Action And Clinical Pharmacology: Trifluridine is phosphorylated by a cellular thymidine kinase to its nucleotide monophosphate. Trifluridine monophosphate is an inhibitor of thymidylate synthetase, the target enzyme for the action of monofluorinated pyrimidines. Trifluridine has been demonstrated to combine slowly and irreversibly with thymidylate synthetase in a reaction that requires ATP.
Trifluridine monophosphate is further phosphorylated by cellular enzymes to the triphosphate which is incorporated into DNA (but not RNA) by competitively inhibiting the incorporation of the natural nucleotide, thymidine triphosphate (dTTP).
The inhibition of viral replication can be reversed by the addition of thymidine (thymidine rescue).
Viral DNA polymerase has a higher affinity for trifluridine triphosphate than does the DNA polymerase of uninfected cells, resulting in the preferential incorporation of the analogue into viral DNA.
Trifluridine is active against the following DNA viruses: herpes simplex types 1 and 2, varicella zoster, adenovirus and vaccinia virus.
Intraocular penetration of trifluridine was evaluated in 5 patients undergoing intraocular surgery. One drop of 1% trifluridine was instilled into the affected eye 4 times at 10-minute intervals, the last dose being administered 5 minutes before sterile preparation for surgery. Penetration of the drug was demonstrated in 4 of the 5 patients in concentrations ranging from 3.1 to 43.9 M with a mean value of 16.75 M which exceeds the ED50’s for most clinical isolates of HSV-1. There appeared to be a correlation between the degree of corneal integrity and the degree of penetration of trifluridine into the aqueous humor as evidenced by the fact that patients with corneal thinning had higher drug levels (mean 21.3 M) than did the single patient with an intact cornea (3.1 M) The major metabolite of trifluridine (5-carboxy-2′-deoxyuridine) was not detected in any of the eyes.
Pharmacokinetics: The pharmacokinetics of trifluridine in humans is similar to that of animals. The plasma half-life in human cancer patients following i.v. administration of the drug is short and dose-independent. In 3 patients, doses of 5, 15 and 27 mg/kg produced half-lives of 14, 28 and 18 minutes, respectively.
Following i.v. administration trifluridine is excreted in the urine largely as 5-carboxy-2′-deoxyuridine, with trace amounts of its intermediates and unchanged drug. Evidence indicates minimal tissue protein binding both in animals and man.
Samples from 12 volunteers who received topical 1% trifluridine did not reveal detectable serum levels of the drug, indicating that systemic absorption from the eye is minimal.
Indications And Clinical Uses: For the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex viruses, types 1 and 2.
Trifluridine is also effective in the treatment of epithelial keratitis that has not responded clinically to the topical administration of idoxuridine or when ocular toxicity or hypersensitivity to idoxuridine has occurred. In a smaller number of patients found to be resistant to topical vidarabine, trifluridine was also effective.
Note: Trifluridine is not indicated for the treatment of keratitis with deep stromal invasion and uveitis, ocular vaccinia, adenoviral ocular disease, prophylaxis of keratoconjunctivitis and/or recurrent epithelial keratitis, Epstein Barr virus keratitis, or ocular bacterial, fungal, or chlamydial infections.
Contra-Indications: For patients who are known to be hypersensitive or intolerant to trifluridine or any of its nonmedicinal ingredients.
Manufacturers’ Warnings In Clinical States: The recommended dosage and frequency of administration should not be exceeded (see Dosage).
Pregnancy and Lactation: Trifluridine should not be administered to pregnant women or nursing mothers unless the anticipated benefits outweigh the potential risks. The teratogenic potential of this compound in humans is unknown.
The topical application of trifluridine to the eyes of rabbits on days 6 to 18 of gestation produced no teratogenic effects. When administered s.c. to rabbits and rats, fetal toxicity has been observed at doses above 1 mg/kg/day.
The maximum dose anticipated in a human being based on the recommended dosage is approximately 0.1 mg/kg/day, assuming a body weight of 45 kg.
Precautions: General: Trifluridine should be prescribed only for patients who have a clinical diagnosis of herpetic keratitis.
Trifluridine may cause mild local irritation of the conjunctiva and cornea when instilled, but these effects are usually transient.
