Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Differentiation syndrome
Gilteritinib has been associated with differentiation syndrome (see section 4.8).
Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and clinical findings of differentiation syndrome include fever, dyspnoea, pleural effusion, pericardial effusion, pulmonary oedema, hypotension, rapid weight gain, peripheral oedema, rash, and renal dysfunction.

If differentiation syndrome is suspected, corticosteroid therapy should be initiated along with hemodynamic monitoring until symptom resolution. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, Xospata should be interrupted until signs and symptoms are no longer severe (see sections 4.2 and 4.8).
Corticosteroids can be tapered after resolution of symptoms and should be administered for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment.

Posterior reversible encephalopathy syndrome
There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving Xospata (see section 4.8). PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizure, headache, confusion, visual and neurological disturbances, with or without associated hypertension and altered mental status. If PRES is suspected, it should be confirmed by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of Xospata in patients who develop PRES is recommended (see sections 4.2 and 4.8).

Prolonged QT interval
Gilteritinib has been associated with prolonged cardiac ventricular repolarisation (QT Interval) (see sections 4.8 and 5.1). QT prolongation can be observed in the first three months of treatment with gilteritinib. Therefore, electrocardiogram (ECG) should be performed prior to initiation of treatment, on day 8 and 15 of cycle 1, and prior to the start of the next three subsequent months of treatment. Caution is warranted in patients with relevant cardiac history. Hypokalaemia or hypomagnesaemia may increase the QT prolongation risk.
Hypokalaemia or hypomagnesaemia should therefore be corrected prior to and during Xospata treatment.

Xospata should be interrupted in patients who have a QTcF >500 msec (see section 4.2).

The decision to re-introduce gilteritinib treatment after an event of QT prolongation should be based on a careful consideration of benefits and risks. If Xospata is re-introduced at a reduced dose, ECG should be performed after 15 days of dosing, and prior to the start of the next three subsequent months of treatment. In clinical studies, 12 patients had QTcF >500 msec. Three patients interrupted and re-initiated treatment without recurrence of QT prolongation.

Pancreatitis
There have been reports of pancreatitis. Patients who develop signs and symptoms suggestive of pancreatitis should be evaluated and monitored. Xospata should be interrupted and can be resumed at a reduced dose when the signs and symptoms of pancreatitis have resolved (see section 4.2).

Interactions
Co-administration of CYP3A/P-gp inducers may lead to decreased gilteritinib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of gilteritinib with strong CYP3A4/P-gp inducers should be avoided (see section 4.5).

Caution is required when concomitantly prescribing gilteritinib with medicinal products that are strong inhibitors of CYP3A, P-gp and/or breast cancer resistant protein (BCRP) (such as, but not limited to, voriconazole, itraconazole, posaconazole and clarithromycin) because they can increase gilteritinib exposure. Alternative medicinal products that do not strongly inhibit CYP3A, P-gp and/or BCRP activity should be considered. In situations where satisfactory therapeutic alternatives do not exist, patients should be closely monitored for toxicities during administration of gilteritinib (see section 4.5).

Gilteritinib may reduce the effects of medicinal products that target 5HT 2B receptor or sigma nonspecific receptors. Therefore, concomitant use of gilteritinib with these products should be avoided unless use is considered essential for the care of the patient (see section 4.5).

Embryofoetal toxicity and contraception
Pregnant women should be informed of the potential risk to a foetus (see sections 4.6 and 5.3). Females of reproductive potential should be advised to have a pregnancy test within seven days prior to starting treatment with Xospata and to use effective contraception during treatment with Xospata and for at least 6 months after stopping treatment. Women using hormonal contraceptives should add a barrier method of contraception. Males with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 4 months after the last dose of Xospata.

Effects on Driving

4.7   Effects on ability to drive and use machines
Gilteritinib has minor influence on the ability to drive and use machines. Dizziness has been reported in patients taking Xospata and should be considered when assessing a patient’s ability to drive or use machines (see section 4.8).