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Famciclovir, a synthetic acyclic guanine derivative, is a prodrug which, after oral administration, is rapidly metabolised to the highly bioavailable antiviral compound penciclovir. Penciclovir is active in vitro against the herpesviruses herpes simplex virus (HSV)-1, HSV-2 and varicella zoster virus (VZV).
Famciclovir is an effective treatment of immunocompetent patients with acute herpes zoster (shingles) caused by VZV. Comparative studies have demonstrated that famciclovir has therapeutic efficacy similar to that of oral aciclovir (acyclovir) in attenuating the acute signs and symptoms of infection (including pain during the acute phase of infection). In a placebo-controlled study, famciclovir significantly reduced the duration of postherpetic neuralgia; this effect was more pronounced (almost a 3-fold reduction) in patients aged ≥50 years.
In immunocompetent patients with recurrent genital herpes infection, suppressive treatment with oral famciclovir effectively prolonged the time to recurrence of symptomatic episodes of infection compared with placebo. In addition, famciclovir significantly reduced the duration of viral shedding, accelerated healing of genital herpes lesions and reduced the duration of symptoms. Famciclovir is reported to be the first antiviral agent to significantly reduce symptoms associated with multiple genital herpes lesions.
Famciclovir is a well-tolerated drug with a tolerability profile similar to that of placebo and aciclovir.
Thus, famciclovir is now established as an effective treatment of immunocompetent patients with herpes zoster or genital herpes infection, particularly as famciclovir is administered in a convenient dosage regimen that may improve compliance compared with aciclovir.
After oral administration famciclovir is metabolised to penciclovir, an antiviral compound with activity against herpes simplex virus (HSV) and varicella zoster virus (VZV). Penciclovir is selectively phosphorylated (initially by viral thymidine kinase) in herpesvirus-infected cells (in preference to uninfected host cells) to yield high intracellular concentrations of penciclovir triphosphate. Thereafter, by interacting with viral DNA polymerases, penciclovir triphosphate inhibits viral replication. The descending order of viral susceptibility to penciclovir in plaque reduction assays is HSV-1, HSV-2 and VZV. After removal of penciclovir, a prolonged antiviral effect has been demonstrated in HSV-1, HSV-2 and VZV infected cell cultures. For antiviral agents, intracellular pharmacokinetics is a key factor in their efficacy. The prolonged intracellular half-life of penciclovir triphosphate in cells infected with HSV (10–20 hours) and VZV (7–14 hours), compared with aciclovir triphosphate (≤1 hour), may contribute to the demonstrated clinical efficacy of famciclovir despite its less frequent oral administration than aciclovir.
Combinations of penciclovir with aciclovir or ganciclovir exhibited additive in vitro activity against HSV-1 and HSV-2, and synergistic activity occurred with combinations of penciclovir and human interferon-α, interferon-β or interferon-γ against the same viruses. Combination of penciclovir with foscarnet produced synergistic activity against HSV-1 and additive effects against HSV-2 in vitro. In in vitro cross-resistance studies, most aciclovir-resistant strains of HSV and VZV were also resistant to penciclovir. The aciclovir-resistant strains that were susceptible to penciclovir had altered thymidine kinase and DNA polymerase substrate specificity.
Oral famciclovir and oral, intravenous and subcutaneous penciclovir were effective inhibitors of HSV-1 and HSV-2 in mice; topical penciclovir was an effective inhibitor of HSV-1 in guinea-pigs.
After oral administration, famciclovir is rapidly metabolised in the intestine and liver to yield penciclovir. Penciclovir (from oral famciclovir) is highly bioavailable (77%) and has a linear dose-proportional pharmacokinetic profile over the 125 to 750mg dose range. In healthy volunteers or patients with uncomplicated herpes zoster infection, maximum plasma concentrations of penciclovir ranged from 2.73 to 3.97 mg/L within 1 hour of a single oral 500mg dose of famciclovir. Penciclovir is excreted primarily by the renal route, and elimination of famciclovir was found to decrease in patients with varying degrees of renal impairment. Following administration of single doses of famciclovir 125, 500, and 750mg to healthy volunteers, plasma elimination half-life values for penciclovir ranged from 2.06 to 2.66 hours. In formal interaction studies, no clinically significant pharmacokinetic interactions have been observed between famciclovir and allopurinol, digoxin, cimetidine, theophylline or zidovudine.
Clinical trials of famciclovir have included approximately 1200 immunocompetent patients (aged ≥18 years) with herpes zoster (shingles). A double-blind, placebo-controlled clinical trial demonstrated that famciclovir, initiated within 72 hours of the onset of zoster rash, was significantly more effective than placebo in attenuating symptoms of the zoster rash and, in patients with >50 lesions at enrolment, in resolving acute phase zoster pain. In addition, the duration of post-herpetic neuralgia was significantly less in recipients of famciclovir 500 and 750mg administered 3 times a day for 7 days than in placebo recipients. This benefit was more pronounced in a subgroup of patients aged ≥50 years, in whom the duration of postherpetic neuralgia was reduced by almost 3-fold. Randomised double-blind comparisons of famciclovir with aciclovir demonstrated equal efficacy in healing cutaneous lesions and in attenuating acute phase pain (while the zoster rash was present). Famciclovir 250, 500 or 750mg 3 times daily for 7 days significantly reduced the duration of zoster-associated pain (measured as a continuum from onset to complete cessation of pain) by about 1.5-fold compared with aciclovir 800mg 5 times a day, when patients received treatment within 48 hours of rash onset.
Data are accumulating on the therapeutic efficacy of famciclovir in immuno-competent patients with genital herpes infection, although studies published to date have been in abstract form only. A randomised double-blind placebo-controlled study of suppressive famciclovir treatment reported a significant prolongation of the time to recurrence of symptomatic episodes of genital herpes. Other placebo-controlled studies of short term treatment demonstrated that famciclovir was significantly more effective than placebo in reducing the time to cessation of viral shedding, healing cutaneous lesions, and reducing the time to cessation of symptoms. Oral famciclovir and aciclovir appear to be equally effective in treating the acute symptoms of patients with symptomatic episodes of genital herpes. Famciclovir has been reported to be the first antiviral agent to significantly reduce symptoms associated with multiple genital herpes lesions.
Preliminary tolerability data indicate that famciclovir is a well-tolerated drug with a profile similar to that of placebo and aciclovir. Headache, nausea and diarrhoea were the most commonly observed adverse events. Higher total daily doses of famciclovir did not appear to correlate with an increased incidence of adverse events compared with lower doses of the drug.
Dosage and Administration
Famciclovir treatment should be initiated as soon as signs and symptoms of herpes zoster infection become apparent and within 72 hours of the onset of zoster rash. The recommended oral dosage of the drug is 250 or 500mg 3 times daily (depending on different country recommendations) for 7 days. Dosage modification is not required in elderly patients. In patients with moderate to severe renal impairment, prolongation of the dosage interval is necessary to avoid penciclovir accumulation.
In the treatment of first episode genital herpes, the recommended oral dosage of famciclovir is 250mg 3 times a day for 5 days; for acute recurrent genital herpes infection the dosage is 125mg twice a day for 5 days.
KeywordsHerpes Zoster Varicella Zoster Virus Genital Herpes Postherpetic Neuralgia Famciclovir
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