XOSPATA 40mg tablets medication leaflet

Xospata 40 mg film-coated tablets

Each film-coated tablet contains 40 mg gilteritinib (as fumarate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Round, light yellow film-coated tablet of approximately 7.1 mm, debossed with the company logo and‘235’ on the same side.

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

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

Before taking gilteritinib, relapsed or refractory AML patients must have confirmation of FMS-liketyrosine 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).

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 oftreatment, on day 15 and monthly for the duration of treatment (see section 4.4).

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

Females of reproductive potential should be advised to have a pregnancy test within seven days priorto starting treatment with Xospata (see sections 4.4 and 4.6).

Treatment should continue until the patient is no longer clinically benefiting from Xospata or untilunacceptable toxicity occurs. Response may be delayed; therefore, continuation of treatment at theprescribed 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 4weeks of treatment, the dose can be increased to 200 mg (five 40 mg tablets) once daily, if tolerated orclinically warranted.

Table 1: Xospata dose interruption, reduction and discontinuation recommendations in patientswith relapsed or refractory AML

Criteria Xospata dosing

Differentiation syndrome * If differentiation syndrome is suspected,administer corticosteroids and initiatehemodynamic monitoring (see section 4.4).

* Interrupt gilteritinib if severe signs and/orsymptoms persist for more than 48 hoursafter initiation of corticosteroids.

* Resume gilteritinib at the same dose whensigns and symptoms improve to Grade 2a orlower.

Posterior reversible encephalopathy * Discontinue gilteritinib.syndrome

QTcF interval >500 msec * Interrupt gilteritinib.

* Resume gilteritinib at a reduced dose (80 mgor 120 mgb) when QTcF interval returns towithin 30 msec of baseline or ≤ 480 msec.

QTcF interval increased by >30 msec on * Confirm with ECG on day 9.

ECG on day 8 of cycle 1 * If confirmed, consider dose reduction to80 mg.

Pancreatitis * Interrupt gilteritinib until pancreatitis isresolved.

* Resume treatment with gilteritinib at areduced dose (80 mg or 120 mgb).

Other Grade 3a or higher toxicity * Interrupt gilteritinib until toxicity resolves orconsidered related to treatment. improves to Grade 1a.

* Resume treatment with gilteritinib at areduced dose (80 mg or 120 mgb).

Planned HSCT * Interrupt treatment with gilteritinib one weekprior to administration of the conditioningregimen for HSCT.

* Treatment can be resumed 30 days after

HSCT if engraftment was successful, thepatient did not have grade ≥2 acute graftversus host disease and was in CRcc.

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 allcriteria for CR except for incomplete haematological recovery with residual neutropenia <1 x109/L with or without complete platelet recovery).

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

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 (seesection 5.2).

No dose adjustment is necessary in patients with mild, moderate or severe renal impairment (seesections 4.4 and 5.2).

The safety and efficacy of Xospata in children aged below 18 years has not yet been established.

No data are available. Due to in vitro binding to 5HT2B (see section 4.5), there is a potential impact oncardiac development in patients less than 6 months of age.

Xospata is for oral use.

The tablets can be taken with or without food. They should be swallowed whole with water and shouldnot be broken or crushed.

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

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

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

If differentiation syndrome is suspected, corticosteroid therapy should be initiated along withhemodynamic monitoring until symptom resolution. If severe signs and/or symptoms persist for morethan 48 hours after initiation of corticosteroids, gilteritinib should be interrupted until signs andsymptoms are no longer severe (see sections 4.2 and 4.8).

Corticosteroids can be tapered after resolution of symptoms and should be administered for aminimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuationof corticosteroid treatment.

There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receivinggilteritinib (see section 4.8). PRES is a rare, reversible, neurological disorder which can present withrapidly evolving symptoms including seizure, headache, confusion, visual and neurologicaldisturbances, 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 and4.8).

