VA Class:OP230
ATC Class:S01AD02
Trifluridine, a fluorinated pyrimidine nucleoside, is an antiviral agent active against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and vaccinia virus.100, 104, 109
Trifluridine 1% ophthalmic solution is used for the topical treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by herpes simplex virus (HSV).100, 109, 111 Trifluridine 1% ophthalmic solution also is recommended for the topical treatment and prevention of ocular infections caused by vaccinia virus† that occur as a complication of smallpox vaccination or inadvertent exposure to vaccinia virus in or near the eyes.101, 103 Safety and efficacy of topical trifluridine for the treatment of ophthalmic infections caused by adenovirus† have not been established.100, 109
Herpes Simplex Virus Keratitis and Keratoconjunctivitis
Trifluridine 1% ophthalmic solution is used for the topical treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by HSV types 1 and 2 (HSV-1 and HSV-2).100, 109, 110, 111 Efficacy of topical trifluridine for the treatment of stromal keratitis and uveitis caused by HSV has not been established.100, 109 In addition, topical trifluridine has not been shown to be effective for prophylaxis of HSV keratoconjunctivitis or epithelial keratitis.100, 109
In controlled clinical studies in patients with HSV dendritic or geographic corneal ulcers, 95% of patients treated with trifluridine 1% ophthalmic solution had complete corneal reepithelialization within the 14-day study period;100, 109 the mean time to corneal reepithelialization was 6 days for dendritic ulcers and 7 days for geographic ulcers.100, 109 Topical trifluridine has been shown to be effective in treating HSV keratitis in patients intolerant of or resistant to topical idoxuridine (no longer commercially available in the US) and/or topical vidarabine (no longer commercially available in the US).100, 109
Vaccinia Virus Ophthalmic Infections
Although safety and efficacy of topical trifluridine for the treatment of ophthalmic vaccinia virus infections have not been established,100, 109 trifluridine 1% ophthalmic solution is recommended for the topical treatment and prophylaxis of ocular vaccinia infections† that occur as a complication of smallpox vaccination.101, 103 Trifluridine 1% ophthalmic solution also is recommended for prophylaxis following possible inadvertent inoculation with vaccinia virus in or near the eye† (e.g., splash to the eye) involving smallpox vaccine or a laboratory strain of vaccinia virus.102, 103
Inadvertent inoculation (infection) with vaccinia virus at sites other than the vaccination site (e.g., face, eye, eyelid) is a frequently reported adverse effect of smallpox vaccination.103 Although experience treating these infections is limited, the US Centers for Disease Control and Prevention (CDC) and a panel of ophthalmology and infectious disease experts suggest the use of topical ophthalmic antivirals (e.g., trifluridine, vidarabine [no longer commercially available in the US]) for the management of ocular vaccinia that occurs as a result of inadvertent autoinoculation of the eye or eyelid of a vaccinee or as the result of transmission of the vaccine virus from a vaccinee to the eye of a close contact.101, 103 Suspected ocular vaccinia infections should be managed in consultation with an ophthalmologist to ensure a thorough and accurate eye evaluation and the specialized expertise needed to manage potentially vision-threatening disease.101, 103 If keratitis or conjunctivitis occurs as a complication of smallpox vaccination, CDC and other experts state that use of topical trifluridine 1% ophthalmic solution can be considered to minimize progression and begin resolution of the infection.101, 103 In addition, in patients with blepharitis or vaccinia lesions on or near the eyelid (including the eyelid margin or adjacent to the eye), topical trifluridine 1% ophthalmic solution can be used for prophylaxis to prevent extension of vaccinia infection to the conjunctiva and cornea.101, 103 In cases of moderate or severe blepharitis and blepharoconjunctivitis (without keratitis) or cases of keratitis with vision-threatening conditions, use of vaccinia immune globulin may also be indicated.101, 103
If inadvertent exposure to vaccinia virus occurs in or near the eye (e.g., eyesplash) in the laboratory or other setting and the exposure occurred within the last few hours, the affected eye should immediately be irrigated with sterile water or saline; high pressure irrigation should be avoided to prevent iatrogenic corneal abrasions.102, 103 The patient should receive a baseline ophthalmology consultation to assist in evaluation, management, and follow-up and should be observed closely.102 CDC and other experts state that topical antiviral prophylaxis with trifluridine 1% ophthalmic solution is recommended if the exposure in or near the eye occurred within the last 7-10 days;102, 103 if the exposure occurred more than 7-10 days ago, no immediate treatment is indicated but the patient should be observed closely and an ophthalmology consultation obtained if symptoms develop.102 Use of vaccinia immune globulin may also be indicated in some cases (e.g., exposure to laboratory strain of vaccinia virus that may be of high concentration and virulence).102
