Gilteritinib

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).

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.

Concomitant use of gilteritinib 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.

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 gilteritinib.

Gilteritinib 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.

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 gilteritinib unless use is considered essential for the care of the patient.

Hypokalaemia or hypomagnesaemia may increase the QT prolongation risk. Hypokalaemia or hypomagnesaemia should therefore be corrected prior to and during gilteritinib treatment.

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. Gilteritinib is not recommended during pregnancy and in women of childbearing potential not using effective contraception.

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.

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.

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.

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 gilteritinib and should be considered when assessing a patient’s ability to drive or use machines.

Summary of the safety profile

The safety of gilteritinib 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.

Adverse reactions:

^* Frequency is based on central laboratory values.

Description of selected adverse reactions

Differentiation syndrome

Of 319 patients treated with gilteritinib 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 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 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.

PRES

Of the 319 patients treated with gilteritinib 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.

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.