Prolonged QT interval

Gilteritinib has been associated with prolonged cardiac ventricular repolarisation (QT Interval) (seesections 4.8 and 5.1). QT prolongation can be observed in the first three months of treatment withgilteritinib. 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 hypomagnesaemiamay increase the QT prolongation risk. Hypokalaemia or hypomagnesaemia should therefore becorrected prior to and during gilteritinib treatment.

Gilteritinib 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 basedon a careful consideration of benefits and risks. If gilteritinib is re-introduced at a reduced dose, ECGshould be performed after 15 days of dosing, and prior to the start of the next three subsequent monthsof treatment. In clinical studies, 12 patients had QTcF >500 msec. Three patients interrupted and re-initiated treatment without recurrence of QT prolongation.

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

Gilteritinib exposure may be increased in patients with severe renal impairment or end stage renaldisease. Patients should be closely monitored for toxicities during administration of gilteritinib (seesection 5.2).

Co-administration of CYP3A/P-gp inducers may lead to decreased gilteritinib exposure andconsequently 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 stronginhibitors of CYP3A, P-gp and/or breast cancer resistant protein (BCRP) because they can increasegilteritinib 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 notexist, patients should be closely monitored for toxicities during administration of gilteritinib (seesection 4.5).

Gilteritinib may reduce the effects of medicinal products that target 5HT2B receptor or sigmanonspecific receptors. Therefore, concomitant use of gilteritinib with these products should be avoidedunless 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 priorto starting treatment with gilteritinib and to use effective contraception during treatment withgilteritinib and for at least 6 months after stopping treatment. Women using hormonal contraceptivesshould add a barrier method of contraception. Males with female partners of reproductive potentialshould be advised to use effective contraception during treatment and for at least 4 months after thelast dose of gilteritinib.

Gilteritinib is primarily metabolised by CYP3A enzymes, which can be induced or inhibited by anumber 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. Inhealthy subjects, co-administration of rifampicin (600 mg), a strong CYP3A/P-gp inducer, to steadystate with a single 20 mg dose of gilteritinib decreased gilteritinib mean Cmax by 27% and mean AUCinfby 70%, respectively, compared to subjects administered a single dose of gilteritinib alone (seesection 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 gilteritinibplasma concentrations. A single, 10 mg dose of gilteritinib co-administered with itraconazole (200 mgonce daily for 28 days), a strong CYP3A, P-gp and BCRP inhibitor, to healthy subjects resulted in anapproximate 20% increase in mean Cmax and 2.2-fold increase in mean AUCinf relative to subjectsadministered a single dose of gilteritinib alone. Gilteritinib exposure increased approximately 1.5-foldin 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. Thepharmacokinetics of midazolam (a sensitive CYP3A4 substrate) were not significantly (Cmax and AUCincreased approximately 10%) affected after once-daily administration of gilteritinib (300 mg) for15 days in patients with FLT3-mutated relapsed or refractory AML. Additionally, thepharmacokinetics of cephalexin (a sensitive MATE1 substrate) were not significantly (Cmax and AUCdecreased by less than 10%) affected after once daily administration of gilteritinib (200 mg) for15 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 cannotbe excluded that gilteritinib could inhibit these transporters at a therapeutic dose. Caution is advisedduring 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 5HT2Breceptor or sigma nonspecific receptor (selective serotonin reuptake inhibitors e.g., escitalopram,fluoxetine, sertraline). Avoid concomitant use of these medicinal products with gilteritinib unless useis considered essential for the care of the patient.

Pregnancy testing is recommended for females of reproductive potential seven days prior to initiatinggilteritinib treatment. Women of childbearing potential are recommended to use effectivecontraception (methods that result in less than 1% pregnancy rates) during and up to 6 months aftertreatment. 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 andfor at least 4 months after the last dose of gilteritinib (see section 4.4).

