THERAPEUTIC FOCUS

Ganciclovir is Here

Topical anti-viral selectively targets HSV-infected cells.

Paul M. Karpecki, O.D., F.A.A.O.

Because both the amount and severity of Herpes simplex virus (HSV) keratitis outbreaks often result in ocular inflammation and corneal scarring, which raises the risk of blindness, and blindnesss results in the need for a corneal transplant, it's essential we have treatments on hand to limit this outcome.

Last September, the Food and Drug Adminstration (FDA) approved ganciclovir ophthalmic gel 0.15% (Zirgan, Bausch + Lomb) for the treatment of acute herpetic keratitis (dendritic ulcers) — the first ophthalmic antiviral in the United States in almost 30 years. (Bausch + Lomb obtained the U.S. marketing rights from Sirion Therapeutics for the drug this past May.)

Here, I provide a brief background on the drug, describe its mechanism of action and discuss data from FDA-approved clinical trials, so you can see why you should consider adding this now commercially available medication to your arsenal of ophthalmic medications.

Background

Zirgan, which comes in a 5g polyfoil tube, is a synthetic nucleoside analogue of 2′-deoxyguanosine and is a pro-drug that inhibits herpes simplex virus (HSV) infection and replication by targeting only HSV-infected cells — something that may decrease corneal toxicity. Also, it's formulated with a tonicity of 300mOsmol, similar to that of human tears, and a physiological pH of 7.45 — other characteristics which make it tolerable for the patient, who, incidentally, must be age two or older to use the drug.

Zirgan is the first ophthalmic antiviral in the United States in almost 30 years.

Because Zirgan is formulated in a gel, it ensures a prolonged period of contact time for potentially more availability of the medication. (I've found that the gel consistency of Zirgan is similar to that of an artificial tear gel, with only transient blur.) This, combined with the drug's mechanism of action (explained below) allows for a dosing of one drop in the affected eye five times a day (approximately every three hours during waking hours) until the dendritic ulcer resolves, and then one drop t.i.d. for seven days, likely to ensure the active virus is eradicated and possibly to prevent stromal keratitis or other long-term sequelae of HSV.

In addition, Zirgan doesn't require refrigeration, and it has a shelf life of 18 months.

Eyecare practitioners in Europe have been prescribing the drug, known overseas as Virgan, for the successful treatment of herpetic viral infections for more than a decade. Also, the FDA granted Sirion Therapeutics, Inc. orphan drug designation for Zirgan in 2007.

Mechanism of action

Zirgan is inactive until it penetrates the HSV-infected cells and is then altered by enzymes from the virus. Viral thymidine kinases convert the drug into an active derivative of itself. Once phosphorylated, the drug inhibits the synthesis of viral DNA in two ways:

1. competitive inhibition of viral DNA-polymerase
2. direct incorporation into the viral primer strand of DNA. This results in viral DNA chain termination and prevents viral replication.¹ (See "Adenovirus Treatment?" below.)

ADENOVIRUS TREATMENT? Although the FDA approved Zirgan for acute herpetic keratitis (dendritic ulcers), questions exist on its potential for treating adenovirus — one of the most common and highly contagious viral conditions we, as eyecare practitioners, face. In fact, epidemic cases of the virus have occurred, affecting public health and even closing clinical practices. Adenovirus usually starts in one eye and then progresses to a bilateral condition. It can be relatively painful with pre-auricular lymph adeonopathy. Drugs that have been shown effective against adenoviral infections include the nucloeoside analogues, which are pro-drugs, including ganciclovir, at concentrations higher than those usually used for HSV inhibition. For instance, one study revealed that nine adenovirus keratoconjunctivitis patients who received Zirgan vs. nine such patients who received preservative-free artificial tears, had a mean recovery time of 7.7 days (range seven to 12 days) compared with 18.5 days (range seven to 30 days) for the artificial tear group.4

Clinical trials

The FDA based its approval of Zirgan for the treatment of acute herpetic keratitis on the results of several clinical trials.

For instance, in one open-label, randomized, controlled, multicenter clinical trial of 164 herpetic keratitis patients, results showed that 77% (55/71) of those who used Zirgan achieved clinical resolution.²

This dendritic herpetic keratitis patient had a visual acuity of 20/80 O.U. with extreme photophobia and discomfort prior to treatment. Seven days post-Zirgan treatment, however, the patient had no symptoms at all, and sent me a huge box of chocolates as a thank you.

Also, in three randomized, single-masked, controlled, multicenter clinical trials, all of which included a total of 213 patients, pooled results revealed that 72% (41/57 patients) who used Zirgan achieved clinical resolution at day seven.³

The most common adverse events of Zirgan noted in the clinical trials were blurred vision (60%), eye irritation (20%), punctate keratitis (5%) and conjunctival hyperemia (5%).³

Given Zirgan's patient-friendly characteristics (e.g. dosing, tolerability, efficacy, etc.), prior track record in Europe, pro-drug anti-viral properties, combined with it's dual mechanism of action and specificity for only infected cells, you should definitely consider adding this new drug to your arsenal of medications. OM

1. Colin J. Ganciclovir ophthalmic gel, 0.15%: a valuable tool for treating ocular herpes. Clin Ophthalmol. 2007 Dec;1(4):441-53
2. Clermon-Ferrand. Etude clinique comparative multicentrique de l'effet de l'instillation de GV 550 dans l'herpès conrneen superficiel. Rapport clinique no. 44.GV 550/12.90–46.GV 550/07.90;1993.
3. Highlights of Prescribing Information : Zirgan (ganciclovir ophthalmic gel 0.15%) www.bausch.com/en_US/downloads/ecp/pharma/Zirganpackage_insert.pdf (Accessed June 18, 2010.)
4. Tabbara KF. Treatment of Herpetic keratitis. Ophthalmology. 2005 Sep;112(9):1640

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Dr. Karpecki focuses on corneal disease, ocular surface disease and clinical research at Koffler Vision Group in Lexington, Ky. He is a paid consultant for Bausch + Lomb, though he has no financial interest in Zirgan. E-mail him at Paul@Karpecki.com.