TRIFLURIDINE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRIFLURIDINE (TRIFLURIDINE).
Trifluridine is a thymidine analog that inhibits thymidylate synthase and incorporates into DNA, leading to DNA damage and cell death.
| Metabolism | Trifluridine is primarily metabolized by thymidine phosphorylase to inactive metabolites. Tipiracil inhibits thymidine phosphorylase to increase trifluridine exposure. |
| Excretion | Renal excretion accounts for approximately 40-50% of the administered dose, primarily as the inactive metabolite 5-trifluorothymidine. Fecal excretion is minimal (<5%). The remainder is eliminated via metabolic degradation. |
| Half-life | The terminal elimination half-life of trifluridine is approximately 12-18 hours. This prolonged half-life supports twice-daily dosing and provides sustained exposure for antiviral activity. |
| Protein binding | Trifluridine is approximately 20% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | The volume of distribution is approximately 0.6 L/kg, indicating distribution into total body water with minimal tissue binding. |
| Bioavailability | Oral bioavailability is low (<30%) due to first-pass metabolism. Ophthalmic bioavailability is negligible systemically due to local administration; however, corneal penetration is approximately 20-30% of the applied dose. |
| Onset of Action | For ophthalmic administration (1% solution), clinical effect (reduction in viral shedding and symptom improvement) typically begins within 2-4 hours. For systemic administration (investigational), onset is approximately 1-2 hours post-dose. |
| Duration of Action | The duration of action for ophthalmic use is approximately 6-8 hours, requiring frequent administration (every 2 hours while awake) for acute infections. For systemic use, duration is approximately 12 hours, allowing twice-daily dosing. |
| Molecular Weight | 296.2 |
Topical: Apply one drop to affected eye every 2 hours while awake (maximum 9 drops/day) until re-epithelialization, then one drop every 4 hours for 7 days. Ophthalmic solution 1%.
| Dosage form | SOLUTION/DROPS |
| Renal impairment | No dose adjustment required; trifluridine is primarily metabolized and renally eliminated. However, use with caution in severe renal impairment (CrCl <30 mL/min) due to potential accumulation. |
| Liver impairment | No dose adjustment recommended. Safety and efficacy not established in hepatic impairment; use with caution in Child-Pugh C cirrhosis. |
| Pediatric use | Children ≥2 years: Same as adult topical dose; one drop every 2 hours while awake (maximum 9 drops/day) until re-epithelialization, then one drop every 4 hours for 7 days. Safety and efficacy in children <2 years not established. |
| Geriatric use | Elderly: No specific dose adjustment; use same dosing as adults. Monitor for ocular adverse effects; consider baseline renal function due to age-related decline. |
| 1st trimester | Avoid: Contraindicated due to teratogenicity (embryotoxic in animals). |
| 2nd trimester | Avoid: Fetal risk; no human studies, animal data show developmental toxicity. |
| 3rd trimester | Avoid: Potential harm to fetus; use only if clearly needed and benefits outweigh risks. |
Clinical note
Comprehensive clinical and safety monograph for TRIFLURIDINE (TRIFLURIDINE).
| Placental transfer | Completely crosses placenta (approx. 100% transfer in vitro and animal models). |
| Breastfeeding | Unknown if excreted in human milk; due to potential for serious adverse reactions in nursing infants, discontinue drug or nursing, considering importance of drug to mother. |
| Lactation Rating |
■ FDA Black Box Warning
Trifluridine/tipiracil is not indicated as a single agent for chemotherapy.
| Serious Effects |
Hypersensitivity to trifluridine or any componentSevere immunosuppression (e.g., bone marrow suppression)
| Precautions | Severe myelosuppression (neutropenia, thrombocytopenia, anemia), Gastrointestinal toxicity (diarrhea, nausea, vomiting), Hepatotoxicity (elevated liver enzymes), Embryo-fetal toxicity |
| Food/Dietary | No known dietary restrictions or food interactions. |
| Clinical Pearls |
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| L5 (Contraindicated) |
| Teratogenic Risk | Trifluridine is FDA pregnancy category D. In the first trimester, there is evidence of fetal harm based on animal studies and its mechanism as a DNA synthesis inhibitor. Second and third trimester use may cause fetal myelosuppression and potential growth restriction. Inadequate human data, but risk cannot be excluded. |
| Fetal Monitoring | Monitor complete blood count with differential at baseline and before each cycle. Assess for myelosuppression. Fetal monitoring with ultrasound for growth and well-being if used in pregnancy. Monitor for signs of infection or bleeding. |
| Fertility Effects | In animal studies, trifluridine caused impaired fertility in males and females. Human data are lacking. It may cause azoospermia or amenorrhea based on its mechanism. Patients should be counseled on fertility preservation. |
| Trifluridine is a topical antiviral used for herpes simplex keratitis. It is not effective against stromal keratitis or uveitis. Use with caution in patients with corneal epithelial defects as it may delay healing. Prolonged use can cause corneal toxicity. Avoid concomitant use with topical corticosteroids unless specifically indicated. |
| Patient Advice | Apply one drop to the affected eye every 2 hours while awake, up to 9 drops daily. · Do not touch the dropper tip to any surface to avoid contamination. · Wash hands before and after administration. · Do not use contact lenses during treatment. · Report any worsening of symptoms, eye pain, or vision changes immediately. |