Gilteritinib can cause foetal harm when administered to pregnant women. There are no or limitedamount of data from the use of gilteritinib in pregnant women. Reproductive studies in rats haveshown that gilteritinib caused suppressed foetal growth, embryo-foetal deaths and teratogenicity (seesection 5.3). Gilteritinib is not recommended during pregnancy and in women of childbearing potentialnot using effective contraception.

It is unknown whether gilteritinib or its metabolites are excreted in human milk. Available animal datahave shown excretion of gilteritinib and its metabolites in the animal milk of lactating rats anddistribution 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 duringtreatment with gilteritinib and for at least two months after the last dose.

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

Gilteritinib has minor influence on the ability to drive and use machines. Dizziness has been reportedin patients taking gilteritinib and should be considered when assessing a patient’s ability to drive oruse machines (see section 4.8).

The safety of Xospata was evaluated in 319 patients with relapsed or refractory AML who havereceived 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%), ALTincreased (4.1%), dyspnea (3.4%), AST increased (3.1%) and hypotension (2.8%). Other clinicallysignificant serious adverse reactions included differentiation syndrome (2.2%), electrocardiogram QTprolonged (0.9%) and posterior reversible encephalopathy syndrome (0.6%).

Adverse reactions observed during clinical studies are listed below by MedDRA system oragan classand 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 frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions

All Grades Frequency

MedDRA system organ class Grades ≥3 category

Preferred Term % %

Anaphylactic reaction 1.3 1.3 Common

Dizziness 20.4 0.3 Very common

Posterior reversible encephalopathysyndrome 0.6 0.6 Uncommon

Electrocardiogram QT prolonged 8.8 2.5 Common

Pericardial effusion 4.1 0.9 Common

Pericarditis 1.6 0 Common

Cardiac failure 1.3 1.3 Common

Hypotension 17.2 7.2 Very common

Cough 28.2 0.3 Very common

Dyspnoea 24.1 4.4 Very common

Differentiation syndrome 3.4 2.2 Common

Diarrhoea 35.1 4.1 Very common

Nausea 29.8 1.9 Very common

Constipation 28.2 0.6 Very common

Alanine aminotransferase increased* 82.1 12.9 Very common

Aspartate aminotransferase increased* 80.6 10.3 Very common

Blood creatine phosphokinaseincreased* 53.9 6.3 Very common

Blood alkaline phosphatase increased* 68.7 1.6 Very common

Pain in extremity 14.7 0.6 Very common

Arthralgia 12.5 1.3 Very common

Myalgia 12.5 0.3 Very common

Musculoskeletal pain 4.1 0.3 Common

Acute kidney injury 6.6 2.2 Common

Fatigue 30.4 3.1 Very common

Peripheral oedema 24.1 0.3 Very common

Asthenia 13.8 2.5 Very common

Malaise 4.4 0 Common

* Frequency is based on central laboratory values.

Of 319 patients treated with Xospata in the clinical studies, 11 (3%) experienced differentiationsyndrome. Differentiation syndrome is associated with rapid proliferation and differentiation ofmyeloid cells and may be life-threatening or fatal if not treated. Symptoms and clinical findings ofdifferentiation syndrome in patients treated with Xospata included fever, dyspnoea, pleural effusion,pericardial effusion, pulmonary oedema, hypotension, rapid weight gain, peripheral oedema, rash, andrenal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiationsyndrome occurred as early as one day and up to 82 days after Xospata initiation and has beenobserved with or without concomitant leukocytosis. Of the 11 patients who experienced differentiationsyndrome, 9 (82%) recovered after treatment or after dose interruption of Xospata. Forrecommendations 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 reversibleencephalopathy syndrome (PRES). PRES is a rare, reversible, neurological disorder, which can presentwith rapidly evolving symptoms including seizure, headache, confusion, visual and neurologicaldisturbances, with or without associated hypertension. Symptoms have resolved after discontinuationof treatment (see sections 4.2 and 4.4).