If inadvertent inoculation with vaccinia virus occurs in a smallpox vaccine recipient or close contact of the vaccinee or if inadvertent exposure to vaccinia virus occurs in a laboratory or other setting, clinicians should consult state/local health departments or the CDC at 800-232-4636 to obtain guidance regarding antiviral treatment or prophylaxis and use of vaccinia immune globulin.101, 102 Healthcare providers for US military personnel should consult US Department of Defense Vaccine Health Resources at 866-210-6469 or the US Army Medical Research Institute of Infectious Diseases (USAMRIID) at 888-872-7443 or 301-619-2257.101, 102 All complications of smallpox vaccination should be reported to state/local health departments and the Vaccine Adverse Event Reporting System (VAERS) at [Web] or 800-822-7967.101, 102
Trifluridine is applied topically to the eye as a 1% ophthalmic solution.100, 109
Herpes Simplex Virus Keratitis and Keratoconjunctivitis
For the topical treatment of primary keratoconjunctivitis and recurrent keratitis (dendritic or geographic ulcers) caused by herpes simplex virus (HSV) in adults and children 6 years of age or older, 1 drop of trifluridine 1% ophthalmic solution should be instilled onto the cornea of the affected eye every 2 hours during waking hours (maximum 9 drops daily) until complete reepithelialization occurs.100, 109 Following reepithelialization, 1 drop of trifluridine 1% ophthalmic solution should be instilled every 4 hours during waking hours (minimum 5 drops daily) for an additional 7 days.100, 109
If there are no signs of improvement after 7 days or if complete reepithelialization has not occurred after 14 days of topical trifluridine treatment, other forms of therapy should be considered.100, 109 The manufacturers state that use of trifluridine 1% ophthalmic solution for more than 21 days should be avoided because of potential ocular toxicity.100, 109
Vaccinia Virus Ophthalmic Infections
For the topical treatment of ocular vaccinia† (i.e., to minimize progression and begin resolution of vaccinia infection in the cornea and conjunctiva), 1 drop of trifluridine 1% ophthalmic solution should be instilled into the affected eye every 2 hours while awake (i.e., 9 times daily) for up to 14 days or until all lesions have healed.101 When trifluridine 1% ophthalmic solution is used for prophylaxis to prevent extension of vaccinia infection to the conjunctiva and cornea† in patients with blepharitis or vaccinia lesions on or near the eyelid, 1 drop of the solution should be instilled into the affected eye every 4 hours while awake (i.e., 5 times daily) for up to 14 days or until all periocular and/or lid lesions have healed and scabs have fallen off.101 If there is no clinical improvement or if manifestations worsen after 24-48 hours of topical trifluridine therapy, increasing the dosage to 1 drop instilled into the affected eye every 2 hours while awake (i.e., 9 times daily) can be considered.101
When trifluridine 1% ophthalmic solution is used for prophylaxis following inadvertent exposure to vaccinia virus in or near the eye† (e.g., eye splash) with smallpox vaccine or laboratory strain of vaccinia virus, 1 drop of the solution should be instilled into the affected eye 5 times daily (i.e., every 4 hours while awake) for up to 5 days.102 If there is no evidence of vaccinial infection after 5 days, topical trifluridine should be discontinued.102
The most common adverse effects of trifluridine 1% ophthalmic solution are mild, transient burning or stinging upon installation (4.6%) and palpebral edema (2.8%).100, 109 Local irritation of the conjunctiva and cornea usually are transient.100, 109
Other adverse effects that have been reported with trifluridine ophthalmic solution include superficial punctate keratopathy,100, 109 epithelial keratopathy,100, 109 stromal edema,100, 109 keratitis sicca,100, 109 increased intraocular pressure,100, 109 and hypersensitivity reactions.100, 109 Hyperemia also has been reported,100, 101, 109 especially when trifluridine ophthalmic solution was used for more than 14 days.101
Precautions and Contraindications
Trifluridine 1% ophthalmic solution is contraindicated in patients with hypersensitivity or chemical intolerance to the drug.100, 109
The ophthalmic solution is for topical ophthalmic use only100, 109 and should be used under the close supervision of an ophthalmologist.105
Because of the risk of ocular toxicity, the recommended dosage and frequency of administration of trifluridine ophthalmic solution should not be exceeded.100, 109 (See Dosage and Administration: Dosage.)
