TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE
Clinical safety rating
cautionComprehensive clinical and safety monograph for TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE (TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE).
Comprehensive clinical and safety monograph for TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE (TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE).
Metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.Metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of therapy including a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.
Trifluridine is a thymidine-based nucleoside analog that incorporates into DNA, interfering with DNA synthesis and function. Tipiracil hydrochloride inhibits thymidine phosphorylase, preventing trifluridine degradation and increasing its systemic exposure.
| Metabolism | Trifluridine is primarily metabolized by thymidine phosphorylase to 5-(trifluoromethyl)uracil (inactive). Tipiracil is metabolized mainly via hepatic carboxylesterases and aldehyde oxidase, not significantly via CYP enzymes. |
| Excretion | Trifluridine is primarily eliminated via metabolism and renal excretion. Approximately 29% of the trifluride dose is recovered in urine as trifluridine and its metabolites, with less than 3% as unchanged drug. Fecal excretion accounts for about 38% of the dose, mainly as metabolites. Tipiracil is predominantly excreted renally (about 55% as unchanged drug and metabolites) and fecally (about 19%). |
| Half-life | The terminal elimination half-life of trifluridine is approximately 1.4 to 2.1 hours. For tipiracil, the half-life is about 2.1 to 3.3 hours. The short half-lives necessitate twice-daily dosing to maintain therapeutic concentrations. |
| Protein binding | Trifluridine: <1% bound to plasma proteins. Tipiracil: about 8% bound to plasma proteins. |
| Volume of Distribution | Trifluridine: Vd/F is approximately 0.4 ± 0.1 L/kg, indicating distribution into total body water. Tipiracil: Vd/F is about 0.3 ± 0.1 L/kg. |
| Bioavailability | Following oral administration of the combination tablet, trifluridine has an absolute bioavailability of approximately 57% (fasted). Tipiracil bioavailability is about 70% (fasted). Food may alter absorption. |
| Onset of Action | Oral administration: Clinical effect (e.g., antitumor activity) is observed after repeated dosing; no immediate onset. Time to peak plasma concentration (Tmax) for trifluridine is about 1-2 hours; tipiracil Tmax is about 2-3 hours. |
| Duration of Action | The pharmacodynamic effect (thymidine phosphorylase inhibition by tipiracil) persists beyond the plasma half-life due to intracellular retention. Twice-daily dosing maintains thymidine phosphorylase inhibition throughout the dosing interval. |
| Molecular Weight | 357.25 |
35 mg/m² orally twice daily on days 1-5 and 8-12 of each 28-day cycle. Maximum dose: 80 mg per dose.
| Dosage form | TABLET |
| Renal impairment | For GFR 30-59 mL/min: reduce dose to 20 mg/m² twice daily. For GFR 15-29 mL/min: reduce dose to 15 mg/m² twice daily. Contraindicated if GFR <15 mL/min. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose to 25 mg/m² twice daily. Child-Pugh C: not recommended. |
| Pediatric use | Not established. Safety and efficacy in pediatric patients have not been studied. |
| Geriatric use | No specific dose adjustment recommended; monitor renal function and adjust based on renal impairment. Elderly patients may have increased risk of myelosuppression and infections. |
| 1st trimester | Avoid. Teratogenic and embryotoxic in animal studies; human data limited. Alternative therapies recommended. |
| 2nd trimester | Avoid. Based on animal data, there is potential for fetal harm; no well-controlled human studies. |
| 3rd trimester | Avoid. May cause fetal toxicity; consider alternatives during third trimester. |
Clinical note
Comprehensive clinical and safety monograph for TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE (TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE).
