Trifluridine Tipipiridine Tablets

Pharmacological action Trifluridine tipiprimidine includes trifluridine (thymidine nucleotide analog) and tipiprimidine (thymidine phosphorylase inhibitor), the molar ratio of the two is 1:0.5 (weight ratio is 1:0.471). Tipiprimidine increases the exposure of trifluridine by inhibiting thymidine phosphorylase involved in the metabolism of trifluridine. Trifluridine is taken up into cancer cells and can be incorporated into DNA, interfering with DNA synthesis and inhibiting cell proliferation. Trifluridine/tiprimidine showed antitumor activity in KRAS wild-type and mutant human colorectal cancer xenograft mouse models. Toxicological studies Genetic toxicity: The results of trifluridine/tiprimidine Ames test, Chinese hamster ovary cell chromosome aberration test, and mouse micronucleus test were all positive. Reproductive toxicity: Animal experiments showed that trifluridine/tiprimidine had no effect on the fertility of male rats, and a dose-related increase in the number of corpora lutea and implantation in female rats was observed, but no effect on the fertility of female rats was observed. Female rats were orally administered trifluridine/tipirimidine 15, 50, 150 mg/kg (calculated as trifluridine) once a day during the period of organogenesis. Trifluridine ≥ 50 mg/kg (approximately 0.33 times the exposure at the clinical dose (35 mg/m, twice daily)) caused reduced fetal weight, and trifluridine 150 mg/kg (approximately 0.92 times the exposure at the clinical dose (35 mg/m, twice daily)) caused embryolethality and structural abnormalities (distorted tail, cleft palate, missing fingers/toes, generalized edema, changes in large blood vessels, and skeletal abnormalities). Radioactivity was detected in the milk of lactating rats given \°C-labeled trifluridine and \°C-labeled tipiracil. The exposure level of radioactivity derived from trifluridine in breast milk is about 50% of that in maternal plasma at 1 hour after administration, and reaches the maternal plasma level 12 hours after administration. The exposure level of radioactivity derived from tipiracil in breast milk is higher than the plasma level 2 hours after administration and is maintained at least until 12 hours after administration. Carcinogenicity: Carcinogenicity studies of trifluridine/tipiracil have not been conducted. Other toxicities: Trifluridine ≥ 50 mg/kg (approximately 0.33 times the exposure at the clinical dose (35 mg/m, twice daily)) causes tooth toxicity in rats, including whitening, breakage, and malocclusion (degeneration and disorder of ameloblasts, papillary cells, and odontoblasts).

This product is a compound preparation, the main ingredients are trifluridine and tipiracil hydrochloride. Chemical name of trifluridine: 2'-deoxy-5-(trifluoromethyl)uridine Molecular formula: C10H11F3N2O5 Molecular weight: 296.20 Chemical name of tipiracil hydrochloride: 5-chloro-6-[(2-iminopyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione hydrochloride Molecular formula: C9H11ClN4O2・HCl Molecular weight: 279.12 Excipients: lactose, low-substituted hydroxypropyl cellulose, magnesium stearate, film coating premix (gastric soluble).

15mg specification: white film-coated tablets, which are white or off-white after removing the coating. 20mg specification: light red film-coated tablets, which are white or off-white after removing the coating.

Patients with metastatic colorectal cancer (mCRC) who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and who have previously received or are not suitable for anti-vascular endothelial growth factor (VEGF) therapy or anti-epidermal growth factor receptor (EGFR) therapy (RAS wild type).

Recommended dose and administration method The recommended starting dose for adults is approximately 35 mg/m2/time, orally taken within 1 hour after breakfast and dinner, twice a day, orally on days 1-5 and 8-12 of each course of treatment, and a course of treatment is 28 days. It should be taken continuously until disease progression or intolerable toxicity occurs. The dose is calculated based on body surface area (BSA) (see Table 1). The maximum dose is 80 mg/time. If a dose is missed, the missed dose should not be taken. Dose adjustment The dose is adjusted according to the patient's safety and tolerability. A maximum of 3 dose reductions are allowed to the lowest dose of 20 mg/m2/time, twice a day. The dose should not be increased after the dose reduction. If hematological and/or non-hematological toxicity occurs, appropriate measures should be taken according to the suspension, resumption and reduction criteria in Tables 2, 3 and 4. Special patient populations Abnormal liver function・Mild liver function abnormalities No adjustment of the starting dose is recommended for patients with mild liver function abnormalities (see [Pharmacokinetics]). Moderate or severe liver dysfunction Although based on very limited data, the use of this product is not recommended for patients with moderate or severe liver dysfunction at baseline (National Cancer Institute [NCI] criteria groups C and D, total bilirubin >1.5×ULN) (see [Precautions] and [Pharmacokinetics]). Renal dysfunction Mild renal dysfunction (CLcr 60-89 mL/min) or moderate renal dysfunction (CLcr 30-59 mL/min) No adjustment in the starting dose is recommended for patients with mild or moderate renal dysfunction (see [Precautions] and [Pharmacokinetics]). Severe renal dysfunction (CLcr <30 mL/min) or end-stage renal disease This product is not recommended for patients with severe renal dysfunction or end-stage renal disease, as there are no data for these patients (see [Precautions]). Pediatric patients The safety and effectiveness of this product in pediatric patients with metastatic colorectal cancer have not been established. Elderly Patients No starting dose adjustment is required for patients aged ≥ 65 years. Efficacy and safety data for patients aged ＞ 75 years are limited.

