Trifluridine warnings and precautions

# Warnings
The recommended dosage and frequency of administration should not be exceeded (see DOSAGE AND ADMINISTRATION).

# Precautions

### General
VIROPTIC Ophthalmic Solution, 1% should be prescribed only for patients who have a clinical diagnosis of herpetic keratitis.
VIROPTIC may cause mild local irritation of the conjunctiva and cornea when instilled, but these effects are usually transient.
Although documented in vitro viral resistance to trifluridine has not been reported following multiple exposures to VIROPTIC, the possibility of the development of viral resistance exists.

### Carcinogenesis, Mutagenesis, Impairment of Fertility
Trifluridine has been shown to exert mutagenic, DNA-damaging and cell-transforming activities in various standard in vitro test systems, and clastogenic activity in Vicia faba cells. It did not induce chromosome aberrations in bone marrow cells of male or female rats following a single subcutaneous dose of 100 mg/kg, but was weakly positive in female, but not in male, rats following daily subcutaneous administration at 700 mg/kg/day for 5 days.
Although the significance of these test results is not clear or fully understood, there exists the possibility that mutagenic agents may cause genetic damage in humans.
Lifetime carcinogenicity bioassays in rats and mice given daily subcutaneous doses of trifluridine have been performed. Rats tested at 1.5, 7.5, and 15 mg/kg/day had increased incidences of adenocarcinomas of the intestinal tract and mammary glands, hemangiosarcomas of the spleen and liver, carcinosarcomas of the prostate gland, and granulosa-thecal cell tumors of the ovary. Mice were tested at 1, 5, and 10 mg/kg/day; those given 10 mg/kg/day trifluridine had significantly increased incidences of adenocarcinomas of the intestinal tract and uterus. Those given 10 mg/kg/day also had a significantly increased incidence of testicular atrophy as compared to vehicle control mice.

### Pregnancy Category: C
Teratogenic Effects
Trifluridine was not teratogenic at doses up to 5 mg/kg/day (23 times the estimated human exposure) when given subcutaneously to rats and rabbits. However, fetal toxicity consisting of delayed ossification of portions of the skeleton occurred at dose levels of 2.5 and 5 mg/kg/day in rats and at 2.5 mg/kg/day in rabbits. In addition, both 2.5 and 5 mg/kg/day produced fetal death and resorption in rabbits. In both rats and rabbits, 1 mg/kg/day (5 times the estimated human exposure) was a no-effect level. There were no teratogenic or fetotoxic effects after topical application of VIROPTIC Ophthalmic Solution, 1% (approximately 5 times the estimated human exposure) to the eyes of rabbits on the 6th through the 18th days of pregnancy. In a non-standard test, trifluridine solution has been shown to be teratogenic when injected directly into the yolk sac of chicken eggs. There are no adequate and well-controlled studies in pregnant women. VIROPTIC Ophthalmic Solution, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

### Nursing Mothers
It is unlikely that trifluridine is excreted in human milk after ophthalmic instillation of VIROPTIC because of the relatively small dosage (5 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 benefits outweigh the potential risks.

### Pediatric Use
Safety and effectiveness in pediatric patients below six years of age have not been established.

### Geriatric Use
No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.