Mechanism of action: Virovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown. Antiviral activity: In cell culture studies, penciclovir is inhibitory to the following herpes viruses: HSV-1, HSV-2 and VZV. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV and 10 days postinfection for VZV. The median EC 50 values of penciclovir against laboratory and clinical isolates of HSV-1, HSV-2, and VZV were 2 µM (range 1.2 to 2.4 µM, n = 7), 2.6 µM (range 1.6 to 11 µM, n = 6), and 34 μM (range 6.7 to 71 μM, n = 6), respectively. Resistance: Penciclovir-resistant mutants of HSV and VZV can result from mutations in the viral thym >50 values observed in a plaque reduction assay with penciclovir resistant HSV-1, HSV-2, and VZV were 69 µM (range 14 to 115 µM, n = 6), 46 µM (range 4 to >395 µM, n = 9), and 92 μM (range 51 to 148 μM, n = 4), respectively. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy. Cross-resistance: Cross-resistance has been observed among HSV DNA polymerase inhibitors. The most commonly encountered acyclovir resistant mutants that are TK negative are also resistant to penciclovir.
After oral administration, Virovir (prodrug) is converted to penciclovir (active drug). There are no adequate and well-controlled studies of Virovir or penciclovir use in pregnant women. No adverse effects on embryofetal development were observed in animal reproduction studies using Virovir and penciclovir at doses higher than the maximum recommended human dose (MRHD) and human exposure. Because animal reproduction studies are not always predictive of human response, Virovir should be used during pregnancy only if needed.
In animal reproduction studies, pregnant rats and rabbits received oral Virovir at doses (up to 1000 mg/kg/day) that provided 2.7 to 10.8 times (rats) and 1.4 to 5.4 times (rabbits) the human systemic exposure based on AUC. No adverse effects were observed on embryo-fetal development. In other studies, pregnant rats and rabbits received intravenous Virovir at doses (360 mg/kg/day) 1.5 to 6 times (rats) and (120 mg/kg/day) 1.1 to 4.5 times (rabbits) or penciclovir at doses (80 mg/kg/day) 0.3 to 1.3 times (rats) and (60 mg/kg/day) 0.5 to 2.1 times (rabbits) the MRHD based on body surface area comparisons. No adverse effects were observed on embryo-fetal development.
Mechanism Of Action
Virovir is an orally administered prodrug of the antiviral agent penciclovir .
Virovir-treated patients had approximately 1/5 the median number of recurrences as compared to placebo-treated patients. Higher doses of Virovir were not associated with an increase in efficacy.
Virovir (Famvir) has been around for a while as a treatment for feline herpesvirus infection. Until now, though, we haven’t really known how much to use, or how often. A new study has some answers.
First, though – when should we consider using Famvir? It’s not always straightforward. If there is severe stress and overcrowding, URI can be severe and difficult to resolve, regardless of what treatment is used. The other catch is that, in experimental studies, investigators treat a known infection involving one pathogen. In shelters, we are often treating two or more organisms, and we usually don’t know which ones are present in an individual cat.
That said, if the clinical signs are consistent with FHV, there’s a really good chance the cat does have it – simply because it’s such a common infection, particularly in shelters.
According to Koret Shelter Medicine, Famvir should be considered in severe or refractory FHV, or for severe ocular signs (corneal ulcers, severe conjunctivitis). It might also be of some use in chronic rhinosinusitis (Malik 2009), though this was a small and preliminary study. There have even been some recent indications that it might also be helpful for severe calicivirus infections in cats (Cervone 2016).
So, what’s that dose? The new pharmacokinetic study (Sebbag 2016) established that the optimal dose for cats is 90mg/kg twice a day. This mg/kg dose was previously shown to be clinically effective in experimental infections (Thomasy 2011). At 90 mg/kg, it will be a challenge both financially and logistically, but it’s a great tool to have in reserve for severe infections, especially in kittens, which are often hardest hit.
UPDATE: For a more in-depth look at when to use antiviral treatment for feline herpes, and other Virovir dosage options, visit our follow-up blog here.
Herpes Labialis (Cold Sores)
A randomized, double-blind, placebo-controlled trial was conducted in 701 immunocompetent adults with recurrent herpes labialis. Patients self-initiated therapy within 1-hour of first onset of signs or symptoms of a recurrent herpes labialis episode with Virovir 1500 mg as a single dose (n=227), Virovir 750 mg twice daily (n=220) or placebo (n=254) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.4 days in the Virovir 1500 mg single-dose group (n=152) as compared to 6.2 days in the placebo group (n=168). The median difference in time to healing between the placebo and Virovir 1500 mg treated groups was 1.3 days (95% CI: 0.6 to 2). No differences in proportion of patients with aborted lesions (not progressing beyond the papule stage) were observed between patients receiving Virovir or placebo: 33% for Virovir 1500 mg single dose and 34% for placebo. The median time to loss of pain and tenderness was 1.7 days in Virovir 1500 mg single dose-treated patients vs. 2.9 days in placebo-treated patients.
Herpes Zoster (Shingles)
Two randomized, double-blind trials, 1 placebo-controlled and 1 active-controlled, were conducted in 964 immunocompetent adults with uncomplicated herpes zoster. Treatment was initiated within 72 hours of first lesion appearance and was continued for 7 days.
In the placebo-controlled trial, 419 patients were treated with either Virovir 500 mg three times daily (n=138), Virovir 750 mg three times daily (n=135) or placebo (n=146). The median time to full crusting was 5 days among Virovir 500 mg-treated patients as compared to 7 days in placebo-treated patients. The times to full crusting, loss of vesicles, loss of ulcers, and loss of crusts were shorter for Virovir 500 mg-treated patients than for placebo-treated patients in the overall study population. The effects of Virovir were greater when therapy was initiated within 48 hours of rash onset; it was also more profound in patients 50 years of age or older. Among the 65.2% of patients with at least 1 positive viral culture, Virovir treated patients had a shorter median duration of viral shedding than placebo-treated patients (1 day and 2 days, respectively).
There were no overall differences in the duration of pain before rash healing between Virovir-and placebo-treated groups. In addition, there was no difference in the incidence of pain after rash healing (postherpetic neuralgia) between the treatment groups. In the 186 patients (44.4% of total study population) who developed postherpetic neuralgia, the median duration of postherpetic neuralgia was shorter in patients treated with Virovir 500 mg than in those treated with placebo (63 days and 119 days, respectively). No additional efficacy was demonstrated with higher dose of Virovir.
In the active-controlled trial, 545 patients were treated with 1 of 3 doses of Virovir three times daily or with acyclovir 800 mg five times daily. Times to full lesion crusting and times to loss of acute pain were comparable for all groups and there were no statistically significant differences in the time to loss of postherpetic neuralgia between Virovir and acyclovir-treated groups.
The most common side effects associated with the use of Virovir are:
Other important side effects which are serious, but rare, include
- serious allergic reactions,
- serious skin reactions,
- abnormal tests of liver function, and
- reduced white blood cells (neutropenia) or platelets (thrombocytopenia).
Cases of kidney failure have been reported when higher than recommended doses of Virovir were administered to patients with underlying kidney problems.