Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Gilteritinib is primarily metabolised by CYP3A enzymes, which can be induced or inhibited by a number of concomitant medicinal products.

Effects of other medicinal products on Xospata
CYP3A/P-gp Inducers
Concomitant use of Xospata with strong CYP3A/P-gp inducers (e.g., phenytoin, rifampin and St. John’s Wort) should be avoided because they can decrease gilteritinib plasma concentrations. In healthy subjects, co-administration of rifampicin (600 mg), a strong CYP3A/P-gp inducer, to steady state with a single 20 mg dose of gilteritinib decreased gilteritinib mean Cmax by 27% and mean AUCinf by 70%, respectively, compared to subjects administered a single dose of gilteritinib alone (see section 4.4).

CYP3A, P-gp and/or BCRP inhibitors
Strong inhibitors of CYP3A, P-gp and/or BCRP (e.g., voriconazole, itraconazole, posaconazole, clarithromycin, erythromycin, captopril, carvedilol, ritonavir, azithromycin) can increase gilteritinib plasma concentrations. A single, 10 mg dose of gilteritinib co-administered with itraconazole (200 mg once daily for 28 days), a strong CYP3A, P-gp and BCRPinhibitor, to healthy subjects resulted in an approximate 20% increase in mean C max and 2.2-fold increase in mean AUCinf relative to subjects administered a single dose of gilteritinib alone. Gilteritinib exposure increased approximately 1.5-fold in patients with relapsed or refractory AML when co-administered with a strong CYP3A, P-gp and/or BCRPinhibitor (see section 4.4).

Effects of Xospata on other medicinal products
Gilteritinib as an inhibitor or inducer
Gilteritinib is not an inhibitor or inducer of CYP3A4 or an inhibitor of MATE1 in vivo. The pharmacokinetics of midazolam (a sensitive CYP3A4 substrate) were not significantly (Cmax and AUC increased approximately 10%) affected after once-daily administration of gilteritinib (300 mg) for 15 days in patients with FLT3-mutated relapsed or refractory AML.
Additionally, the pharmacokinetics of cephalexin (a sensitive MATE1 substrate) were not significantly (Cmax and AUC decreased by less than 10%) affected after once daily administration of gilteritinib (200 mg) for 15 days in patients with FLT3-mutated relapsed or refractory AML.

Gilteritinib is an inhibitor of P-gp, BCRP and OCT1 in vitro. As no clinical data is available, it cannot be excluded that gilteritinib could inhibit these transporters at a therapeutic dose.
Caution is advised during co-administration of gilteritinib with substrates of P-gp (e.g., digoxin, dabigatran etexilate), BCRP (e.g., mitoxantrone, methotrexate, rosuvastatin) and OCT1 (e.g., metformin).


5HT2B receptor or sigma nonspecific receptor
Based on in vitro data, gilteritinib may reduce the effects of medicinal products that target 5HT2B receptor or sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline).
Avoid concomitant use of these medicinal products with Xospata unless use is considered essential for the care of the patient.