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Viroptic (Trifluridine Ophthalmic) - Description and Clinical Pharmacology

 
 



DESCRIPTION

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.

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.

VIROPTIC 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, VIROPTIC 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 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.

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 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 trophic lesions.

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.

Whereas 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.

Rx Only

LAB-0727-1.0

June 2014

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