Trifluridine + Tipiracil

• Approved Indications:
• Treatment of metastatic colorectal cancer (mCRC) in patients previously treated with or not candidates for standard chemotherapy, including fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy, and anti-EGFR therapy (if RAS wild-type).
• Treatment of metastatic gastric or gastroesophageal junction adenocarcinoma in patients who have received at least two prior chemotherapy regimens.
• Off-label Uses:
• Investigational use in other refractory solid tumors; not routinely approved for other cancers.

• Adults:
• Oral administration as fixed-dose combination tablets.
• Recommended dose: 35 mg/m² (based on body surface area) taken twice daily (morning and evening, approximately 12 hours apart) on days 1–5 and days 8–12 of each 28-day treatment cycle.
• Tablets should be swallowed whole with water within one hour after morning and evening meals.
• Dose Adjustments:
• Dose modifications should be based on hematologic toxicity (e.g., neutropenia, thrombocytopenia) and overall tolerability.
• Treatment may be delayed or dose reduced according to severity of adverse effects.
• No specific dosing adjustment is recommended for mild to moderate renal or hepatic impairment; caution advised in severe impairment due to limited data.
• Pediatrics & Elderly:
• Safety and efficacy have not been established in pediatric patients.
• Elderly patients may receive standard dosing with close monitoring for toxicity.

Trifluridine is a thymidine-based nucleoside analog that incorporates into DNA during replication, causing DNA dysfunction and inhibition of tumor cell proliferation. Tipiracil is a thymidine phosphorylase inhibitor that prevents rapid degradation of trifluridine, thus increasing its systemic exposure and enhancing antitumor efficacy. The combination results in sustained cytotoxic effects against cancer cells by maintaining effective plasma levels of trifluridine.

• Absorption: Oral trifluridine alone is rapidly degraded by thymidine phosphorylase; co-administration with tipiracil inhibits this degradation, improving bioavailability.
• Distribution: Both agents distribute extensively; trifluridine incorporates into DNA in proliferating cells.
• Metabolism: Trifluridine is metabolized by thymidine phosphorylase; tipiracil inhibits this enzyme. Tipiracil undergoes minimal metabolism.
• Elimination: Trifluridine and metabolites are primarily excreted in urine; tipiracil is mostly excreted unchanged via feces.
• Half-life: Trifluridine has a short half-life (~2 hours) alone; prolonged when administered with tipiracil.
• Onset of Action: Antitumor activity develops over multiple treatment cycles.

• Pregnancy:
• Use is contraindicated in pregnancy due to potential for fetal harm; animal studies demonstrate embryotoxicity and teratogenicity.
• Effective contraception is recommended during and after treatment.
• Lactation:
• Unknown whether the drugs are excreted in human milk. Breastfeeding is not recommended during treatment due to potential toxicity.

• Primary Therapeutic Class: Antineoplastic agent
• Subclass: Nucleoside analog combination with thymidine phosphorylase inhibitor

• Hypersensitivity to trifluridine, tipiracil, or any formulation components.
• Severe bone marrow suppression (e.g., neutropenia, thrombocytopenia).
• Uncontrolled infections or severe organ dysfunction precluding chemotherapy.

• Myelosuppression: Severe neutropenia, anemia, and thrombocytopenia are common and may be dose-limiting. Regular blood counts are mandatory.
• Infection Risk: Increased susceptibility due to neutropenia; monitor closely for signs of infection.
• Gastrointestinal Toxicity: Monitor for nausea, vomiting, diarrhea, and mucositis; provide supportive care as needed.
• Renal and Hepatic Impairment: Use with caution and monitor closely in severe impairment.
• Embryo-Fetal Toxicity: Strongly advise contraception during and post-therapy.

• Hematologic: Neutropenia, anemia, thrombocytopenia.
• Gastrointestinal: Nausea, vomiting, diarrhea, decreased appetite, stomatitis.
• General: Fatigue, weakness, fever.
• Rare: Severe hypersensitivity reactions.

• No significant CYP450 enzyme interactions reported.
• Additive myelosuppression may occur when combined with other cytotoxic or myelosuppressive agents.
• Avoid concomitant use of hepatotoxic drugs or alcohol.

• Approval as a treatment option for refractory metastatic colorectal and gastric cancers after failure of multiple lines of therapy.
• Guidelines emphasize hematologic monitoring and supportive care for adverse effects.
• No recent changes in dosing or administration recommendations.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep tablets in original packaging until use.
• Keep out of reach of children.
• No refrigeration or special handling required.