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Trifluridine

Class: Antivirals
CAS Number: 70-00-8
Brands: Viroptic

Introduction

Antiviral; fluorinated pyrimidine nucleoside.100 104 109

Uses for Trifluridine

Herpes Simplex Virus Keratitis and Keratoconjunctivitis

Topical treatment of primary keratoconjunctivitis and recurrent epithelial keratitis (dendritic or geographic ulcers) caused by herpes simplex virus types 1 and 2 (HSV-1 and HSV-2).100 109 110 111

Vaccinia Virus Ophthalmic Infections

Topical treatment and prophylaxis of ocular vaccinia infections that occur as a complication of smallpox vaccination in the vaccine recipient or close contact.101 103 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

Topical 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

Although safety and efficacy of topical trifluridine not established for treatment or prevention of ocular vaccinia infections,100 109 CDC and other experts recommend use of topical ophthalmic antivirals (e.g., trifluridine, vidarabine [no longer commercially available in the US]) for management of such infections.101 102 103 Vaccinia immune globulin may also be recommended in some cases.101 102 103

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, 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 Report all complications of smallpox vaccination to state/local health departments and the Vaccine Adverse Event Reporting System (VAERS) at or 800-822-7967.101 102

Trifluridine Dosage and Administration

Administration

Ophthalmic Administration

Apply 1% ophthalmic solution topically onto the cornea of the eye.100 109

Dosage

Pediatric Patients

Herpes Simplex Virus Keratitis and Keratoconjunctivitis
Ophthalmic

Children ≥6 years of age: Instill 1 drop of 1% ophthalmic solution onto the cornea of the affected eye every 2 hours while awake (maximum 9 drops daily) until reepithelialization occurs.100 109 Following reepithelialization, instill 1 drop every 4 hours while awake (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 therapy, consider other forms of treatment.100 109

Avoid treatment duration >21 days.100 109

Adults

Herpes Simplex Virus Keratitis and Keratoconjunctivitis
Ophthalmic

Instill 1 drop of 1% ophthalmic solution onto the cornea of the affected eye every 2 hours while awake (maximum 9 drops daily) until reepithelialization occurs.100 109 Following reepithelialization, instill 1 drop every 4 hours while awake (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 therapy, consider other forms of treatment.100 109

Avoid treatment duration >21 days.100 109

Vaccinia Virus Ophthalmic Infections
Treatment of Vaccinia Ocular Infections
Ophthalmic

Instill 1 drop of 1% ophthalmic solution in the affected eye every 2 hours while awake (i.e., 9 times daily) for up to 14 days or until all lesions heal.101

Prophylaxis in Patients with Blepharitis or Vaccinia Lesions On or Near the Eyelid
Ophthalmic

Instill 1 drop of 1% ophthalmic solution in 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 heal and scabs have fallen off.101

If there is are no signs of improvement or if manifestations worsen after 24–48 hours of therapy, may increase dosage to 1 drop instilled into the affected eye every 2 hours while awake (i.e., 9 times daily).101

Prophylaxis Following Inadvertent Exposure to Vaccinia Virus in Laboratory Setting
Ophthalmic

Instill 1 drop of 1% ophthalmic solution in the affected eye every 4 hours while awake (i.e., 5 times daily) for up to 5 days.102

Discontinue if there is no evidence of vaccinia infection after 5 days.102

Prescribing Limits

Pediatric Patients

Herpes Simplex Virus Keratitis and Keratoconjunctivitis
Ophthalmic

Maximum 9 drops of 1% ophthalmic solution daily;100 109 avoid treatment duration >21 days.100 109

Adults

Herpes Simplex Virus Keratitis and Keratoconjunctivitis
Ophthalmic

Maximum 9 drops of 1% ophthalmic solution daily;100 109 avoid treatment duration >21 days.100 109

Vaccinia Virus Ophthalmic Infections
Ophthalmic

Treatment of vaccinia virus ophthalmic infections: Maximum 9 drops of 1% ophthalmic solution daily for up to 14 days.101

