VIROPTIC is the brand name for trifluridine (also
known as trifluorothymidine, F3TdR,F3T), an
antiviral drug for topical treatment of epithelial keratitis caused
by herpes simplex virus. The chemical name of trifluridine is α,α,α -trifluorothymidine;
it has the following structural formula:
VIROPTIC sterile ophthalmic solution contains 1% trifluridine in
an aqueous solution with acetic acid and sodium acetate (buffers),
sodium chloride, and thimerosal 0.001% (added as a preservative).
The pH range is 5.5 to 6.0 and osmolality is approximately 283 mOsm.
Trifluridine is a fluorinated pyrimidine nucleoside
with in vitro and in vivo activity against herpes simplex
virus, types 1 and 2 and vacciniavirus. Some strains of adenovirus
are also inhibited in vitro.
VIROPTIC is also effective in the treatment
of epithelial keratitis that has not responded clinically to the topical
adminstration 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, VIROPTIC was also effective.
Trifluridine interferes with DNA synthesis in cultured
mammalian cells. However, its antiviral mechanism of action is not
In vitro perfusion studies on excised rabbit corneas have
shown that trifluridine penetrates the intact cornea as evidenced
by recovery of parental drug and its major metabolite, 5-carboxy-2'-deoxyuridine,
on the endothelial side of the cornea. Absence of the corneal epithelium
enhances the penetration of trifluridine approximately two-fold.
Intraocular penetration of trifluridine occurs after topical
instillation of VIROPTIC into human eyes. Decreased corneal integrity
or stromal or uveal inflammation may enhance the penetration of trifluridine
into the aqueous humor. Unlike the results of ocular penetration of
trifluridine in vitro, 5-carboxy-2'-deoxyuridine
was not found in detectable concentrations within the aqueous humor
of the human eye.
Systemic absorption of trifluridine
following therapeutic dosing with VIROPTIC appears to be negligible.
No detectable concentrations of trifluridine or 5-carboxy-2'-deoxyuridine
were found in the sera of adult healthy normal subjects who had VIROPTIC
instilled into their eyes seven times daily for 14 consecutive days.
During a controlled multicenter clinical trial, 92
of 97 (95%) patients (78 of 81 with dendritic and 14 of 16 with geographic
ulcers) responded to therapy with VIROPTIC as evidenced by complete
corneal re-epithelialization within the 14-day therapy period. Fifty-six
of 75 (75%) patients (49 of 58 with dendritic and 7 of 17 with geographic
ulcers) responded to idoxuridine therapy. The mean time to corneal
re-epithelialization for dendritic ulcers (6 days) and geographic
ulcers (7 days) was similar for both therapies.
In other clinical studies, VIROPTIC was evaluated in the treatment
of herpes simplex virus keratitis in patients who were unresponsive
or intolerant to the topical administration of idoxuridine or vidarabine.
VIROPTIC was effective in 138 of 150 (92%) patients (109 of 114 with
dendritic and 29 of 36 with geographic ulcers) as evidenced by corneal
re-epithelialization. The mean time to corneal re-epithelialization
was 6 days for patients with dendritic ulcers and 12 days for patients
with geographic ulcers.
The clinical efficacy
of VIROPTIC in the treatment of stromal keratitis and uveitis due
to herpes simplex virus or ophthalmic infections caused by vacciniavirus
and adenovirus has not been established by well-controlled clinical
trials. VIROPTIC has not been shown to be effective in the prophylaxis
of herpes simplex virus keratoconjunctivitis and epithelial keratitis
by well-controlled clinical trials. VIROPTIC is not effective against
bacterial, fungal, or chlamydial infections of the cornea or nonviral
Indications and Usage
VIROPTIC Ophthalmic Solution, 1% (trifluridine ophthalmic
solution) is indicated for the treatment of primary keratoconjunctivitis
and recurrent epithelial keratitis due to herpes simplex virus, types
1 and 2.
VIROPTIC Ophthalmic Solution, 1% is contraindicated
for patients who develop hypersensitivity reactions or chemical intolerance
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 clastogenicactivity 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. 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.
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.
Safety and effectiveness in pediatric patients below
six years of age have not been established.
No overall clinical differences in safety or effectiveness
have been observed between elderly and other adult patients.
The most frequent adverse reactions reported during
controlled clinical trials were mild, transient burning or stinging
upon instillation (4.6%) and palpebral edema (2.8%). Other adverse
reactions in decreasing order of reported frequency were superficial
punctate keratopathy, epithelial keratopathy, hypersensitivity reaction,
stromal edema, irritation, keratitis sicca, hyperemia, and increased
Overdosage by ocular instillation is unlikely because
any excess solution should be quickly expelled from the conjunctival
Acute overdosage by accidental oral ingestion
of VIROPTIC has not occurred. However, should such ingestion occur,
the 75 mg dosage of trifluridine in a 7.5 mL bottle of VIROPTIC is
not likely to produce adverse effects. Single intravenous 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 three to five courses of therapy.
The acute oral LD50 in the mouse and rat was 4379 mg/kg
Dosage and Administration
Instill one drop of VIROPTIC Ophthalmic Solution,
1% onto the cornea of the affected eye every 2 hours while awake for
a maximum daily dosage of nine drops until the corneal ulcer has completely
re-epithelialized. Following re-epithelialization, treatment for an
additional 7 days of one drop every 4 hours while awake for a minimum
daily dosage of five drops is recommended.
there are no signs of improvement after 7 days of therapy or complete
re-epithelialization has not occurred after 14 days of therapy, other
forms of therapy should be considered. Continuous administration of
VIROPTIC for periods exceeding 21 days should be avoided because of
potential ocular toxicity.
VIROPTIC Ophthalmic Solution, 1% is supplied as
a sterile ophthalmic solution in a plastic Drop Dose® dispenser bottle of 7.5 mL (NDC 61570-037-75).
Store under refrigeration 2° to 8°C
(36° to 46°F).
Animal Pharmacology and Animal Toxicology
Corneal wound healing studies in rabbits showed that
VIROPTIC did not significantly retard closure of epithelial wounds.
However, mild toxic changes such as intracellular edema of the basal
cell layer, mild thinning of the overlying epithelium and reduced
strength of stromal wounds were observed.
instillation of VIROPTIC into rabbit eyes during a subchronic toxicity
study produced some degree of corneal epithelial thinning, a 12-month
chronic toxicity study in rabbits in which VIROPTIC was instilled
into eyes in intermittent, multiple, full-therapy courses showed no
drug-related changes in the cornea.