If trifluridine is used for prophylaxis to prevent extension of vaccinia infection to the conjunctiva or cornea in patients with vaccinia lesions on or near the eyelid† (see Uses: Vaccinia Virus Ophthalmic Infections), the potential benefit of the drug should be balanced against the minimal but potential risk of drug toxicity and of introducing the virus into the eye by frequent manipulation.101
Safety and efficacy of trifluridine ophthalmic solution in children younger than 6 years of age have not been established.100, 109
No overall differences in safety or effectiveness of trifluridine 1% ophthalmic solution have been observed between geriatric and younger adults.100, 109
Mutagenicity and Carcinogenicity
Trifluridine has caused mutagenic, DNA damaging, and cell-transforming effects in vitro and has caused clastogenic effects in Vicia faba cells.100, 109 While the importance of these effects is not fully understood, the possibility exists that mutagenic agents may cause heritable genetic damage.100, 109 Chromosomal aberrations were not seen in bone marrow cells of male or female rats following a single subcutaneous 100-mg/kg dose of trifluridine; however, the drug produced minor chromosomal aberrations in female, but not male, rats following subcutaneous administration of 700 mg/kg daily for 5 days.100, 109
Lifetime carcinogenicity bioassays in rats and mice given subcutaneous doses of trifluridine have revealed evidence of carcinogenicity.100, 109 An increased incidence of adenocarcinomas of the GI tract and mammary glands, hemangiosarcomas of the spleen and liver, carcinosarcomas of the prostate gland, and granulosa-thecal cell tumors of the ovary occurred in rats receiving trifluridine dosages of 1.5, 7.5, and 15 mg/kg daily.100, 109 In mice, there was an increased incidence of adenocarcinomas of the GI tract and uterus and an increased incidence of testicular atrophy in those receiving 10 mg/kg daily.100, 109
There are no adequate and well-controlled studies in pregnant women, and trifluridine 1% ophthalmic solution should be used during pregnancy only if potential benefits to the woman justify possible risks to the fetus.100, 109
Although trifluridine was not teratogenic at dosages up to 5 mg/kg daily (23 times the estimated human exposure) when given subcutaneously to rats and rabbits, fetal toxicity consisting of delayed ossification of portions of the skeleton was evident at dosage levels of 2.5 and 5 mg/kg daily in rats and 2.5 mg/kg daily in rabbits.100, 109 In addition, fetal death and resorptions were reported in rabbits at dosages of 2.5 and 5 mg/kg daily.100, 109 There were no effects in rats or rabbits using subcutaneous trifluridine dosages of 1 mg/kg daily (5 times the estimated human exposure) and there were no teratogenic or fetotoxic effects following topical application of trifluridine 1% ophthalmic solution to the eyes of rabbits (approximately 5 times the estimated human exposure) from days 6-18 of pregnancy.100, 109 Trifluridine has been shown to be teratogenic when injected directly into the yolk sac of chicken eggs.100, 109
It is unlikely that trifluridine is distributed into milk following topical application to the eye because of the relatively small dosage used, dilution in body fluids, and the short half-life of the drug (approximately 12 minutes).100, 109 However, the drug should not be used in nursing women unless potential benefits to the woman justify possible risks to the infant.100, 109
Overdosage of trifluridine following topical application to the eye of the commercially available 1% ophthalmic solution is unlikely since any excess solution should be quickly expelled from the conjunctival sac.100, 109 Acute overdosage by accidental or intentional oral ingestion of trifluridine 1% ophthalmic solution has not been reported to date; however, if the contents of the commercially available 7.5-mL bottle of the drug (75 mg of trifluridine) were ingested, it is not likely to produce adverse effects.100, 109 IV administration of single doses of 1.5-30 mg/kg of trifluridine in children and adults with neoplastic disease has produced reversible bone marrow depression as the only potentially serious toxic effect and only after 3-5 courses of therapy.100, 109
The oral LD50 of trifluridine in mice and rats is 4.38 g/kg or higher.100, 109
The exact mechanism of antiviral activity of trifluridine has not been fully elucidated, but appears to involve inhibition of viral DNA synthesis and viral replication.100, 104, 109 Trifluridine monophosphate irreversibly inhibits thymidylate synthetase,104 an enzyme required for DNA synthesis; the triphosphate competitively inhibits DNA polymerases with respect to thymidine triphosphate.104 The drug is incorporated into viral and, to a lesser extent, cellular DNA and inhibits DNA synthesis at relatively low concentrations.104 Trifluridine also exhibits mutagenic, teratogenic, and antineoplastic activities.104
Trifluridine is active in vitro and in vivo against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2),100, 104, 108, 109 and may be active against some acyclovir-resistant strains.104, 110 Trifluridine is active in vitro against vaccinia virus,100, 104, 109 and has shown in vivo activity in the treatment of vaccinia keratitis in rabbits.107, 112 The drug also has shown antiviral activity in cell culture against some strains of adenovirus.100, 104, 106, 109 Trifluridine is inactive against bacteria, fungi, and Chlamydia .100, 109
Although the clinical importance is unknown, trifluridine-resistant strains of herpes simplex virus (HSV) have been produced in vitro.104
Following topical application of trifluridine 1% ophthalmic solution to the eye, the drug penetrates the cornea and can be detected in the aqueous humor.100, 109 Intraocular penetration of the drug is increased in patients with an epithelial defect in the cornea or with stromal or uveal inflammation.100, 109 During in vitro studies using excised rabbit corneas, the major metabolite of trifluridine, 5-carboxy-2'-deoxyuridine, was found on the endothelial side of the cornea in addition to the parent compound; however, detectable levels of the metabolite have not been found in the aqueous humor in humans.100, 109 The major metabolite of trifluridine appears to have some antiviral activity, but substantially less than that of the parent drug.