Of the 317 patients treated with Xospata 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%) withrelapsed/refractory AML had a maximum post-baseline QTcF interval >500 msec (see sections 4.2,4.4 and 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no known specific antidote for Xospata. In the event of an overdose, treatment with Xospatashould be stopped. Patients must be closely monitored for signs or symptoms of adverse reactions, andappropriate symptomatic and supportive treatment initiated, taking into consideration the long half-lifeestimated at 113 hours.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EX13

Gilteritinib fumarate is a FLT3 and AXL inhibitor.

Gilteritinib inhibits FLT3 receptor signalling and proliferation in cells exogenously expressing FLT3including FLT3-ITD, FLT3-D835Y, and FLT3-ITD-D835Y, and it induces apoptosis in leukemic cellsexpressing FLT3-ITD.

In patients with relapsed or refractory AML receiving gilteritinib 120 mg, substantial (> 90%)inhibition of FLT3 phosphorylation was rapid (within 24 hours after first dose) and sustained, ascharacterised by an ex vivo plasma inhibitory activity (PIA) assay.

Prolonged QT interval

A concentration-related increase in change from baseline of QTcF was observed across gilteritinibdoses ranging from 20 to 450 mg. The predicted mean change from baseline of QTcF at the meansteady-state Cmax (282.0 ng/mL) at the 120 mg daily dose was 4.96 msec with an upper 1-sided 95% CI= 6.20 msec.

Relapsed or refractory AML

Efficacy and safety were evaluated in the active-controlled, phase 3 study (2215-CL-0301).

ADMIRAL study (2215-CL-0301)

The ADMIRAL study is a Phase 3, open-label, multicentre, randomised clinical study of adult patientswith relapsed or refractory AML with a FLT3 mutation as determined by the LeukoStrat® CDx FLT3

Mutation Assay. In this study, 371 patients were randomised in a 2:1 ratio to receive gilteritinib or oneof the following salvage chemotherapies (247 in the gilteritinib arm and 124 in the salvagechemotherapy arm):

* cytarabine 20 mg twice daily by subcutaneous injection (SC) or intravenous infusion (IV) for10 days (days 1 through 10) (LoDAC)

* azacitidine 75 mg/m2 once daily by SC or IV for 7 days (days 1 through 7)

* mitoxantrone 8 mg/m2, etoposide 100 mg/m2 and cytarabine 1000 mg/m2 once daily by IV for5 days (days 1 through 5) (MEC)

* granulocyte colony-stimulating factor 300 mcg/m2 once daily by SC for 5 days (days 1 to 5),fludarabine 30 mg/m2 once daily by IV for 5 days (days 2 through 6), cytarabine 2000 mg/m2once daily by IV for 5 days (days 2 through 6), idarubicin 10 mg/m2 once daily by IV for 3 days(days 2 through 4) (FLAG-Ida).

Patients included were relapsed or refractory after first line AML therapy and were stratified byresponse to prior AML treatment and preselected chemotherapy i.e. high or low intensity. While thestudy included patients with various AML-related cytogenetic abnormalities, patients with acutepromyelocytic leukaemia (APL) or therapy-related AML were excluded.

Sixteen patients were randomised but not treated in the study (1 patient in the gilteritinib arm and15 patients in the chemotherapy arm). Gilteritinib was given orally at a starting dose of 120 mg dailyuntil unacceptable toxicity or lack of clinical benefit. Dose reductions were allowed, to manageadverse reactions, and dose increases were allowed, for those patients who did not respond at thestarting dose of 120 mg.

Of the patients who were pre-selected to receive salvage chemotherapy, 60.5% were randomised tohigh intensity and 39.5% to low intensity. MEC and FLAG-Ida were given for up to two cyclesdepending on response to first cycle. LoDAC and azacitidine were given in continuous 4-week cyclesuntil unacceptable toxicity or lack of clinical benefit.

The demographic and baseline characteristics were well-balanced between the two treatment arms.