Prophylaxis in patients with blepharitis or vaccinia lesions on or near eyelid: Maximum 9 drops of 1% ophthalmic solution daily for up to 14 days.101

Prophylaxis following inadvertent exposure to vaccinia virus in laboratory setting: Maximum 5 drops of 1% ophthalmic solution daily for up to 5 days.102

Cautions for Trifluridine

Contraindications

  • Known hypersensitivity or chemical intolerance to trifluridine.100 109

Warnings/Precautions

Administration Precautions

For topical ophthalmic use only;100 109 use under close supervision of an ophthalmologist.105

Because of risk of ocular toxicity, do not exceed recommended dosage and frequency of administration.100 109 (See Prescribing Limits under Dosage and Administration.)

If used for topical 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), balance potential benefits of the drug against the minimal potential risk of drug toxicity and of introducing the virus into the eye by frequent manipulation.101

Mutagenic and Carcinogenic Effects

Mutagenic, DNA damaging, and cell-transforming effects reported in vitro; possible heritable genetic damage.100 109

Malignancies (e.g., adenocarcinomas of the GI tract and mammary glands, hemangiosarcomas of the spleen and liver, carcinosarcomas of the prostate gland, granulosathecal cell tumors of the ovary) reported in rats.100 109

Specific Populations

Pregnancy

Category C.100 109

Use during pregnancy only if potential benefits to the woman justify possible risks to the fetus.100 109

Lactation

Distribution into milk unlikely following topical application to the eye.100 109

Do not use in nursing women unless possible benefits to the woman outweigh potential risks to the infant.100 109

Pediatric Use

Safety and efficacy not established in children <6 years of age.100 109

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.100 109

Common Adverse Effects

Mild, transient burning, stinging, or local irritation upon instillation, palpebral edema.100 109 Hyperemia also reported,100 101 109 especially if used for >14 days.101

Trifluridine Pharmacokinetics

Absorption

Bioavailability

Systemic absorption following topical application of trifluridine 1% ophthalmic solution appears to be negligible.100 109

Distribution

Extent

Following topical application of trifluridine 1% solution to the eye, the drug penetrates the cornea and can be detected in aqueous humor.100 109 Intraocular penetration is increased in patients with epithelial defect in the cornea or with stromal or uveal inflammation.100 109

Stability

Storage

Ophthalmic

Solution

2–8°C.100 109

Contains sodium chloride, acetic acid and sodium acetate as buffers and thimerosal 0.001% as a preservative.100 109

Actions and Spectrum

  • Fluorinated pyrimidine nucleoside antiviral.100 104 109

  • Exact mechanism of antiviral activity of trifluridine not completely known;100 104 109 appears to interfere with viral DNA synthesis and viral replication.100 104 109

  • Irreversibly inhibits thymidylate synthetase,104 an enzyme required for DNA synthesis;b competitively inhibits DNA polymerases.104

  • Incorporates into viral and, to a lesser extent, cellular DNA and inhibits DNA synthesis at relatively low concentrations.104 Also exhibits mutagenic, teratogenic, and antineoplastic activities.104

  • Active in vitro and in vivo against HSV-1 and HSV-2;100 104 108 109 may be active against some acyclovir-resistant strains.104 110 Active in vitro against vaccinia virus;100 104 109 has shown in vivo activity in the treatment of vaccinia keratitis in rabbits.107 112 Also has shown antiviral activity in cell culture against some strains of adenovirus.100 104 106 109

  • Although clinical importance unknown, trifluridine-resistant HSV have been produced in vitro.104

Advice to Patients

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.100 109

  • Importance of informing patients of other important precautionary information.100 109 (See Cautions.)

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Trifluridine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Ophthalmic

Solution

1%*

Trifluridine Ophthalmic Solution

Viroptic

Monarch

AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions May 6, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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.

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.

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.

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. [PubMed 24937819]

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.

111. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst Rev. 2015; 1:CD002898. [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. [PubMed 21278209]

b. AHFS drug information 2016. McEvoy GK, ed. Trifluridine. Bethesda, MD: American Society of Health-System Pharmacists; 2016.

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