Systemic absorption following topical application of trifluridine 1% ophthalmic solution appears to be negligible.100, 109 In one study in healthy individuals, topical application of trifluridine 1% ophthalmic solution to the eyes 7 times daily for 14 consecutive days did not result in detectable serum concentrations of trifluridine or 5-carboxy-2'-deoxyuridine.100, 109
Trifluridine, a fluorinated pyrimidine nucleoside,100, 104, 109 is structurally related to idoxuridine (no longer commercially available in the US) and thymidine. Trifluridine differs structurally from thymidine in the presence of 3 fluorine atoms in place of 3 hydrogen atoms in the methyl group of the latter compound. Trifluridine occurs as a white, crystalline powder and is soluble in water and in alcohol.
The commercially available trifluridine 1% ophthalmic solution has a pH of 5.5-6 and an osmolality of approximately 283 mOsm.100, 109 The ophthalmic solution contains sodium chloride, acetic acid and sodium acetate as buffers, and thimerosal 0.001% as a preservative.100, 109
Trifluridine 1% ophthalmic solution should be stored at 2-8°C.100, 109
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Ophthalmic | Solution | 1%* | Trifluridine Ophthalmic Solution | |
Viroptic® | Monarch |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
100. Monarch Pharmaceuticals. Viroptic® (trifluridine) 1% ophthalmic solution prescribing information. Bristol, TN; 2014 Jun.
101. Centers for Disease Control and Prevention. Clinical evaluation tool for smallpox vaccine adverse reactions; ophthalmologic reactions/inadvertent inoculation in a vaccinee (or close contact). (01-19-2011 version). From the CDC website. Accessed 2016 Jan 15. [Web]
102. Centers for Disease Control and Prevention. Clinical evaluation tool for smallpox vaccine adverse reactions; ophthalmologic reactions/eye splash or other potential exposure to vaccinia virus. (01-19-2011 version). From the CDC web site. Accessed 2016 Jan 15. [Web]
103. Centers for Disease Control and Prevention. Smallpox vaccination and adverse reactions: guidance for clinicians. MMWR Morb Mortal Wkly Rep . 2003; 52(No. RR-4):1-28. [PubMed 12549898]
104. Hayden FG. Antiviral drugs (other than antiretrovirals). In: Mandell GL, Bennett, JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and practice of infectious diseases. 5th ed. Philadelphia, PA: Churchill Livingston; 2000:479.
105. . Antiviral drugs. Treat Guidel Med Lett . 2013; 11:19-30. [PubMed 23459414]
106. Lennette DA, Eiferman RA. Inhibition of adenovirus replication in vitro by trifluridine. Arch Ophthalmol . 1978; 96:1662-3. [PubMed 99133]
107. Hyndiuk RA, Seideman S, Leibsohn JM. Treatment of vaccinial keratitis with trifluorothymidine. Arch Ophthalmol . 1976; 94:1785-6. [PubMed 823931]
108. Nozawa C, Hattori LY, Galhardi LC et al. Herpes simplex virus: isolation, cytopathological characterization and antiviral sensitivity. An Bras Dermatol . 2014 May-Jun; 89:448-52.
109. Falcon Pharmaceuticals. Trifluridine 1% ophthalmic solution prescribing information. Fort Worth, TX.
110. White ML, Chodosh J. Herpes simplex virus keratitis: a treatment guideline. 2014 Jun. From American Academy of Ophthamology website. Accessed Oct 29, 2015. [Web]
111. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst Rev . 2015; 1:CD002898. [PubMedCentral][PubMed 25879115]
112. Altmann S, Brandt CR, Murphy CJ et al. Evaluation of therapeutic interventions for vaccinia virus keratitis. J Infect Dis . 2011; 203:683-90. [PubMedCentral][PubMed 21278209]