LYTGOBI Film-coated tablet Ref.[51058] Active ingredients: Futibatinib

Hyperphosphatemia

Hyperphosphatemia is a pharmacodynamic effect expected with futibatinib administration (see section 5.1). Prolonged hyperphosphatemia may cause soft tissue mineralization, including cutaneous calcification, vascular calcification, and myocardial calcification, anaemia, hyperparathyroidism, and hypocalcemia that may cause muscle cramps, QT interval prolongation, and arrythmias (see section 4.2).

Recommendations for management of hyperphosphatemia include dietary phosphate restriction, administration of phosphate-lowering therapy, and dose modification when required (see section 4.2). Phosphate-lowering therapy was used by 83.4% of patients during treatment with futibatinib (see section 4.8).

Serous retinal detachment

Futibatinib can cause serous retinal detachment, which may present with symptoms such as blurred vision, visual floaters, or photopsia (see section 4.8). This can moderately influence the ability to drive and use machines (see section 4.7).

Ophthalmological examination should be performed prior to initiation of therapy, 6 weeks thereafter, and urgently at any time for visual symptoms. For serous retinal detachment reactions, the dose modification guidelines should be followed (see section 4.2).

During the conduct of the clinical study, there was no routine monitoring, including optical coherence tomography (OCT), to detect asymptomatic serous retinal detachment; therefore, the incidence of asymptomatic serous retinal detachment with futibatinib is unknown.

Careful consideration should be taken with patients that have clinically significant medical eye disorders, such as retinal disorders, including but not limited to, central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, and previous retinal detachment.

Dry eye

Futibatinib can cause dry eye (see section 4.8). Patients should use ocular demulcents, in order to prevent or treat dry eye, as needed.

Embryo-foetal toxicity

Based on the mechanism of action and findings in an animal study (see section 5.3), futibatinib can cause foetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus. An effective method of contraception should be used in women of childbearing potential and in men with women partners of childbearing potential during treatment with Lytgobi and for 1 week following completion of therapy, barrier methods should be applied as a second form of contraception to avoid pregnancy (see section 4.6). A pregnancy test should be performed before treatment initiation to exclude pregnancy.

Combination with strong CYP3A/P-gp inhibitors

Concomitant use of strong CYP3A/P-gp inhibitors should be avoided because it may increase futibatinib plasma concentration (see sections 4.2 and 4.5).

Combination with strong or moderate CYP3A/P-gp inducers

Concomitant use of strong or moderate CYP3A/P-gp inducers should be avoided because it may decrease futibatinib plasma concentration (see sections 4.2 and 4.5).

Lactose

Lytgobi contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

Lytgobi contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Effects of other medicinal products on futibatinib

CYP3A/P-gp inhibitors

Co-administrations of multiple doses of 200 mg itraconazole, a strong CYP3A/P-gp inhibitor, increased futibatinib C_max by 51% and AUC by 41% following a single oral dose of 20 mg futibatinib. Therefore, the concomitant use of strong CYP3A/P-gp inhibitors (e.g. clarithromycin, itraconazole) may increase futibatinib plasma concentration and should be avoided. If this is not possible, consider a reduction in the futibatinib dose to the next lower dose level based on tolerability observed should be considered (see sections 4.2 and 4.4).

CYP3A/P-gp inducers

Co-administrations of multiple doses of 600 mg rifampin, a strong CYP3A/P-gp inducer, decreased futibatinib C_max by 53% and AUC by 64% following a single oral dose of 20 mg futibatinib. Therefore, the concomitant use of strong and moderate CYP3A/P-gp inducers (e.g. carbamazepine, phenytoin, phenobarbital, efavirenz, rifampin) may decrease futibatinib plasma concentration and should be avoided. If this is not possible, consider gradually increasing the futibatinib dose based on careful monitoring of tolerability should be considered (see sections 4.2 and 4.4).

Proton pump inhibitors

Futibatinib geometric mean ratios for C_max and AUC were 108 % and 105 %, respectively, when co-administered in healthy subjects with lansoprazole (a proton pump inhibitor) relative to futibatinib alone. Co-administrations of a proton pump inhibitor (lansoprazole) did not result in a clinically important change in futibatinib exposure.

Effects of futibatinib on other medicinal products

Effect of futibatinib on CYP3A substrate

Midazolam (a CYP3A sensitive substrate) geometric mean ratios for C_max and AUC were 95% and 91%, respectively, when co-administered in healthy subjects with futibatinib relative to midazolam alone. Co-administrations of futibatinib had no clinically significant impact on midazolam exposure.