The median age at randomisation was 62 years (range 20 to 84 years) in the gilteritinib arm and62 years (range 19 to 85 years) in the salvage chemotherapy arm. In the study 42% of patients were65 years or older and 12% were 75 years or older. Fifty-four percent of the patients were female. Mostpatients in the study were Caucasian (59.3%); 27.5% Asian, 5.7% Black, 4% other races and 3.5%unknown. The majority of patients (83.8%) had an ECOG performance status score of 0 or 1. Patientshad the following confirmed mutations: FLT3-ITD alone (88.4%), FLT3-TKD alone (8.4%) or both

FLT3-ITD and FLT3-TKD (1.9%). Twelve percent of patients received previous treatment withanother FLT3 inhibitor. A majority of patients had AML with intermediate risk cytogenetics (73%),10% had unfavourable, 1.3% had favourable and 15.6% had unclassified cytogenetics.

Prior to treatment with gilteritinib, 39.4% of patients had primary refractory AML and the majority ofthese patients were classified as refractory after 1 cycle of chemotherapy induction treatment, 19.7%had relapsed AML after an allogeneic haematopoietic stem cell transplant (HSCT) and 41% hadrelapsed AML with no allogeneic HSCT.

The primary efficacy endpoint for the final analysis was OS in the intent-to-treat (ITT) population,measured from the date of randomisation until death by any cause (number of events analysed was261). Patients randomised to the gilteritinib arm had significantly longer survival compared to thechemotherapy arm (HR 0.637; 95% CI 0.490 - 0.830; 1 sided p-value: 0.0004). The median OS was9.3 months for patients receiving gilteritinib and 5.6 months for those receiving chemotherapy.

Efficacy was further supported by the rate of complete remission (CR)/complete remission with partialhaematologic recovery (CRh) (Table 3, Figure 1).

Table 3: ADMIRAL study overall survival and complete remission in patients with relapsed orrefractory AML

Gilteritinib Chemotherapy(N=247) (N=124)

Overall survival

Deaths, n (%) 171 (69.2) 90 (72.6)

Median in months (95% CI) 9.3 (7.7, 10.7) 5.6 (4.7, 7.3)

Hazard Ratio (95% CI) 0.637 (0.490, 0.830)p-value (1-sided) 0.00041 year survival rate, % (95% CI) 37.1 (30.7, 43.6) 16.7 (9.9, 25)

Complete remission

CRa (95% CIb) 21.1% (16.1, 26.7) 10.5% (5.7, 17.3)

CRhc (95% CIb) 13% (9, 17.8) 4.8% (1.8, 10.2)

CR/CRh (95% CIb) 34% (28.1, 40.3) 15.3% (9.5, 22.9)

CI: confidence interval

a. CR was defined as an absolute neutrophil count ≥1.0 x 109/L, platelets ≥100 x 109/L, normalmarrow differential with <5% blasts, must have been red blood cells, platelet transfusionindependent and no evidence of extramedullary leukemia.

b. The 95% CI rate was calculated using the exact method based on binomial distribution.

c. CRh was defined as marrow blasts <5%, partial haematologic recovery absolute neutrophil count≥0.5 x 109/L and platelets ≥50 x 109/L, no evidence of extramedullary leukemia and could nothave been classified as CR.

Figure 1: Kaplan-Meier plot of overall survival in ADMIRAL study

For patients who achieved a CR/CRh, the median time to first response was 3.7 months (range, 0.9 to10.6 months) in the gilteritinib arm and 1.2 months (range: 1 to 2.6 months) in the salvagechemotherapy arm. The median time to best response of CR/CRh was 3.8 months (range, 0.9 to 16months) in the gilteritinib arm and 1.2 months (range: 1 to 2.6 months) in the salvage chemotherapyarm.

