Loncil Tablet

Trifluridine and Tipiracil consists of a thymidine-based nucleoside analog, Trifluridine, and the thymidine phosphorylase inhibitor, tipiracil, at a molar ratio 1:0.5 (weight ratio, 1:0.471). Inclusion of Tipiracil increases Trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. Following uptake into cancer cells, Trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation. Trifluridine/Tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice.

The recommended dosage of Trifluridine and Tipiracil is 35 mg/m2 up to a maximum of 80 mg per dose (based on the Trifluridine component) orally twice daily with food on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity. Round dose to the nearest 5 mg increment. Instruct patients to swallow the tablet whole. Instruct patients not to retake doses of Trifluridine and Tipiracil that are vomited or missed and to continue with the next scheduled dose. Trifluridine and Tipiracil is a cytotoxic drug. Follow applicable special handling and disposal procedures.

In vitro studies indicated that Trifluridine, Tipiracil, and FTY did not inhibit the CYP enzymes and had no inductive effect on CYP1A2, CYP2B6, or CYP3A4/5. In vitro studies indicated that Trifluridine was not an inhibitor of or substrate for human uptake and efflux transporters.

The most common adverse reactions or laboratory abnormalities (≥10%) are anemia, neutropenia, fatigue/ asthenia, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, and pyrexia.

Pregnancy: Based on animal data and its mechanism of action Trifluridine and Tipiracil can cause fetal harm.

Lactation: There are no data on the presence of Trifluridine, Tipiracil or its metabolites in human milk or its effects on the breastfed child or on milk production.

Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating Trifluridine and Tipiracil.

Contraception: Trifluridine and Tipiracil can cause fetal harm when administered to a pregnant woman.

Females: Advise females of reproductive potential to use effective contraception during treatment with Trifluridine and Tipiracil and for at least 6 months after the final dose.

Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with Trifluridine and Tipiracil and for at least 3 months after the final dose.

Severe Myelosuppression: In the 868 patients who received Trifluridine and Tipiracil in RECOURSE and TAGS, Trifluridine and Tipiracil caused severe and life-threatening myelosuppression (Grade 3-4) consisting of anemia (18%), neutropenia (38%), thrombocytopenia (5%) and febrile neutropenia (3%). Two patients (0.2%) died due to neutropenic infection/sepsis and four other patients (0.5%) died due to septic shock. A total of 12% of Trifluridine and Tipiracil-treated patients received granulocyte-colony stimulating factors. Obtain complete blood counts prior to and on Day 15 of each cycle of Trifluridine and Tipiracil and more frequently as clinically indicated. Withhold Trifluridine and Tipiracil for severe myelosuppression and resume at the next lower dosage.

Embryo-Fetal Toxicity: Based on animal studies and its mechanism of action, Trifluridine and Tipiracil can cause fetal harm when administered to a pregnant woman. Trifluridine/tipiracil caused embryo-fetal lethality and embryo-fetal toxicity in pregnant rats when orally administered during gestation at dosage levels resulting in exposures lower than those achieved at the recommended dosage of 35 mg/m2 twice daily. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with Trifluridine and Tipiracil and for at least 6 months after the final dose.

Patients with Renal Impairment: In a dedicated renal impairment study, all patients received Trifluridine and Tipiracil 35 mg/m2 twice daily except for patients with severe renal impairment who received 20 mg/m2 twice daily. Mild renal impairment (CrCl of 60 to 89 mL/min as determined by the Cockcroft-Gault formula) had no clinically important effect on steady-state AUC0-last of trifluridine and tipiracil. Moderate renal impairment (CrCl of 30 to 59 mL/min) increased steady-state AUC0-last of Trifluridine by 56% and Tipiracil by 139% compared to normal renal function (CrCl ≥ 90 mL/min). Severe renal impairment (CrCl of 15 to 29 mL/min) increased the dose-normalized steady-state AUC0-last of Trifluridine by 140% and Tipiracil by 614% compared to normal renal function. The pharmacokinetics of Trifluridine and Tipiracil have not been studied in patients with end stage renal disease.

Patients with Hepatic Impairment: No clinically important differences in the mean exposures of Trifluridine and Tipiracil were observed between patients with mild hepatic impairment (total bilirubin ≤ULN and AST > ULN or total bilirubin <1 to 1.5 times ULN and any AST) to moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST) and patients with normal hepatic function (total bilirubin and AST ≤ ULN); however, 5 of 6 patients with moderate hepatic impairment experienced Grade 3 or 4 increased bilirubin levels. The pharmacokinetics of Trifluridine and Tipiracil have not been studied in patients with severe hepatic impairment.

Pediatric Use: Safety and effectiveness of Trifluridine and Tipiracil in pediatric patients have not been established.

Geriatric Use: No overall differences in effectiveness were observed in patients 65 or older versus younger patients.

Store below 30°C, in a cool and dry place. Keep away from light. Keep out of the reach of children.