Futibatinib

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.

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.

Concomitant use of strong CYP3A/P-gp inhibitors, such as itraconazole, should be avoided because it may increase futibatinib plasma concentration. If this is not possible, based on careful monitoring of tolerability, a futibatinib dose reduction to the next lower level should be considered.

Co-administrations of multiple doses of 200 mg itraconazole 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.

Co-administration of futibatinib with strong or moderate CYP3A4/P-gp inducers, such as rifampicin, should be avoided. If this is not possible, gradually increasing the futibatinib dose based on careful monitoring of tolerability should be considered.

Co-administrations of multiple doses of 600 mg rifampin 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.

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 futibatinib treatment and for at least 1 week after the last dose.

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

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

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 futibatinib and for 1 week after the last dose.

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 futibatinib 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.

Fertility

There are no data on the effect of futibatinib on human fertility. Animal fertility studies have not been conducted with futibatinib. 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 futibatinib.

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

The table below 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.

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.

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.