Zirgan (ganciclovir ophthalmic gel)

Company: Sirion Therapeutics
Approval Status: Approved September 2009
Treatment for: acute herpetic keratitis
Areas: Immunology/Infectious Diseases; = Ophthalmology

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Zirgan is a topical gel formulation of ganciclovir. Ganciclovir is a guanosine derivative that upon phosphor ylation inhibits DNA replication by herpes simplex viruses (HSV).

Zirgan is specifically indicated for the treatment of herpetic keratitis (dendritic ulcers).

Zirgan is supplied as a 0.15% gel designed for topical ophthalmic administration. The recommended initial dose is 1 drop in the affected eye 5 times per day (approximately every 3 hours while awake) until the corneal ulcer heals and then 1 drop 3 times per day for 7 days.

Clinical Results

FDA Approval

The FDA approval of Zirgan was based on the following studies:

One open-label randomized controlled multicenter clinical trial enrolled 164 subjects with herpetic keratitis. Zirgan was compared to acyclovir ophthalmic ointment 3% and evaluated for non-inferiority. Zirgan was determined to be non-inferior to acyclovir ophthalmic ointment. Clinical resolution (healed ulcers) at Day 7 was achieved in 77% of the Zirgan arm versus 72% of the acyclovir arm.

Three randomized single-masked controlled multicenter clinical trials enrolled 213 total patients. Zirgan was agained compared to acyclovir ophthalmic ointment 3% in terms of non-inferiority. Zirgan was non-inferior to acyclovir ophthalmic ointment 3% in patients with dendritic ulcers. Clinical resolution at Day 7 was achieved in 72% of the Zirgan arm versus 69% of the acyclovir arm.

Side Effects

Adverse events associated with the use of Zirgan may include but are not limited to the following:

blurred vision
eye irritation
punctate keratitis
conjunctival hyperemia

Mechanism of Action

Zirgan (ganciclovir ophthalmic gel) contains the active ingredient ganciclovir which is a guanosine derivative that upon phosphorylation inhibits DNA replication by herpes simplex viruses (HSV). Ganciclovir is transformed by viral and cellular thymidine kinases (TK) to ganciclovir triphosphate which works as an antiviral agent by inhibiting the synthesis of viral DNA in 2 ways: competitive inhibition of viral DNA-polymerase and direct incorporation into viral primer strand DNA resulting in DNA chain termination and prevention of replication.

Literature References

Colin J Ganciclo vir ophthalmic gel 0.15%: a valuable tool for treating ocular herpes. Clinical Ophthalmology 2007 Dec;1(4):441-5 3

Colin J Hoh HB Easty DL Herbort CP Resnikoff S Rigal D Romdane K Ganciclovir ophthalmic gel (Virgan; 0.15%) in the treatment of herpes simplex keratitis. Cornea 1997 Jul;16(4):393-9

Hoh HB Hurley C Claoue C Viswalingham M Easty DL Goldschmidt P Collum LM Randomised trial of ganciclovir and acyclovir in the treatment of herpes simplex dendritic keratitis: a multicentre study. The British Journal of Ophthalmology 1996 Feb;80(2):140-3

Additional Information

For additional information regarding Zirgan or acute herpetic keratitis please visit the Zirgan web page.

Viroptic

Company: King Pharmaceuticals
Approval Status: Approved February 1998
Treatment for: inflammation of the cornea due to herpes simplex virus
Areas: Immunology/Infectious Diseases; = Ophthalmology; Pediatrics/Neonatology

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Viroptic Oththalmic Solution (trifluridine) 1% has been approved for use in children (ages 6+) as a treatment for inflammation of the cornea caused by the herpes simplex virus. The antiviral agent was previously approved for use in adults.

Valcyte (valganciclovir HCl)

Company: Roche
Approval Status: Approved March 2001
Treatment for: Cytomegalovirus retinitis in patients with AIDS
Areas: Immunology/Infectious Diseases; = Ophthalmology

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Valcyte tablets have been approved by the FDA for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). Valcyte is an oral prodrug of Cytovene a currently approved and widely prescribed anti-CMV medication.

