Dasnib Dosage/Direction for Use

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 Precautions).
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. 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. Dose increase or reduction is recommended based on individual patient response and tolerability. There is no experience with DASNIB treatment in children under 1 year of age.
The recommended starting daily dosage of DASNIB tablets in paediatric patients is shown in Table 1. (See Table 1.)


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Treatment duration: In clinical studies, treatment with dasatinib 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 dasatinib 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, DASNIB can be administered for an additional year post-transplantation.
To achieve the recommended dose, dasatinib 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.
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. (See Table 2.)


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Dose escalation is not recommended for paediatric patients with Ph+ ALL, as dasatinib 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. (See Tables 3 and 4.)


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For paediatric patients with Ph+ CML-CP, if Grade ≥3 neutropaenia or thrombocytopaenia recurs during complete haematologic response (CHR), dasatinib 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, dasatinib 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 DASNIB 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 dasatinib 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 previously 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 previously.
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 Precautions and Adverse Reactions). 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 dasatinib should be avoided (see Interactions). If possible, an alternative concomitant medication with no or minimal enzyme inhibition potential should be selected. If dasatinib must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to: 40 mg daily for patients taking dasatinib 140 mg tablet daily; 20 mg daily for patients taking dasatinib 100 mg tablet daily; 20 mg daily for patients taking dasatinib 70 mg tablet daily.
For patients taking dasatinib 60 mg or 40 mg daily, consider interrupting the dose of dasatinib until the CYP3A4 inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating dasatinib.
These reduced doses of dasatinib 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 dasatinib is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt dasatinib until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the dasatinib 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, dasatinib should be used with caution in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No clinical studies were conducted with dasatinib 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: DASNIB 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.
DASNIB can be taken with or without a meal and should be taken consistently either in the morning or in the evening (see Pharmacology: Pharmacokinetics under Actions). DASNIB should not be taken with grapefruit or grapefruit juice (see Interactions).