Effect of futibatinib on P-gp and BCRP substrates

In vitro, futibatinib is an inhibitor of P-gp and BCRP. Co-administration of futibatinib with P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g, rosuvastatin) substrates may increase their exposure.

Effect of futibatinib on CYP1A2 substrates

In vitro studies indicate that futibatinib has the potential to induce CYP1A2. Co-administration of futibatinib with CYP1A2 sensitive substrates (e.g, olanzapine, theophylline) may decrease their exposure and therefore may affect their activity.

Hormonal contraceptives

It is currently unknown whether futibatinib may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should add a barrier method during Lytgobi treatment and for at least 1 week after the last dose (see section 4.6).

Women of childbearing potential / Contraception in males and females

An effective method of contraception should be used in women of childbearing potential and in men with women partners of childbearing potential during treatment with Lytgobi and for 1 week following completion of therapy. Since the effect of futibatinib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception to avoid pregnancy.

Pregnancy

There are no available data from the use of futibatinib in pregnant women. Studies in animals have shown embryo-foetal toxicity (see section 5.3). Lytgobi should not be used during pregnancy unless the potential benefit for the women justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether futibatinib or its metabolites are excreted in human milk. A risk to the breast-fed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Lytgobi and for 1 week after the last dose.

Fertility

There are no data on the effect of futibatinib on human fertility. Animal fertility studies have not been conducted with futibatinib (see section 5.3). Based on the pharmacology of futibatinib, impairment of male and female fertility cannot be excluded.

Futibatinib has moderate influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or operating machines in case they experience fatigue or visual disturbances during the treatment with Lytgobi (see section 4.4).

Summary of the safety profile

The most common (≥20%) adverse reactions were hyperphosphatemia (89.7%), nail disorders (44.1%), constipation (37.2%), alopecia (35.2%), diarrhoea (33.8%), dry mouth (31.0%), fatigue (31.0%), nausea (28.3%), dry skin (27.6%), increased AST (26.9%), abdominal pain (24.8%), stomatitis (24.8%), vomiting (23.4%), palmar-plantar erythrodysaesthesia syndrome (22.8%), arthralgia (21.4%), and decreased appetite (20.0%).

The most common serious adverse reactions were intestinal obstruction (1.4%) and migraine (1.4%).

Permanent discontinuation due to adverse reactions was reported in 7.6% of patients; the most common adverse reaction led to dose discontinuation was stomatitis (1.4%),all other adverse reactions were single occurrence.

Tabulated list of adverse reactions

Table 5 summarises the adverse reactions occurring in 145 patients treated in the indicated population of Study TAS-120-101. Median duration of exposure of futibatinib was 8.87 months (min: 0.5, max: 31.7). Adverse reactions are listed according to MedDRA system organ class (SOC). Frequency categories are very common (≥1/10) and common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5. Adverse reactions observed in the indicated population in TAS-120-101 study (N=145) – frequency reported by incidence of treatment emergent events:

^a Includes serous retinal detachment, detachment of retinal pigment epithelium, subretinal fluid, chorioretinopathy, and maculopathy. See below “Serous retinal detachment”.
^b Includes nail toxicity, nail bed tenderness, nail disorder, nail discolouration, nail dystrophy, nail hypertrophy, nail infection, nail pigmentation, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis and paronychia

Description of selected adverse reactions

Hyperphosphatemia

Hyperphosphatemia was reported in 89.7% of patients treated with futibatinib and 27.6% patients had Grade 3 events, defined as serum phosphate >7 mg/dL and ≤10 mg/dL irrespective of clinical symptoms. The median time to onset of hyperphosphatemia of any grade was 6.0 days (range: 3.0 to 117.0 days).

None of the reactions were Grade 4 or 5 in severity, serious, or led to discontinuation of futibatinib. Dose interruption occurred in 18.6% patients and reduction in 17.9% of patients. Hyperphosphatemia was manageable with dietary phosphate restriction and/or administration of phosphate lowering therapy and/or dose modification.

Recommendations for management of hyperphosphatemia are provided in sections 4.2 and 4.4.

Serous retinal detachment

Serous retinal detachment occurred in 6.2% of patients treated with futibatinib. Reactions were all Grade 1 or 2 in severity. Dose interruption occurred in 2.1% patients and reduction in 2.1% of patients. None of the reactions led to discontinuation of futibatinib. Serous retinal detachment was generally manageable.

Recommendations for management of serous retinal detachment are provided in sections 4.2 and 4.4.

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.