1. Adverse reactions in clinical studies This instruction manual describes the adverse reactions observed in clinical studies that are judged to be possibly caused by this product and their approximate incidence. Because clinical studies are conducted under various conditions, the incidence of adverse reactions observed in one clinical study cannot be directly compared with the incidence of adverse reactions observed in another clinical study, and may not reflect the actual incidence in clinical practice. Global Phase III Clinical Trial Safety (RECOURSE) The RECOURSE study is a randomized (2:1), double-blind, placebo-controlled clinical trial conducted in patients with metastatic colorectal cancer with a history of previous treatment. In this study, 533 patients (median age of 63 years; 61% male patients; 57% white, 35% Asian, 1% black) received monotherapy with this product, with a starting dose of 35 mg/m2/time, orally twice a day after breakfast and dinner, orally on days 1-5 and 8-12 of each course of treatment, with a course of 28 days. The average treatment duration of this product is 12.7 weeks. The most common adverse reactions (all grades ≥ 10%) and laboratory abnormalities in patients treated with levofloxacin and with an incidence higher than placebo were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. In the RECOURSE study, 3.6% of patients discontinued levofloxacin due to adverse events, and 13.7% required dose reductions. The most common adverse reactions leading to dose reductions were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. In the RECOURSE study, the incidence of infections in patients treated with levofloxacin (27%) was higher than that in the placebo group (15%). The most common infections in patients treated with levofloxacin with an incidence higher than that in the placebo group were nasopharyngitis (4% vs. 2%) and urinary tract infection (4% vs. 2%). In the RECOURSE study, the incidence of pulmonary embolism in patients treated with levofloxacin (2%) was higher than that in the placebo group (0%). The safety of this product was evaluated in a multicenter, randomized, double-blind, Phase III study (TERRA) conducted in China, South Korea and Thailand. A total of 406 patients were randomized (2:1) to two treatment groups. A total of 271 patients (median age of 58 years; all patients were Asian/Oriental, with a proportion of 75.3%, 20.3%, and 4.4% in China, South Korea, and Thailand) received treatment with this product. The starting dose was 35 mg/m2/time, taken orally twice a day after breakfast and dinner, on days 1-5 and 8-12 of each course of treatment, and a course of treatment of 28 days. The average treatment duration of this product was 14.9 weeks. The most common adverse reactions (all grades ≥ 10%) and abnormal laboratory test results in patients treated with this product with an incidence higher than that in the placebo group were anemia, leukopenia, neutropenia, nausea, thrombocytopenia, decreased appetite, fatigue, vomiting, diarrhea, and increased blood bilirubin. In the TERRA study, 10% of patients discontinued the drug due to adverse events. 2. Post-marketing experience A total of 35 reports of interstitial lung disease were received after the first launch, with an estimated incidence of 34/100,000.

Patients with hypersensitivity to the ingredients of this product are contraindicated.

Precautions for children: The safety and effectiveness of this product in children with metastatic colorectal cancer have not been established. Precautions for pregnancy and lactation: There is no data on the use of this product in pregnant women. Based on its mechanism of action, taking trifluridine during pregnancy may cause congenital malformations in the fetus. Animal studies have shown that this product is reproductively toxic (see [Pharmacology and Toxicology]). Lactation It is not clear whether this product or its metabolites are excreted in human milk. Animal studies have shown that trifluridine, tipiracil hydrochloride and/or its metabolites are excreted in breast milk (see [Pharmacology and Toxicology]). The risk of this product to breast-fed infants cannot be ruled out, and breastfeeding must be stopped during treatment with this product and one day after the last dose. Contraception Based on the results of animal studies, taking trifluridine during pregnancy may cause harm to the fetus. Women of childbearing age should avoid pregnancy during treatment with this product and within 6 months after treatment. Therefore, women of childbearing potential should take highly effective contraceptive measures during this period. It is not clear whether this product reduces the effect of hormonal contraceptives, so women using hormonal contraceptives should add barrier contraceptive methods. Men with reproductive partners should take effective contraceptive measures during treatment and for 6 months after treatment. Fertility There is no data on the effect of this product on human fertility. Animal study results show that it does not affect the fertility of male and female animals (see [Pharmacology and Toxicology]). Elderly precautions: In the RECOURSE study, 533 patients were treated with this product; 44% were over 65 years old, and 7% were over 75 years old. No overall difference in effectiveness was observed between patients over 65 years old and younger patients, and it is not recommended to adjust the starting dose of this product based on age. Compared with patients under 65 years old, the incidence of the following in patients over 65 years old treated with this product was higher: Grade 3 or 4 neutropenia (48% vs. 30%), Grade 3 anemia (26% vs. 12%), and Grade 3 or 4 thrombocytopenia (9% vs. 2%).

Trifluridine is a substrate for thymidine phosphorylase and is not metabolized by cytochrome P450 (CYP) enzymes. Tipipiracil is not metabolized in human liver or hepatocytes. In vitro studies have shown that trifluridine, tipipiracil, and FTY do not inhibit CYP enzymes and have no induction effect on CYP1A2, CYP2B6, or CYP3A4/5. In vitro studies have shown that trifluridine is not an inhibitor or substrate of human uptake and efflux transporters.

Seal tightly and store below 30℃.

20mg x 10 tablets x 2 bags

36 months

Qilu Pharmaceutical Co., Ltd.

• Founded in:

  1992-08-21

• Address:

  No. 317, Xinluo Street, High-tech Zone, Jinan City, Shandong Province

• Tax NO.:

  91370000614073351Q

• Registered Funds:

  600 million yuan

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