XOSPATA Film-coated tablet Ref.[109315] Active ingredients: Gilteritinib

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 reinitiated 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).

Severe renal impairment

Gilteritinib exposure may be increased in patients with severe renal impairment or end stage renal disease. Patients should be closely monitored for toxicities during administration of Xospata (see section 5.2).

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 5HT2B 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.

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 C_max by 27% and mean AUC_inf 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 AUC_inf 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 BCRP inhibitor (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 (C_max 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 (C_max 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).

5HT_2B receptor or sigma nonspecific receptor

Based on in vitro data, gilteritinib may reduce the effects of medicinal products that target 5HT_2B 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.

Women of childbearing potential / Contraception in males and females

Pregnancy testing is recommended for females of reproductive potential seven days prior to initiating Xospata treatment. Women of childbearing potential are recommended to use effective contraception (methods that result in less than 1% pregnancy rates) during and up to 6 months after treatment. It is unknown whether gilteritinib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method of contraception. Males of reproductive potential should be advised to use effective contraception during treatment and for at least 4 months after the last dose of Xospata (see section 4.4).

Pregnancy

Gilteritinib can cause foetal harm when administered to pregnant women. There are no or limited amount of data from the use of gilteritinib in pregnant women. Reproductive studies in rats have shown that gilteritinib caused suppressed foetal growth, embryo-foetal deaths and teratogenicity (see section 5.3). Xospata is not recommended during pregnancy and in women of childbearing potential not using effective contraception.

Breast-feeding

It is unknown whether gilteritinib or its metabolites are excreted in human milk. Available animal data have shown excretion of gilteritinib and its metabolites in the animal milk of lactating rats and distribution to the tissues in infant rats via the milk (see section 5.3).

A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with Xospata and for at least two months after the last dose.

Fertility

There are no data on the effect of gilterinitib on human fertility.

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).

Summary of the safety profile

The safety of Xospata was evaluated in 319 patients with relapsed or refractory AML who have received at least one dose of 120 mg gilteritinib.

The most frequent adverse reactions with gilteritinib were alanine aminotransferase (ALT) increased (82.1%), aspartate aminotransferase (AST) increased (80.6%), blood alkaline phosphatase increased (68.7%), blood creatine phosphokinase increased (53.9%), diarrhoea (35.1%), fatigue (30.4%), nausea (29.8%), constipation (28.2%), cough (28.2%), peripheral oedema (24.1%), dyspnea (24.1%), dizziness (20.4%), hypotension (17.2%), pain in extremity (14.7%), asthenia (13.8%), arthralgia (12.5%) and myalgia (12.5%).

The most frequent serious adverse reactions were acute kidney injury (6.6%), diarrhoea (4.7%), ALT increased (4.1%), dyspnea (3.4%), AST increased (3.1%) and hypotension (2.8%). Other clinically significant serious adverse reactions included differentiation syndrome (2.2%), electrocardiogram QT prolonged (0.9%) and posterior reversible encephalopathy syndrome (0.6%).

Tabulated list of adverse reactions

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2. Adverse reactions:

^* Frequency is based on central laboratory values.

Description of selected adverse reactions

Differentiation syndrome

Of 319 patients treated with Xospata in the clinical studies, 11 (3%) experienced differentiation syndrome. 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 in patients treated with Xospata included fever, dyspnoea, pleural effusion, pericardial effusion, pulmonary oedema, hypotension, rapid weight gain, peripheral oedema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as one day and up to 82 days after Xospata initiation and has been observed with or without concomitant leukocytosis. Of the 11 patients who experienced differentiation syndrome, 9 (82%) recovered after treatment or after dose interruption of Xospata. For recommendations in case of suspected differentiation syndrome see sections 4.2 and 4.4.

PRES

Of the 319 patients treated with Xospata in the clinical studies, 0.6% experienced posterior reversible encephalopathy syndrome (PRES). 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. Symptoms have resolved after discontinuation of treatment (see sections 4.2 and 4.4).

QT prolongation

Of the 317 patients treated with gilteritinib at 120 mg with a post-baseline QTC value in clinical studies, 4 patients (1%) experienced a QTcF >500 msec. Additionally, across all doses, 12 patients (2.3%) with relapsed/refractory AML had a maximum post-baseline QTcF interval >500 msec (see sections 4.2, 4.4 and 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.