CHRYSALIS study (2215-CL-0101)

The supportive Phase 1/2 dose-escalation study 2215-CL-0101 included 157 patients with FLT3mutated AML treated with either 1 or >1 prior lines of treatment in the combined dose group (i.e.80 mg, 120 mg or 200 mg); 31.2% received 1 prior line of treatment and 68.8% received >1 prior linesof treatment.

The response rate (CR/CRh) observed in Study 2215-CL-0101 in the patients who received more than1 line of prior therapy was 21.4% and 15.7% for the 120 mg dose and the combined dose levels,respectively. The median OS was 7.2 months and 7.1 months for the 120 mg dose and the combineddose levels, respectively.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Xospata in one or more subsets of the paediatric population in the treatment of acute myeloidleukaemia. See 4.2 for information on paediatric use.

Following oral administration of gilteritinib, peak plasma concentrations are observed at a median tmaxapproximately between 4 and 6 hours in healthy volunteers and patients with relapsed orrefractory AML. Gilteritinib undergoes first-order absorption with an estimated absorption rate (ka) of0.43 h-1 with a lag time of 0.34 hours based on population PK modelling. Median steady-statemaximum concentration (Cmax) is 282.0 ng/mL (CV% = 50.8), and area under the plasmaconcentration curve during 24-hour dosing interval (AUC0-24) is 6180 ng·h/mL (CV% = 46.4) afteronce-daily dosing of 120 mg gilteritinib. Steady-state plasma levels are reached within 15 days ofonce-daily dosing with an approximate 10-fold accumulation.

In healthy adults, gilteritinib Cmax and AUC decreased by approximately 26% and less than 10%,respectively, when a single 40 mg dose of gilteritinib was co-administered with a high fat mealcompared to gilteritinib exposure in fasted state. Median tmax was delayed 2 hours when gilteritinibwas administered with a high-fat meal.

The population estimate of central and peripheral volume of distribution were 1092 L and 1100 L,respectively. These data indicate gilteritinib distributes extensively outside of plasma, which mayindicate extensive tissue distribution. In vivo plasma protein binding in humans is approximately 90%and gilteritinib is primarily bound to albumin.

Based on in vitro data, gilteritinib is primarily metabolised via CYP3A4. The primary metabolites inhumans include M17 (formed via N-dealkylation and oxidation), M16 and M10 (both formed via

N-dealkylation) and were observed in animals. None of these three metabolites exceeded 10% ofoverall parent exposure. The pharmacological activity of the metabolites against FLT3 and AXLreceptors is unknown.

Transporter drug-drug interactions

In vitro experiments demonstrated that gilteritinib is a substrate of P-gp and BCRP. Gilteritinib maypotentially inhibit BCRP, P-gp and OCT1 at clinically relevant concentrations (see section 4.5).

After a single dose of [14C] -gilteritinib, gilteritinib is primarily excreted in faeces with 64.5% of thetotal administered dose recovered in faeces. Approximately 16.4% of the total dose was excreted inurine as unchanged drug and metabolites. Gilteritinib plasma concentrations declined in abi-exponential manner with a population mean estimated half-life of 113 hours. The estimatedapparent clearance (CL/F) based on the population PK model is 14.85 L/h.

In general, gilteritinib exhibited linear, dose-proportional pharmacokinetics after single and multipledose administration at doses ranging from 20 to 450 mg in patients with relapsed or refractory AML.

A population pharmacokinetic analysis was performed to evaluate the impact of intrinsic and extrinsiccovariates on the predicted exposure of gilteritinib in patients with relapsed or refractory AML.

Covariate analysis indicated that age (20 years to 90 years), and body weight (36 kg to 157 kg) werestatistically significant; however predicted change in gilteritinib exposure was less than 2-fold.

