Trifluridine
Description
Trifluridine
(also known as trifluorothymidine, F3TdR,F3T), is 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
:
Trifluridine
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 -
Clinical Pharmacology
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.
Trifluridine
Ophthalmic Solution, 1% 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 Ophthalmic Solution, 1% was also effective.
Trifluridine
interferes with DNA synthesis in cultured mammalian cells. However, its
antiviral mechanism of action is not completely known.
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 Trifluridine
Ophthalmic Solution, 1% 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 Trifluridine
Ophthalmic Solution, 1% 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 Trifluridine Ophthalmic Solution, 1% instilled
into their eyes seven times daily for 14 consecutive days.
Clinical Studies
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
Trifluridine Ophthalmic Solution, 1% 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, Trifluridine Ophthalmic Solution, 1% 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.
Trifluridine Ophthalmic Solution, 1% 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 Trifluridine Ophthalmic Solution, 1% 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. Trifluridine Ophthalmic Solution, 1% has not
been shown to be effective in the prophylaxis of herpes simplex virus
keratoconjunctivitis and epithelial keratitis by well-controlled clinical
trials. Trifluridine Ophthalmic Solution, 1% is not effective against
bacterial, fungal, or chlamydial infections of the cornea or nonviral trophic
lesions.
Indications and
Usage for Trifluridine
Trifluridine
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.
Contraindications
Trifluridine
Ophthalmic Solution, 1% is contraindicated for patients who develop
hypersensitivity reactions or chemical intolerance to Trifluridine.
Warnings
The recommended
dosage and frequency of administration should not be exceeded (see DOSAGE AND
ADMINISTRATION).
Precautions
General
Trifluridine
Ophthalmic Solution, 1% should be prescribed only for patients who have a
clinical diagnosis of herpetic keratitis.
Trifluridine
Ophthalmic Solution, 1% 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 Trifluridine Ophthalmic Solution, 1% ,
the possibility of the development of viral resistance exists.
Carcinogenesis,
Mutagenesis, Impairment of Fertility
Mutagenic Potential
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.
Oncogenic Potential
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
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 Trifluridine 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. Trifluridine 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
Trifluridine Ophthalmic Solution, 1% 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.
Adverse
Reactions
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
intraocular pressure.
Overdosage
Overdosage by
ocular instillation is unlikely because any excess solution should be quickly
expelled from the conjunctival sac.
Acute overdosage
by accidental oral ingestion of Trifluridine Ophthalmic Solution, 1% has not
occurred. However, should such ingestion occur, the 75 mg dosage of
Trifluridine in a 7.5 mL bottle of Trifluridine Ophthalmic Solution, 1% 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 or higher.
Trifluridine
Dosage and Administration
Instill one drop
of Trifluridine 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.
If 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 Trifluridine Ophthalmic Solution, 1%
for periods exceeding 21 days should be avoided because of potential ocular
toxicity.
How is
Trifluridine Supplied
Trifluridine
Ophthalmic Solution, 1% is supplied as a sterile ophthalmic solution in a
plastic Drop Dose®dispenser bottle of 7.5 mL (NDC 59762-0040-1).
Store under
refrigeration 2° to 8°C (36° to 46°F).
ANIMAL
PHARMACOLOGY AND ANIMAL TOXICOLOGY
Corneal wound
healing studies in rabbits showed that Trifluridine Ophthalmic Solution, 1% 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.
Whereas
instillation of Trifluridine Ophthalmic Solution, 1% 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 Trifluridine Ophthalmic
Solution, 1% was instilled into eyes in intermittent, multiple, full-therapy
courses showed no drug-related changes in the cornea.
Rx Only.
LAB-0596-2.0
August 2016
PRINCIPAL
DISPLAY PANEL - 7.5 mL Bottle Label
NDC 59762-0040-1
Drop Dose®
7.5 mL
GREENSTONE® BRAND
Trifluridine
ophthalmic
solution,
1% sterile
PRINCIPAL
DISPLAY PANEL - 7.5 mL Bottle Carton
NDC 59762-0040-1
Drop Dose®
7.5 mL
GREENSTONE® BRAND
Trifluridine
ophthalmic solution,
1% sterile
Rx only
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Trifluridine Trifluridine
solution
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Product Information
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Product Type
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HUMAN PRESCRIPTION DRUG LABEL
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Item Code (Source)
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NDC:59762-0040
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Route of Administration
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OPHTHALMIC
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DEA Schedule
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Active Ingredient/Active Moiety
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Ingredient Name
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Basis of Strength
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Strength
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Trifluridine (Trifluridine)
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Trifluridine
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1 g in 100 mL
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Inactive Ingredients
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Ingredient Name
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Strength
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ACETIC ACID
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SODIUM ACETATE
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SODIUM CHLORIDE
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THIMEROSAL
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Packaging
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#
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Item Code
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Package Description
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1
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NDC:59762-0040-1
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1 BOTTLE, DROPPER in 1 CARTON
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1
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7.5 mL in 1 BOTTLE, DROPPER
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Marketing Information
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Marketing Category
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Application Number or Monograph Citation
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Marketing Start Date
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Marketing End Date
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NDA AUTHORIZED GENERIC
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NDA018299
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04/10/1980
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11/30/2017
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Labeler - Greenstone LLC (825560733)
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Registrant - Pfizer Inc (113480771)
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Revised: 10/2017
Greenstone LLC
