Famciclovir

Famciclovir (Famvir®) is the oral prodrug of penciclovir, an agent that has demonstrated antiviral activity against herpes simplex viruses, type 1 (HSV-1) and 2 (HSV-2) [which cause orolabial and/or genital herpes simplex], and against varicella zoster virus (VZV) [a reactivation of which leads to herpes zoster].

Famciclovir has efficacy similar to that of aciclovir (in immunocompetent or immunocompromised patients) or valaciclovir (in immunocompetent patients) in the treatment of herpes zoster, and efficacy similar to aciclovir in the treatment of first or recurrent episodes of genital herpes (in immunocompetent or immunocompromised patients). Famciclovir also has efficacy in the suppression of recurrent episodes of genital herpes, and in the treatment of orolabial herpes, in immunocompetent patients.

As such, famciclovir is a well tolerated first-line option for the treatment of herpes zoster and the treatment and suppression of genital herpes, and is approved for the treatment of recurrent orolabial herpes. Convenient patient-initiated single-day (for recurrent genital herpes) and single-dose (for orolabial herpes) dosage regimens may contribute to treatment compliance, patient acceptability and subsequent treatment outcomes.

The proposed mechanism of antiviral action of penciclovir, which is the active form of orally administered famciclovir, involves the competitive inhibition by the phosphorylated agent, penciclovir triphosphate, of viral DNA polymerase, thereby inhibiting DNA synthesis and replication in virus-infected cells.

Famciclovir/penciclovir had antiviral activity generally similar to that of aciclovir in in vivo and in vitro studies. The higher intracellular concentrations of penciclovir triphosphate and its greater stability in infected cells may outweigh the greater affinity of aciclovir for viral DNA polymerase than that of penciclovir triphosphate for the same substrate, and account for the prolonged in vivo antiviral activity of penciclovir relative to that of aciclovir.

Famciclovir is extensively and consistently absorbed after oral administration (bioavailability 77%), and is rapidly converted to penciclovir. The pharmacokinetics of penciclovir are linear and dose proportional, with no accumulation of the drug after multiple doses. The volume of distribution indicates extensive distribution into the tissues. Penciclovir is poorly (<20%) bound to plasma proteins and is excreted in the urine.

In large, well designed trials, famciclovir has shown efficacy in the treatment of herpes zoster, the treatment and suppression of genital herpes, and the treatment of orolabial herpes.

Seven-day regimens of famciclovir demonstrated efficacy that was no different (in terms of time to lesion healing and/or resolution of pain or other symptoms) to those of aciclovir, valaciclovir or brivudine in the treatment of herpes zoster in immunocompetent patients, and demonstrated a significantly shorter time to resolution of post-herpetic neuralgia than placebo. The efficacies of famciclovir and aciclovir did not differ significantly in the treatment of immunocompromised patients.

In the treatment of first or recurrent episodes of genital herpes in immunocompetent patients, 5-day regimens of famciclovir and aciclovir had similar efficacy. A single-day famciclovir regimen has shown clinical benefit compared with placebo in immunocompetent patients with recurrent episodes. In immunocompromised patients with recurrent genital or orolabial herpes, similar proportions of famciclovir and aciclovir recipients developed new lesions during the 7-day treatment period, and the median time to complete lesion healing was similar for both treatment groups.

Suppressive treatment with famciclovir was significantly more effective than placebo in immunocompetent patients with recurrent genital herpes in terms of time to recurrence, number of recurrences and proportion of patients recurrence-free for a specified period, and in HIV-infected patients with anogenital or orolabial herpes with regard to number of days with symptoms and number of days that HSV virus was isolated from the affected area. In one study of immunocompetent patients with recurrent genital herpes, approximately two-thirds of famciclovir and valaciclovir recipients were recurrence free during the 16-week treatment period.

In immunocompetent patients with recurrent orolabial herpes, early treatment with a patient-initiated, single-dose famciclovir regimen significantly reduced lesion healing time compared with placebo.

Individual trial reports and a pooled analysis of several clinical trials indicate that famciclovir is well tolerated, and the nature, severity and incidence of adverse events reported with famciclovir are generally similar to those with placebo or aciclovir. The most frequently reported treatment-emergent adverse events were headaches and gastrointestinal symptoms. In the pooled analysis, the incidences in famciclovir versus placebo recipients of adverse events considered to be at least possibly treatment-related were 9.3% versus 7.9% for headache, 4.5% versus 4.2% for nausea and 2.4% versus 2.3% for diarrhoea; the incidences in famciclovir versus aciclovir recipients were 6.0% versus 4.6% for headache, 3.7% versus 2.7% for nausea, 1.7% versus 2.3% for abdominal pain and 1.3% versus 1.9% for diarrhoea. Treatment withdrawal rates due to adverse events were similar with famciclovir (2.4%) and placebo (1.6%), and serious adverse events related to famciclovir therapy were rare.