The active ingredient in Valcyte is valganciclovir which exists as a mixture of two diastereomers (compounds with the same atoms but in different arrangements). In the body the diaste reomers are converted to ganciclovir which inhibits the replication of human cytomegalovirus.

CMV belongs to the family of herpes viruses. The virus remains inactive in individuals with normal immune function; however it can cause illness in those with compromised immune systems such as individuals with AIDS or patients taking post-transplant immunosuppressants. In patients with HIV/AIDS the most common form of CMV is CMV retinitis an infection of the eye that can lead to blindness.

Clinical Results

A randomized open-label controlled trial evaluated 160 subjects with AIDS and newly diagnosed CMV retinitis. Subjects were randomized to receive treatment with either Valcyte tablets or intravenous ganciclovir solution (Cytovene-IV). The median age of the participants was 39 years the median baseline HIV-1 RNA was 4.9 log₁₀ and the median CD4 cell count was 23 cells/mm³. A determination of CMV retinitis progression by the masked review of retinal photographs taken at baseline and week four was the primary outcome measurement of the three week induction therapy. At four weeks Valcyte tablets were found to have comparable efficacy for induction therapy when evaluated against Cytovene-IV.

Side Effects

Adverse events reported from two trials of Valcyte include (but are not limited to) the following:

Diarrhea
Nausea
Pyrexia (fever)
Neutropenia (decreased number of white blood cells)
Anemia
Headache
Vomiting
Abdominal pain
Insomnia
Retinal detachment

Mechanism of Action

Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of two diastereomers. After oral administration both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine which inhibits replication of human cytomegalovirus invitro and in vivo.

In CMV-infected cells ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate which is then slowly metabolized intracellularly. As the phosphorylation is largely dependent on the viral kinase phosphorylation of ganciclovir occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by ganciclovir triphosphate. (from Valcyte Prescribing/Label Information).

Additional Information

For additional information on Valcyte please visit Hoffmann-La Roche.

If you are interested in further information on AIDS and CMV please visit the National Institute of Allergy and Infectious Diseases or the Centers for Disease Control and Prevention.

Acyclovir Capsules

Company: Teva Pharmaceutical
Approval Status: Approved April 1997
Treatment for: anti-viral treatment
Areas: Immunology/Infectious Diseases

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Acyclovir Capsules have been approved as an anti-viral treatment. Acyclovir Capsules are the generic version of GlaxoWellcome's Zovirax.

Famvir (famciclovir)

Company: SmithKline Beecham
Approval Status: Approved September 17 1997
Treatment for: herpes simplex
Areas: Immunology/Infectious Diseases
Possible similar drugs: Famvir

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Famvir has been approved for the suppression of recurrent genital herpesin a daily formulation.

Clinical Results

Patients receiving Famvir 250 mg twice daily had approximately 80% fewer outbreaks.

Additional Information

It is estimated that at least 31 million Americans have genital herpes a sexually transmitted disease spread through sexual contact with an infected partner. Genital herpes is a contagious viral infection caused by the herpes simplex virus (HSV). Each year an estimated 500 000 new cases occur. In the United States alone up to 80 percent of the subjects with genital herpes suffer from symptomatic recurrences of the disease following an initial outbreak.

Despite these epidemic proportions the public does not recognize the prevalence of genital herpes. According to a recent Gallup survey only 17% of people in six Western countries named genital herpes when asked to name STDs other than AIDS. Among United States respondents the vast majority believes that the prevalence of genital herpes is on the order of one in 1000 or one in 500. Only 2% correctly guessed the actual prevalence.

During a recurrence of genital herpes subjects may experience painful sores as well as tenderness and burning in the genital area. Those infected can spread the disease to others throug h viral shedding the time during which the subject is infectious. Many sub jects with genital herpes experience an average of five outbreaks--or recurrences--per year although some may have as many as two to three per month.

Famvir (famciclovir)

Company: SmithKline Beecham
Approval Status: Approved January 1999
Treatment for: Infectious Diseases
Areas: Immunology/Infectious Diseases
Possible similar drugs: Famvir

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For the treatment of recurrent mucocutaneous herpes simplex infections in HIV-infected patients.