Tipanat 20mg Trifluridine And Tipiracil Hydrochloride（Natco）

Product Name: Trifluridine and Tipiracil Hydrochloride Tablets

English Name: Trifluridine and Tipiracil Hydrochloride Tablets

Pinyin: Qufuniaogan Tipimiding Pian

Indian Brand Name: Tipanat 20mg

Composition: This product is a combination preparation; the active ingredients are trifluridine and tipiracil hydrochloride. Trifluridine: Chemical name: 2'-deoxy-5-(trifluoromethyl)uridine; Molecular formula: C10H11F3N2O5; Molecular weight: 296.20. Tipiracil hydrochloride: Chemical name: 2,4(1H,3H)-pyrimidinedione, 5-chloro-6-[(2-imino-1-pyrrolidinyl)methyl]-, hydrochloride (1:1); Molecular formula: C9H11ClN4O2·HCl; Molecular weight: 279.12. Excipients: Lactose hydrate, pregelatinized starch, stearic acid.

Specifications: 20 mg strength: Trifluridine 20 mg, tipiracil hydrochloride 9.420 mg (equivalent to tipiracil 8.19 mg). 

20 mg × 20 tablets/box.

[Indications]

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

[Dosage and Administration]

Recommended dosage and administration: The recommended starting dose for adults is approximately 35 mg/m² per dose, administered orally twice daily within one hour after breakfast and dinner. It is taken on days 1–5 and days 8–12 of each treatment cycle; one cycle consists of 28 days. Treatment should continue until disease progression or the occurrence of intolerable toxicity. The dose is calculated based on body surface area (BSA) (see Table 1). The maximum dose is 80 mg per administration. If a dose is missed, the missed dose must not be taken. Dose adjustment: Adjust the dose based on patient safety and tolerability. A maximum of 3 dose reductions is permitted, down to a minimum dose of 20 mg/m² twice daily. Once the dose has been reduced, it must not be increased. If hematologic and/or non-hematologic toxicities occur, appropriate measures should be taken in accordance with the criteria for interruption, resumption, and dose reduction outlined in Tables 2, 3, and 4. Special patient populations: Hepatic impairment—Mild hepatic impairment: No starting dose adjustment is recommended for patients with mild hepatic impairment (see [Pharmacokinetics]). Moderate or severe hepatic impairment: Although data are very limited, the incidence of Grade 3 or 4 hyperbilirubinemia is higher in patients with baseline moderate hepatic impairment; therefore, use of this product is not recommended for patients with baseline moderate or severe hepatic impairment (NCI criteria Groups C and D; total bilirubin > 1.5 × ULN) (see [Precautions] and [Pharmacokinetics]). Renal impairment—Mild renal impairment (CLcr 60–89 mL/min) or moderate renal impairment (CLcr 30–59 mL/min): No starting dose adjustment is recommended for patients with mild or moderate renal impairment (see [Precautions] and [Pharmacokinetics]). Severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease: Use of this product is not recommended for patients with severe renal impairment or end-stage renal disease, as there are no data available for these patients (see [Precautions]). Pediatric patients: The safety and efficacy 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. Data on efficacy and safety in patients aged > 75 years are limited.

[Adverse Reactions]

1. Adverse reactions in clinical studies: This package insert describes adverse reactions observed in clinical studies that were judged to be possibly caused by this product, along with their approximate incidence rates. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates observed in another clinical trial and may not reflect the rates observed in clinical practice. Global Phase III Clinical Trial Safety (RECOURSE): The RECOURSE study was a randomized (2:1), double-blind, placebo-controlled clinical trial involving patients with previously treated metastatic colorectal cancer. In this study, 533 patients (median age 63 years; 61% male; 57% White, 35% Asian, 1% Black) received this product as a single agent at a starting dose of 35 mg/m² administered orally twice daily after breakfast and dinner on Days 1–5 and Days 8–12 of each 28-day cycle. The mean duration of treatment with this product was 12.7 weeks. The most common adverse reactions and laboratory abnormalities (incidence ≥10% of all grades) occurring at a higher rate in patients treated with this product compared to the placebo group were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. In the RECOURSE study, 3.6% of patients discontinued this product due to adverse events, and 13.7% required dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. In the RECOURSE study, the incidence of infections in patients treated with this product (27%) was higher than in the placebo group (15%). The most common infections occurring at a higher rate in patients treated with this product compared to 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 this product (2%) was higher than in the placebo group (0%). Safety in the Asian Phase III Clinical Trial (TERRA): 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) into two treatment groups. A total of 271 patients (median age: 58 years; all patients were of Asian/Oriental descent, with 75.3%, 20.3%, and 4.4% from China, South Korea, and Thailand, respectively) received treatment with this product. The starting dose was 35 mg/m² administered orally twice daily (after breakfast and dinner) on days 1–5 and 8–12 of each 28-day treatment cycle. The mean duration of treatment with this product was 14.9 weeks. Adverse reactions and abnormal laboratory findings occurring in patients treated with this product that were most common (incidence ≥10% across all grades) and occurred at a higher rate than in the placebo group included anemia, leukopenia, neutropenia, nausea, thrombocytopenia, decreased appetite, fatigue, vomiting, diarrhea, and elevated blood bilirubin. In the TERRA study, 10% of patients discontinued this product due to adverse events. 2. Post-marketing experience: A total of 35 reports (35 cases) of interstitial lung disease have been received since initial market launch; the estimated incidence rate is 34/100,000.