| Placental transfer | Unknown in humans; likely crosses placenta based on small molecular weight (tipiracil: 357.25 Da, trifluridine: 296.21 Da) and lipophilicity; animal studies show fetal exposure. |
| Breastfeeding | No human data on excretion in breast milk; due to potential toxicity, discontinue breastfeeding during therapy and for at least 1 day after last dose. |
| Lactation Rating | L5 (Contraindicated; high risk of adverse effects in infant) |
| Teratogenic Risk | Trifluridine/tipiracil is embryotoxic and teratogenic in animal studies. In humans, avoid use during pregnancy; effective contraception required during treatment and for at least 6 months after last dose. First trimester: highest risk of major malformations; second and third trimesters: risk of fetal growth restriction and adverse neonatal outcomes. |
| Fetal Monitoring | Monitor complete blood counts weekly due to myelosuppression; liver and renal function tests at baseline and periodically. Fetal ultrasound for growth and anatomy if unintended exposure occurs. |
| Fertility Effects | Animal studies show impaired female fertility. In humans, may cause amenorrhea and reduced fertility; effects reversible. Male fertility effects unknown. |
■ FDA Black Box Warning
WARNING: NEUTROPENIA/THROMBOCYTOPENIA; AND GASTROINTESTINAL TOXICITY Neutropenia/Thrombocytopenia: Severe and life-threatening neutropenia and thrombocytopenia can occur. Obtain complete blood counts prior to each cycle and as clinically indicated. Withhold, reduce, or discontinue dosing for severe neutropenia or thrombocytopenia. Gastrointestinal Toxicity: Severe gastrointestinal toxicity including diarrhea, nausea, vomiting, and abdominal pain can occur. Withhold, reduce, or discontinue dosing for severe gastrointestinal toxicity.
| Serious Effects |
Hypersensitivity to tipiracil, trifluridine, or any excipient
| Precautions | Bone Marrow Suppression: May cause severe neutropenia, thrombocytopenia, and anemia. Monitor blood counts., Gastrointestinal Toxicity: Severe diarrhea, nausea, vomiting, abdominal pain, and stomatitis. Manage with supportive care., Renal Toxicity: Proteinuria, nephrotic syndrome. Monitor renal function., Hepatic Toxicity: Elevations of liver enzymes and bilirubin. Monitor liver function., Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of effective contraception and avoid breastfeeding. |
| Food/Dietary | Take within 1 hour after a meal (breakfast and dinner) to reduce variability and improve tolerability. Avoid grapefruit or grapefruit juice? No established interaction; however, general caution due to potential CYP3A4 involvement? (minimal). High-fat meals may reduce peak concentration but do not significantly alter overall exposure; timing with meals is recommended not for efficacy but to mitigate gastrointestinal side effects. |
| Clinical Pearls | Tipiracil hydrochloride/trifluridine (Lonsurf) is a combination oral cytotoxic agent used for refractory metastatic colorectal cancer and gastric cancer. Trifluridine incorporates into DNA, inhibiting thymidylate synthase; tipiracil inhibits trifluridine degradation by thymidine phosphorylase. Administer within 1 hour after morning and evening meals to reduce variation in exposure. Avoid severe neutropenia by monitoring CBCs before and after each cycle; hold for ANC <500/mm³ or febrile neutropenia. Use antiemetics as needed; nausea/vomiting occur in ~50% of patients. Dose reduction recommended for severe myelosuppression, including thrombocytopenia and anemia. No strong CYP interactions; avoid concurrent use of UGT1A1 or thymidine phosphorylase inhibitors? (limited data). Consider growth factor support for prolonged neutropenia. |
| Patient Advice | Take each dose with a glass of water within 1 hour after breakfast and dinner; do not crush or chew tablets. · Swallow tablets whole; do not take if vomiting occurs after a dose—skip that dose and resume next scheduled dose. · Store at room temperature away from moisture and heat; keep bottle tightly closed. · Common side effects include nausea, vomiting, diarrhea, loss of appetite, fatigue, and low blood cell counts. · Contact healthcare provider immediately if fever, signs of infection (sore throat, cough), unusual bleeding/bruising, or severe tiredness occur. · Use effective contraception during treatment and for at least 6 months after the last dose for females and 3 months for males. · Avoid handling crushed or broken tablets; if contact occurs, wash skin thoroughly. · Do not breastfeed during treatment and for at least 1 day after last dose. |
Loading safety data…