haematological 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.

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 daily.
• 20 mg daily for patients taking SPRYCEL 100 mg daily.
• 20 mg daily for patients taking SPRYCEL 70 mg daily

For patients taking SPRYCEL 60 mg or 40 mg daily, consider interrupting the dose of SPRYCEL until the CYP3A4 inhibitor is discontinued. 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
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
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 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).