Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
SPRYCEL is indicated for the treatment of adult patients with:
SPRYCEL is indicated for the treatment of paediatric patients with:
Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia.
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).
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.
Table 1. Dosage of SPRYCEL tablets for paediatric patients with Ph+ CML-CP or Ph+ ALL:
| Body weight (kg)a | Daily dose (mg) |
|---|---|
| 10 to less than 20 kg | 40 mg |
| 20 to less than 30 kg | 60 mg |
| 30 to less than 45 kg | 70 mg |
| at least 45 kg | 100 mg |
a The tablet is not recommended for patients weighing less than 10 kg; the powder for oral suspension should be used for these patients.
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.
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.
Table 2. Dose escalation for paediatric patients with Ph+ CML-CP:
| Dose (maximum dose per day) | ||
|---|---|---|
| Starting dose | Escalation | |
| Tablets | 40 mg | 50 mg |
| 60 mg | 70 mg | |
| 70 mg | 90 mg | |
| 100 mg | 120 mg | |
Dose escalation is not recommended for paediatric patients with Ph+ ALL, as SPRYCEL is administered in combination with chemotherapy in these patients.
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.
Table 3. Dose adjustments for neutropaenia and thrombocytopaenia in adults:
| Adults with chronic phase CML (starting dose 100 mg once daily) | ANC <0.5 × 109/L and/or platelets <50 × 109/L | 1. Stop treatment until ANC ≥1.0 × 109/L and platelets ≥50 × 109/L. |
| 2. Resume treatment at the original starting dose. | ||
| 3. If platelets <25 × 109/L and/or recurrence of ANC <0.5 × 109/L for >7 days, repeat step 1 and resume treatment at a reduced dose of 80 mg 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). | ||
| Adults with accelerated and blast phase CML and Ph+ ALL (starting dose 140 mg once daily) | ANC <0.5 × 109/L and/or platelets <10 × 109/L | 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 × 109/L and platelets ≥20 × 109/L and resume at the original starting dose. | ||
| 3. If recurrence of cytopaenia, repeat step 1 and resume treatment at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode). | ||
| 4. If cytopaenia is related to leukaemia, consider dose escalation to 180 mg once daily. |
Table 4. Dose adjustments for neutropaenia and thrombocytopaenia in paediatric patients with Ph+ CML-CP:
| 1. If cytopaenia persists for more than 3 weeks, check if cytopaenia is related to leukaemia (marrow aspirate or biopsy). | Dose (maximum dose per day) | |||
|---|---|---|---|---|
| Original starting dose | One-level dose reduction | Two-level dose reduction | ||
| 2. If cytopaenia is unrelated to leukaemia, stop treatment until ANC ≥1.0 × 109/L and platelets ≥75 × 109/L and resume at the original starting dose or at a reduced dose. | Tablets | 40 mg | 20 mg | * |
| 60 mg | 40 mg | 20 mg | ||
| 3. If cytopaenia recurs, repeat marrow aspirate/biopsy and resume treatment at a reduced dose. | 70 mg | 60 mg | 50 mg | |
| 100 mg | 80 mg | 70 mg | ||
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 × 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.
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.
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 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.
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:
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.
No clinically relevant age-related pharmacokinetic differences have been observed in these patients. No specific dose recommendation is necessary in elderly.
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).
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.
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).
Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. The highest 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 ingest more than the recommended dose should be closely monitored for myelosuppression and given appropriate supportive treatment.
3 years.
This medicinal product does not require any special storage conditions.
SPRYCEL 20 mg, SPRYCEL 50 mg and SPRYCEL 70 mg film-coated tablets:
Alu/Alu blisters (calendar blisters or perforated unit dose blisters).
HDPE bottle with a polypropylene child-resistant closure.
Carton containing 56 film-coated tablets in 4 calendar blisters of 14 film-coated tablets each.
Carton containing 60 × 1 film-coated tablets in perforated unit dose blisters.
Carton containing one bottle with 60 film-coated tablets.
SPRYCEL 80 mg, SPRYCEL 100 mg and SPRYCEL 140 mg film-coated tablets:
Alu/Alu blisters (perforated unit dose blisters).
HDPE bottle with a polypropylene child-resistant closure.
Carton containing 30 × 1 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 healthcare professionals to the active substance. The use of latex or nitrile gloves for appropriate disposal when handling tablets that are inadvertently crushed or broken is recommended, to minimise the risk of dermal exposure.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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