Caution should be exercised in the use of trifluridine in the treatment of infections caused by strains of herpes simplex virus resistant to other antivirals. Conflicting evidence has been presented on the issue of cross-resistance to other antiviral agents. Resistance of herpes simplex virus type 1 to trifluridine has been produced in vitro and these strains are able to produce trifluridine-resistant infections in vivo. HSV-1 strains insensitive to trifluridine were also resistant to idoxuridine and vidarabine (adenine arabinoside). On the other hand, it has been shown that viruses lacking thymidine kinase and/or DNA polymerase activity may retain complete or reduced sensitivity to trifluridine in vitro and that trifluridine is still of some benefit in rabbit eyes infected with acyclovir-resistant strains of HSV-1. Early work showed that rabbits infected with HSV-1 strains made resistant to idoxuridine could still be treated successfully with trifluridine.
Following re-epithelialization, trifluridine should not be used in an attempt to reduce the rate of recurrence of herpetic keratitis, as supporting experimental and clinical data are lacking, and toxicity may occur with prolonged use.
Children: There is no specific experience respecting efficacy and safety of use in children.
Drug Interactions: Trifluridine should not be applied to the eye simultaneously with other medications. However, the following ophthalmic drugs have been administered topically and concurrently with trifluridine in a limited number of patients without apparent evidence of adverse interaction: antibiotics: chloramphenicol, erythromycin, polymyxin B sulfate, bacitracin, gentamicin sulfate, tetracycline HCl, sodium sulfacetamide, neoymcin sulfate; steroids: dexamethasone sodium phosphate, dexamethasone, prednisolone acetate, prednisolone sodium phosphate, hydrocortisone, fluorometholone; and other ophthalmic drugs: atropine sulfate, scopolamine HBr, naphazoline HCl, cyclopentolate HCl, homatropine HBr, pilocarpine, l-epinephrine HCl and sodium chloride.
Pregnancy: There are no adequate and well-controlled studies in pregnant women. The product should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is unlikely that trifluridine is excreted in human milk after ophthalmic instillation because of the relatively small dosage (£5.0 mg/day), its dilution in body fluids and its extremely short half-life (approximately 12 minutes). The drug should not be prescribed for nursing mothers unless the potential benefit outweighs the potential risk.
Adverse Reactions: The following adverse reactions were noted in controlled and open studies during the administration of trifluridine: 54 of 297 (18%) patients experienced adverse reactions: burning upon instillation (12%); superficial punctate keratitis (2%); and eyelid edema, irritation, epithelial keratopathy, allergic reaction, increased intraocular pressure, keratitis sicca, stromal edema, blurred vision and nausea each occurred in less than 1% of the patients.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage by ocular instillation is unlikely because any excess solution should be quickly expelled from the conjunctival sac.
Acute overdosage by accidental oral ingestion has not been reported. However, should such ingestion occur, the 75 mg of trifluridine in a single bottle of solution would not be expected to produce adverse effects.
Single i.v. doses of 1.5 to 30 mg/kg/day in children and adults with neoplastic disease produce reversible bone marrow depression as the only potentially serious toxic effect and only after at least 5 doses. The acute oral LD50 in the mouse and rat was 4 379 mg/kg or higher.
Dosage And Administration: Adults: Instill 1 drop onto the cornea of the affected eye every 2 hours while awake. The maximum daily dosage is 9 drops.
This therapeutic regimen should be continued until the herpetic lesion has completely re-epithelialized. At this time the dosage should be reduced to 1 drop every 4 hours for a maximum daily dosage of 5 drops. This regimen should be continued for 7 days post-re-epithelialization.
If there are no signs of improvement after 7 days of full therapy or complete re-epithelialization has not occurred after 14 days of full therapy, other forms of therapy should be considered.
Administration of a full dosage regimen for periods exceeding 21 days should be avoided because of potential ocular toxicity.
Children: There is no specific information relating to use in children.
Availability And Storage: Each bottle of sterile, aqueous, ophthalmic solution contains: trifluridine 1%. Nonmedicinal ingredients: acetic acid, benzalkonium chloride (as preservative), sodium acetate and sodium chloride. Plastic drop-dose dispenser bottle of 7.5 mL. Store under refrigeration at 2 to 8°C.
VIROPTIC® Glaxo Wellcome Trifluridine Topical Antiviral