4.1. Therapeutic indications

Gilteritinib Astellas 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).

4.2. Posology and method of administration

Treatment with Gilteritinib Astellas should be initiated and supervised by a physician experienced in the use of anti-cancer therapies.

Before taking gilteritinib, relapsed or refractory AML patients must have confirmation of FMS-like tyrosine kinase 3 (FLT3) mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD]) using a validated test.

Gilteritinib Astellas may be re-initiated in patients following haematopoietic stem cell transplantation (HSCT) (see Table 1).

Posology

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 of treatment, 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 8 and 15 of cycle 1 and prior to the start of the next three subsequent months of treatment (see sections 4.4 and 4.8).

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

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

Dose modifications

Table 1: Gilteritinib Astellas dose interruption, reduction and discontinuation recommendations in patients with relapsed or refractory AML

Criteria

Gilteritinib Astellas dosing

Differentiation syndrome

• If differentiation syndrome is suspected, administer corticosteroids and initiate hemodynamic monitoring (see section 4.4).

• Interrupt gilteritinib if severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids.

• Resume gilteritinib at the same dose when signs and symptoms improve to Grade 2a or lower.

Posterior reversible encephalopathy syndrome

• Discontinue gilteritinib.

QTcF interval >500 msec

• Interrupt gilteritinib.

• Resume gilteritinib at a reduced dose (80 mg or 120 mgb) when QTcF interval returns to within 30 msec of baseline or ≤480 msec.

QTcF interval increased by >30 msec on ECG on day 8 of cycle 1

• Confirm with ECG on day 9.

• If confirmed, consider dose reduction to 80 mg.

Pancreatitis

• Interrupt gilteritinib until pancreatitis is resolved.

• Resume treatment with gilteritinib at a reduced dose (80 mg or 120 mgb).

Other Grade 3a or higher toxicity considered related to treatment.

• Interrupt gilteritinib until toxicity resolves or improves to Grade 1a.

• Resume treatment with gilteritinib at a reduced dose (80 mg or 120 mgb).

Planned HSCT

• Interrupt treatment with gilteritinib one week prior to administration of the conditioning regimen for HSCT.

• Treatment can be resumed 30 days after HSCT if engraftment was successful, the patient did not have grade ≥2 acute graft versus 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 all criteria for CR except for incomplete haematological recovery with residual neutropenia <1 x 109/L with or without complete platelet recovery).

Elderly

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

Hepatic impairment

No dose adjustment is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Gilteritinib Astellas 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 (see section 5.2).

Renal impairment

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

Paediatric population

The safety and efficacy of Gilteritinib Astellas 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 on cardiac development in patients less than 6 months of age.

Method of administration

Gilteritinib Astellas is for oral use.

The tablets can be taken with or without food. They should be swallowed whole with water and should not be broken or crushed.

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

4.3. Contraindications

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

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, 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).

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 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 gilteritinib 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. Gilteritinib 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 and QT prolongation during administration of gilteritinib (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) 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 gilteritinib and to use effective contraception during treatment with gilteritinib 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 gilteritinib.

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 Gilteritinib Astellas

CYP3A/P-gp inducers

Concomitant use of Gilteritinib Astellas 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 Gilteritinib Astellas 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 (selective serotonin reuptake inhibitors e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these medicinal products with gilteritinib unless use is considered essential for the care of the patient.

4.6. Fertility, pregnancy and lactation

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. 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.

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 gilteritinib and should be considered when assessing a patient's ability to drive or use machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The safety of Gilteritinib Astellas 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 organ 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.

Table 2: Adverse reactions

MedDRA system organ class

Preferred Term

All Grades

%

Grades ≥3

%

Frequency category

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

1.3

Common

Vascular disorders

Hypotension

17.2

7.2

Very common

Respiratory, thoracic and mediastinal disorders

Cough

28.2

0.3

Very common

Dyspnoea

24.1

4.4

Very common

Differentiation syndrome

3.4

2.2

Common

Gastrointestinal disorders

Diarrhoea

35.1

4.1

Very common

Nausea

29.8

1.9

Very common

Constipation

28.2

0.6

Very common

Hepatobiliary disorders

Alanine aminotransferase increased*

82.1

12.9

Very common

Aspartate aminotransferase increased*

80.6

10.3

Very common

Musculoskeletal and connective tissue disorders

Blood creatine phosphokinase increased*

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

Renal and urinary disorders

Acute kidney injury

6.6

2.2

Common

General disorders and administration site conditions

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.

Description of selected adverse reactions

Differentiation syndrome

Of 319 patients treated with Gilteritinib Astellas 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 Gilteritinib Astellas 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 Gilteritinib Astellas 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 Gilteritinib Astellas. For recommendations in case of suspected differentiation syndrome (see sections 4.2 and 4.4).

PRES

Of the 319 patients treated with Gilteritinib Astellas 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 Astellas 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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