TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE (TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE).
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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE (TIPIRACIL HYDROCHLORIDE AND TRIFLURIDINE).
| Breastfeeding | No human data on excretion in breast milk. Based on drug properties, likely present; advise against breastfeeding during treatment and for at least 1 day after last dose. M/P ratio unknown. |
| 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. |
■ 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 |
["None reported in prescribing information. Use caution in patients with severe renal impairment (CrCl <30 mL/min) or severe hepatic impairment."]
| 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."] |
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| 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. |