[Contraindications] Contraindicated in patients with hypersensitivity to any component of this product.

[Precautions]

Bone marrow suppression: Treatment with this product is associated with an increased incidence of bone marrow suppression, including anemia, neutropenia, leukopenia, and thrombocytopenia. To monitor for toxicity, complete blood counts must be assessed prior to initiating treatment with this product and as clinically indicated, but at a minimum, prior to the start of each treatment cycle. Treatment with this product should not be initiated if the absolute neutrophil count is <1.5 × 10⁹/L, the platelet count is <75 × 10⁹/L, or if there is unresolved Grade 3 or 4 non-hematological clinically relevant toxicity from prior therapy. Serious infections have been reported in patients treated with this product. Given that most reports were associated with myelosuppression, patients should be closely monitored, and appropriate management measures—such as the administration of antimicrobial agents or granulocyte colony-stimulating factor (G-CSF)—should be taken as clinically indicated. In the RECOURSE study, 9.4% of patients in the treatment group received G-CSF. Gastrointestinal toxicity: This product is associated with an increased incidence of gastrointestinal toxicities, such as nausea, vomiting, and diarrhea. Patients exhibiting symptoms of nausea, vomiting, diarrhea, or other gastrointestinal toxicities should be closely monitored, and measures such as antiemetics, antidiarrheals, and fluid/electrolyte replacement should be implemented as clinically indicated. Dose adjustments, such as treatment delays and/or dose reductions, should be made as necessary (see [Dosage and Administration]). Renal impairment: Use of this product is not recommended in patients with severe renal impairment or end-stage renal disease (creatinine clearance [CLcr] <30 mL/min or requiring dialysis), as there are no data available for these patient populations. Compared with patients having normal renal function (CLcr ≥90 mL/min) or mild renal impairment (CLcr 60–89 mL/min), patients with moderate renal impairment (CLcr 30–59 mL/min) experienced a higher incidence (difference of at least 5%) of Grade ≥3 adverse events (AEs), serious adverse events, treatment delays, and dose reductions. Furthermore, exposure to trifluridine and tipiracil hydrochloride was higher in patients with moderate renal impairment than in those with normal renal function or mild renal impairment. Monitoring for hematological toxicity should be performed more frequently in patients with moderate renal impairment. Hepatic impairment: Although data are very limited, the incidence of Grade 3 or 4 hyperbilirubinemia is higher in patients with moderate hepatic impairment at baseline; therefore, use of this product is not recommended for patients with moderate or severe hepatic impairment at baseline (NCI criteria Groups C and D; total bilirubin > 1.5 × ULN) (see [Pharmacokinetics]). Proteinuria: Monitoring for proteinuria via urine dipstick analysis is recommended prior to initiating treatment and during treatment. Lactose intolerance: This product contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption must not use this product. Effects on ability to drive and use machines: This product has a minor influence on the ability to drive and use machines. Fatigue, dizziness, or malaise may occur during treatment with this product.

[Use in Pregnant and Lactating Women]

Pregnancy: There are no data on the use of this product in pregnant women. Based on its mechanism of action, administration of trifluridine during pregnancy may cause congenital malformations in the fetus. Animal studies have shown reproductive toxicity (see [Pharmacology and Toxicology]). Lactation: It is unknown whether this product or its metabolites are excreted in human milk. Animal studies indicate that trifluridine, tipiracil hydrochloride, and/or their metabolites are excreted in milk (see [Pharmacology and Toxicology]). A risk to the breastfed infant cannot be excluded; breastfeeding must be discontinued during treatment and for one day after the last dose. Contraception: Based on animal studies, administration of trifluridine to pregnant women may cause fetal harm. Women of childbearing potential should avoid pregnancy during treatment and for 6 months after treatment. Therefore, women of childbearing potential should use highly effective contraceptive measures during this period. It is currently unknown whether this product reduces the efficacy of hormonal contraceptives; therefore, women using hormonal contraceptives should also use a barrier method of contraception. Men with partners of childbearing potential should use effective contraceptive measures during treatment and for 6 months after treatment. Fertility: There are no data on the effect of this product on human fertility. Animal studies indicate no impact on the fertility of male or female animals.

