Posology : מינונים

4.2    Posology and method of administration

Treatment with Xospata should be initiated and supervised by a physician experienced in the use of anti-cancer therapies.

Before taking gilteritinib, relapsed or refractory AML patients must have confirmation of FMS-like tyrosine kinase 3 (FLT3) mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD]) using a validated test.

Xospata may be re-initiated in patients following haematopoietic stem cell transplantation (HSCT) (see Table 1).
Posology

The recommended starting dose is 120 mg gilteritinib (three 40 mg tablets) once daily.

Blood chemistries, including creatine phosphokinase, should be assessed prior to initiation of treatment, on day 15 and monthly for the duration of treatment.

An electrocardiogram (ECG) should be performed before initiation of gilteritinib treatment, on day 8 and 15 of cycle 1 and prior to the start of the next three subsequent months of treatment (see sections 4.4 and 4.8).

Treatment should continue until the patient is no longer clinically benefiting from Xospata or until unacceptable toxicity occurs. Response may be delayed; therefore, continuation of treatment at the prescribed dose for up to 6 months should be considered to allow time for a clinical response.
In the absence of a response [patient did not achieve a composite complete remission (CRc)] ) after 4 weeks of treatment, the dose can be increased to 200 mg (five 40 mg tablets) once daily, if tolerated or clinically warranted.

Dose modifications

Table 1. Xospata dose interruption, reduction and discontinuation recommendations in patients with relapsed or refractory AML
Criteria                                       Xospata dosing
Differentiation syndrome                               •    If differentiation syndrome is suspected, administer corticosteroids and initiate hemodynamic monitoring (see section 4.4).
•    Interrupt gilteritinib if severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids.
•    Resume gilteritinib at the same dose when signs and symptoms improve to Grade 2a or lower.
Posterior reversible encephalopathy syndrome           •    Discontinue gilteritinib.
QTcF interval >500 msec                                •    Interrupt gilteritinib.
•    Resume gilteritinib at a reduced dose (80 mg or
120 mgb) when QTcF interval returns to within
30 msec of baseline or ≤ 480 msec.
QTcF interval increased by >30 msec on ECG             •    Confirm with ECG on day 9.
on day 8 of cycle 1                                    •    If confirmed, consider dose reduction to 80mg.
Pancreatitis                                           •    Interrupt gilteritinib until pancreatitis is resolved.
•    Resume treatment with gilteritinib at a reduced dose (80 mg or 120 mgb).
Other Grade 3a or higher toxicity considered           •    Interrupt gilteritinib until toxicity resolves or related to treatment.                                       improves to Grade 1a.
•    Resume treatment with gilteritinib at a reduced dose (80 mg or 120 mgb).
Planned HSCT                                           •    Interrupt treatment with gilteritinib one week prior to administration of the conditioning regimen for HSCT.
•    Treatment can be resumed 30 days after HSCT if engraftment was successful, the patient did not have grade ≥2 acute graft versus host disease and was in CRc.c

 a. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe,, Grade 4 is life-threatening.
b. The daily dose can be reduced from 120 mg to 80 mg or from 200 mg to 120 mg.
c. CRc is defined as the remission rate of all CR (see section 5.1 for definition of CR), CRp [achieved CR except for incomplete platelet recovery (<100 x 109/L)] and CRi (achieved all criteria for CR except for incomplete haematological recovery with residual neutropenia <1 x 109/L with or without complete platelet recovery).

Xospata should be administered at about the same time each day. If a dose is missed or not taken at the usual time, the dose should be administered as soon as possible on the same day, and patients should return to the normal schedule the following day. If vomiting occurs after dosing, patients should not take another dose but should return to the normal schedule the following day.

Elderly
No dose adjustment is required in patients ≥65 years of age (see section 5.2).

Hepatic impairment
No dose adjustment is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Xospata is not recommended for use in patients with severe (Child-Pugh Class C) hepatic impairment, as safety and efficacy have not been evaluated in this population (see section 5.2).

Renal impairment
No dose adjustment is necessary in patients with mild or moderate renal impairment. There is no clinical experience in patients with severe renal impairment (see section 5.2).

Paediatric population
Xospata is not indicated for children and adolescents under 18 years old.
The safety and efficacy of Xospata in children aged below 18 years has not yet been established.

Method of administration
Xospata is for oral use.
The tablets can be taken with or without food. They should be swallowed whole with water and should not be broken or crushed.