Xospata · 4.8 Undesirable effects · 1

HOS-098649 · has-adverse-reaction-information · PDF-Seite 7

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 MedDRA system oragan class and 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. 7 Table 2: Adverse reactions All Grades Frequency MedDRA system organ class Grades ≥3 category Preferred Term % % Immune system disorders Anaphylactic reaction 1.3 1.3 Common Nervous system disorders Dizziness 20.4 0.3 Very common Posterior reversible encephalopathy syndrome 0.6 0.6 Uncommon Cardiac disorders Electrocardiogram QT prolonged 8.8 2.5 Common Pericardial effusion 4.1 0.9 Common Pericarditis 1.6 0 Common Cardiac failure 1.3 1

Auszug; vollständigen Abschnitt im Original lesen.

HOS-098645 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-098644 · has-indication-information · PDF-Seite 2

Xospata is indicated as monotherapy for the treatment of adult patients who have relapsed or refractory acute myeloid leukaemia (AML) with a FLT3 mutation (see sections 4.2 and 5.1).

HOS-098647 · has-interaction-information · PDF-Seite 6

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 BCRP inhibitor, to healthy subjects resulted in an approximate 20% increase in mean Cmax 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 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 (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, dabi

Auszug; vollständigen Abschnitt im Original lesen.

HOS-098648 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential / Contraception in males and females Pregnancy testing is recommended for females of reproductive potential seven days prior to initiating gilteritinib 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. 6 Males of reproductive potential should be advised to use effective contraception during treatment and for at least 4 months after the last dose of gilteritinib (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). Gilteritinib 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 gilteritinib and for at least two months after the last dose. Fertility There are no data on the effect of gilteritinib on human fertility.

HOS-098646 · has-warning-information · PDF-Seite 4

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, gilteritinib 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 gilteritinib (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 gilteritinib in patients who develop PRES is recommended (see sections 4.2 and 4.8). 4 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 gilteritinib treatment. Gilteritinib should be interrupted in patients who have a QTcF >500 msec (see

Auszug; vollständigen Abschnitt im Original lesen.