The effect of hepatic impairment on gilteritinib pharmacokinetics was studied in subjects with mild(Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment. Results indicateunbound gilteritinib exposure in subjects with mild or moderate hepatic impairment is comparable tothat observed in subjects with normal hepatic function. The effect of mild hepatic impairment [asdefined by NCI-ODWG] on gilteritinib exposure was also assessed using the population PK model andthe results demonstrate little difference in predicted steady-state gilteritinib exposure relative to atypical patient with relapsed or refractory AML and normal liver function.

Gilteritinib has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

The pharmacokinetics of gilteritinib were evaluated in five subjects with severe(CrCL 15 - <30 mL/min) renal impairment and in four subjects with end stage renal disease(CrCL <15 mL/min). A 1.4-fold increase in mean Cmax and 1.5-fold increase in mean AUCinf ofgilteritinib was observed in subjects with severe renal impairment or end stage renal disease comparedto subjects with normal renal function (n=8) (see sections 4.2 and 4.4).

Adverse reactions not observed in clinical studies, but seen in animals (safety pharmacology/repeatdose toxicity) at exposure levels similar to clinical exposure levels and with possible relevance toclinical use were as follows:

Safety pharmacology

In rats, decreased urination at 30 mg/kg and higher and decreased defecation at 100 mg/kg wereobserved. In dogs, positive faecal occult blood at 10 mg/kg and higher, a decrease in the blood calciumconcentration at 30 mg/kg, and salivation and an increase followed by a decrease in the blood calciumconcentration at 100 mg/kg were observed. These changes were observed at plasma exposure levelssimilar to or less than clinical exposure levels. A possible clinical relevance of these findings isunknown.

In the repeated dose toxicity studies in rats and dogs, target organs of toxicity were the gastrointestinaltract (heamorrhage in dogs), lymphohaematopoietic system (lymphocyte necrosis and bone marrowhypocellularity with changes in haematological parameters), eye (inflammation and lens opacity inrats, fundus colour change in dogs, retinal vacuolation), lung (interstitial pneumonia in rats andinflammation in dogs), kidney (renal tubule changes with a positive urine occult blood reaction) andliver (hepatocyte vacuolation), urinary bladder (epithelial vacuolation), epithelial tissue (ulcer andinflammation), and phospholipidosis (lung and kidney in rats). These changes were observed at plasmaexposure levels similar to or less than clinical exposure levels. Reversibility of most of the changeswas indicated by the end of the 4-week recovery period. A possible clinical relevance of these findingsis unknown.

Gilteritinib did not induce gene mutation or chromosomal aberrations in vitro. The in vivomicronucleus test showed that gilteritinib has a potential to induce micronuclei in mice.

Gilteritinib showed suppressed foetal growth, and induced embryo-foetal deaths and teratogenicity inthe embryo-foetal development studies in rats at exposure levels similar to clinical exposure levels.

Placental transfer of gilteritinib was shown in the rat resulting in transfer of radioactivity to the foetussimilar to that observed in maternal plasma.

Gilteritinib was excreted into the milk of lactating rats with milk concentrations being higher than inmaternal plasma. Gilteritinib was distributed through the breast milk to different tissues, except for thebrain, of suckling rats.

Juvenile animal toxicity study

In the juvenile toxicity study in rats, the minimum lethal dose level (2.5 mg/kg/day) was much lowerthan that of adult rats (20 mg/kg/day). The gastrointestinal tract was identified as one of the targetorgans similar as in adult rats.

Mannitol (E421)

Hydroxypropylcellulose

Hydroxypropylcellulose, low-substituted

Magnesium stearate

Hypromellose

Talc

Macrogol

Titanium dioxide

Iron oxide yellow (E172)

Not applicable.

4 years.

This medicinal product does not require any special temperature storage conditions. Store in theoriginal package in order to protect from light.

OPA/aluminium/PVC/aluminium blisters containing 21 film-coated tablets.

Each pack contains 84 film-coated tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Astellas Pharma Europe B.V.

Sylviusweg 622333 BE Leiden

The Netherlands

EU/1/19/1399/001

Date of first authorisation: 24 October 2019

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.