[Pediatric Use] The safety and efficacy of this product in pediatric patients with metastatic colorectal cancer have not been established.

[Geriatric Use]

In the RECOURSE study, 533 patients were treated with this product; 44% were aged 65 years or older, and 7% were aged 75 years or older. No overall differences in efficacy were observed between patients aged 65 years or older and younger patients; dose adjustment based on age is not recommended. Compared with patients under 65 years of age, patients aged 65 years or older treated with this product experienced higher incidences of the following: Grade 3 or 4 neutropenia (48% vs. 30%), Grade 3 anemia (26% vs. 12%), and Grade 3 or 4 thrombocytopenia (9% vs. 2%).

[Drug Interactions]

Trifluridine is a substrate of thymidine phosphorylase and is not metabolized by cytochrome P450 (CYP) enzymes. Tipiracil is not metabolized in human liver or hepatocytes. In vitro studies indicate that trifluridine, tipiracil, and FTY do not inhibit CYP enzymes and do not induce CYP1A2, CYP2B6, or CYP3A4/5. In vitro studies indicate that trifluridine is neither an inhibitor nor a substrate of human uptake or efflux transporters.

[Overdose]

The maximum dose administered in clinical trials was 180 mg/m²/day. Reported adverse reactions associated with overdose were consistent with the established safety profile. The primary expected complication of overdose is myelosuppression. There is no known antidote for overdose. Medical management of overdose should include standard treatment and supportive care aimed at correcting clinical manifestations and preventing potential complications.

[Storage] Store in a sealed container at room temperature (10–30°C).

[Manufacturer] Natco Pharma Limited, India

Specifications

Product Name: TAS-102 (Trifluridine/Tipiracil Tablets) – Lonsurf / Tipanat (Natco) 20mg × 20 tablets

Common Name: Trifluridine/Tipiracil Tablets

Ingredients: Trifluridine 20 mg, Tipiracil hydrochloride 9.420 mg (equivalent to Tipiracil 8.19 mg)

Dosage Form: Tablets

Specification: 20mg × 20 tablets/box

Manufacturer: Natco Pharma (India)

Indication: For patients with metastatic colorectal cancer (mCRC) who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and who have previously received—or are not candidates for—anti-VEGF therapy and anti-EGFR therapy (for RAS wild-type).

Dosage and Administration: Recommended starting dose for adults is approximately 35 mg/m² per dose, administered orally twice daily within one hour after breakfast and dinner. It is taken on Days 1–5 and Days 8–12 of each 28-day treatment cycle. Treatment should continue until disease progression or the occurrence of intolerable toxicity. Dosage is calculated based on body surface area (BSA) (see Table 1). The maximum dose is 80 mg per dose. If a dose is missed, it should not be made up. Dose Adjustment: Adjust dosage based on patient safety and tolerability. A maximum of three dose reductions is permitted, down to a minimum dose of 20 mg/m² twice daily. Doses must not be increased after reduction. In the event of hematological and/or non-hematological toxicity, appropriate measures regarding dose interruption, resumption, and reduction should be taken in accordance with Tables 2, 3, and 4. Special Patient Populations: Hepatic Impairment – Mild Hepatic Impairment: No starting dose adjustment is recommended for patients with mild hepatic impairment (see [Pharmacokinetics]). Moderate or severe hepatic impairment: Although data are very limited, the incidence of Grade 3 or 4 hyperbilirubinemia was higher in patients with baseline moderate hepatic impairment; therefore, use of this product is not recommended for patients with baseline moderate or severe hepatic impairment (NCI criteria Groups C and D; total bilirubin > 1.5 × ULN) (see [Precautions] and [Pharmacokinetics]). Renal impairment: Mild (CLcr 60–89 mL/min) or moderate (CLcr 30–59 mL/min) renal impairment—no starting dose adjustment is recommended for patients with mild or moderate renal impairment (see [Precautions] and [Pharmacokinetics]). Severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease—use of this product is not recommended for patients with severe renal impairment or end-stage renal disease, as data for these patients are lacking (see [Precautions]). Pediatric patients: The safety and efficacy 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. Data on efficacy and safety in patients aged > 75 years are limited.