Special Warning : אזהרת שימוש

4.4    Special warnings and precautions for use

Bone marrow suppression
Lonsurf caused an increase in the incidence of myelosuppression including anaemia, neutropenia, leukopenia, and thrombocytopenia.

Complete blood cell counts must be obtained prior to initiation of therapy and as needed to monitor toxicity, but at a minimum, prior to each treatment cycle.

Treatment must not be started if the absolute neutrophil count is <1.5 109/L, if the platelet counts are <75109/L, or if the patient has an unresolved Grade 3 or 4 non-haematological clinically relevant toxicity from prior therapies.

Serious infections have been reported following treatment with Lonsurf (see section 4.8).
Given that the majority were reported in the context of bone marrow suppression, the patient’s condition should be monitored closely, and appropriate measures, such as antimicrobial agents and granulocyte-colony stimulating factor (G-CSF), should be administered as clinically indicated. In RECOURSE, TAGS and SUNLIGHT studies, 9.4%, 17.3% and 19.5% of patients in the Lonsurf group respectively received G-CSF mainly for therapeutic use. In the SUNLIGHT study, 29.3% of patients in the Lonsurf with bevacizumab group received G-CSF including 16.3% for therapeutic use.

Gastrointestinal toxicity

Lonsurf caused an increase in the incidence of gastrointestinal toxicities including nausea, vomiting and diarrhoea.

Patients with nausea, vomiting, diarrhoea and other gastrointestinal toxicities should be carefully monitored, and anti-emetic, anti-diarrhoeal and other measures, such as fluid/electrolyte replacement therapy, should be administered as clinically indicated. Dose modifications (delay and/or reduction) should be applied as necessary (see section 4.2).



Renal impairment
LONS-SPC-1124-V1                   Page 6 of 27
Lonsurf is not recommended for use in patients with end-stage renal disease (creatinine clearance [CrCl] < 15 mL/min or requiring dialysis), as Lonsurf has not been studied in these patients (see section 5.2).
The global incidence of adverse events (AEs) is similar in normal renal function (CrCl ≥ 90 mL/min), mild (CrCl = 60 to 89 mL/min) or moderate (CrCl = 30 to 59 mL/min) renal impairment subgroups.
However, the incidence of serious, severe AEs and AEs leading to dose modification tends to increase with advancing levels of renal impairment. In addition, a higher exposure of trifluridine and tipiracil hydrochloride was observed in patients with moderate renal impairment, compared with patients with normal renal function or patients with mild renal impairment (see section 5.2).
Patients with severe renal impairment (CrCl = 15 to 29 mL/min) and adjusted starting dose of 20 mg/m2 twice daily had a safety profile consistent with the safety profile of Lonsurf in patients with normal renal function or mild renal impairment. Their exposure to trifluridine was similar to that of patients with normal renal function and their exposure to tipiracil hydrochloride was increased compared to patients with normal renal function, mild and moderate renal impairment (see sections 4.2 and 5.2).
Patients with renal impairment should be monitored closely when being treated with Lonsurf; patients with moderate or severe renal impairment should be more frequently monitored for haematological toxicities.

Hepatic impairment

Lonsurf is not recommended for use in patients with baseline moderate or severe hepatic impairment (National Cancer Institute [NCI] Criteria Group C and D defined by total bilirubin >1.5 x ULN), as a higher incidence of Grade 3 or 4 hyperbilirubinaemia is observed in patients with baseline moderate hepatic impairment, although this is based on very limited data (see section 5.2).

Proteinuria

Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy (see section 4.8).

Lactose intolerance

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

Effects on Driving

4.7    Effects on ability to drive and use machines

Lonsurf has minor influence on the ability to drive and use machines. Fatigue, dizziness or malaise may occur during treatment (see section 4.8).