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Famciclovir Therapy (Famvir®) for Herpes Simplex and Herpes Zoster Infections

S. Tyring, MD, PhD
Departments of Dermatology and Microbiology/Immunology, The University of Texas Medical Branch at Galveston, Texas, USA

ABSTRACT

Genital herpes simplex and herpes zoster infections are common afflictions that are associated with significant morbidity and a decreased quality of life. Famciclovir (Famvir®, Novartis) is an orally administered prodrug of the antiviral agent penciclovir. Its unique pharmacokinetic profile makes it an efficacious, convenient and well-tolerated alternative to the traditionally prescribed acyclovir. Famciclovir is used for the acute treatment and suppressive therapy of recurrent genital herpes as well as for herpes zoster and its debilitating comorbidities. Famciclovir allows patients to manage or prevent symptoms, thereby significantly improving their quality of life. Its favorable safety profile makes it a good treatment choice for the elderly as well as for immunocompromised patients, including those infected with HIV.

Key Words: famciclovir, herpes simplex, herpes zoster

Genital herpes simplex virus infection is considered by global health organizations to be a rapidly growing epidemic1, with an estimated 107 million people infected worldwide.2 Herpes simples virus 2 (HSV-2), the primary associated strain, affects as many as one in five people. Herpes simplex virus 1 (HSV-1) also causes genital herpes (GH), but at a lower prevalence.3,4 Of those afflicted with GH, more than 75% who have a first outbreak will experience at least one recurrence, with most suffering approximately four attacks per year.2 In the US, HSV-2 appears to play a major role in the heterosexual spread of HIV, making people more susceptible to HIV infection and making HIV-infected individuals more infectious.5

Herpes zoster (HZ), a condition resulting from reactivation of a latent varicella zoster virus (VZV) infection, is almost equally common, affecting up to 20% of the population. Although HZ can affect patients of any age, it is more often seen in patients over the age of 50. In immunocompetent patients, HZ is typically self-limiting, usually resolving within 4 weeks of rash onset. However, the infection is associated with significant morbidity, and particularly severe pain during the acute phase of infection. Some patients, especially the elderly and immunocompromised, can develop postherpetic neuralgia (PHN), a sharp pain that is a result of injury to peripheral nerves. It can last for an indefinite duration after the zoster rash has healed.6

Oral famciclovir has potent antiviral activity against HSV-1, HSV-2 and VZV, and is the only antiviral proven to reduce the duration of PHN.7,8 It is prescribed for the treatment or suppression of GH in more than 50 countries and for treatment of HZ in more than 70 countries. Its indications include acute treatment of GH infections and suppression of recurrent GH, use in immunocompromised patients with HZ or herpes simplex infections, and treatment of HZ.

Mechanism of Action

In addition to very high and consistent bioavailability (77%), the active metabolite of famciclovir demonstrates extended longevity, with an intracellular half-life of 10–20 hours for HSV-1 and -2, respectively, and up to 11 hours for herpes zoster.9 In many clinical situations, this greater bioavailability allows famciclovir to be utilized at lower doses and/or at reduced dose frequencies than those used for acyclovir.

Upon ingestion, famciclovir undergoes rapid biotransformation to the active antiviral compound penciclovir. Using viral and cellular kinases, infected cells phosphorylate penciclovir, which then blocks replication of viral DNA via competition with deoxyguanosine triphosphate for viral DNA polymerase. In penciclovir-treated uninfected cells, concentrations of penciclovir triphosphate are barely detectable, indicating that herpes viral DNA synthesis and replication are selectively inhibited and the probability of toxicity to host cells is low.9

Drug Interactions

Because neither famciclovir nor penciclovir is metabolized through the P450 enzyme system, there are no clinically significant interactions with many commonly prescribed drugs (e.g., cimetidine, allupurinol, theophylline, digoxin), making it a good treatment choice for patients who are taking multiple medications.10 Use of famciclovir has proven safe and effective in immunocompromised patients, including those with HIV, and it is the only treatment for GH or HZ approved by the US FDA for use in immunocompromised HIV-positive patients.11 In all indicated patient populations, famciclovir is well tolerated, with a safety profile comparable to placebo.

Summary of Clinical Efficacy Trials

A Phase III study of 692 patients with recurrent GH compared selfinitiated famciclovir treatment with placebo. The trial found that famciclovir, 125 mg, bid for five days, significantly reduced symptoms including pain, burning, itching and tenderness. As well, viral shedding, reduced by almost 50% (Table 1) the amount of time that the virus was actively reproducing and able to spread to uninfected cells. Episodic treatment with famciclovir provided convenient and effective therapy, and reduced periods of infectivity for those patients with recurrent GH whose frequency rates do not require continuous antiviral suppression.12

A clinical trial involving 455 patients with frequently recurring GH determined that suppressive therapy with famciclovir, 250 mg, bid for up to 1 year, significantly reduced the recurrence of outbreaks. Patients on famciclovir therapy experienced 1/5 the number of recurrences compared to those on placebo, and an 80% reduction in outbreaks over a 1-year period (Table 2). The median time to first recurrence was extended by 9 months with famciclovir treatment, and almost one-third of famciclovir-treated patients were recurrence-free after one year (compared with only 6% of placebotreated patients). Suppressive therapy with famciclovir proved beneficial for patients experiencing at least six outbreaks per year and effectively helped patients manage GH symptoms by reducing the number of outbreaks and increasing the length of time before the next outbreak.13

Research has also demonstrated the safety and efficacy of famciclovir treatment for recurrent GH in HIV-infected patients. A comparison of famciclovir (500 mg, bid for 7 days) with acyclovir (400 mg, 5 times per day for 8 days) in HIV-infected patients with recurrent HSV infection demonstrated comparable efficacy between the two treatments. However, because it does not interact with zidovudine14 and is taken only twice a day, famciclovir appears to be the better choice.15

Famciclovir has also been shown to be an effective, well tolerated treatment for herpes zoster in immunocompetent7,8,16-18 as well as immunocompromised19 patients, and is the only antiviral to reduce duration of PHN, the disease’s most frequent debilitating complication. A trial involving 419 immunocompetent adults with uncomplicated HZ demonstrated that famciclovir, 500 mg, tid for 7 days, shortened the duration of PHN by 100 days in patients over the age of 50, and healed lesions 30% faster compared with placebo. Among the 44% of patients who developed PHN, the median duration was shorter in famciclovir-treated patients (63 days) when compared with placebo-treated patients (119 days).7

Median time to event (d)

Famciclovir 125 mg, bid for 5 days

Placebo

P value

Complete healing

3.8

4.8

<.001

Loss of vesicles

1.8

2.9

<.02

Loss of ulcers

2.9

4.0

<.01

Loss of crusts

4.0

4.9

<.001

Loss of edema

1.9

2.6

<.01

Loss of all symptoms*

3.2

3.2

<.01

Table 1: Time-to-event analysis of treatment effects on recurrent GH symptoms and signs
*Loss of all symptoms, including tenderness, pain, itching, burning and tingling

Event

Famciclovir 250 mg, bid

Placebo

P value

Median time to first recurrence (d)

336

47

<.001

Median number of episodes, patient reported*

1.0

5.1

<.001

Median number of episodes, investigator reported**

0.0

4.4

<.001

Table 2: Treatment effects on time to first recurrence and lesional GH episodes per year
*Patient-reported lesional episode following self-assessment and not necessarily clinically confirmed by the investigator
**Lesional episode clinically confirmed lesional episode by investigator

Side effects

The frequency, nature and severity of adverse events did not differ significantly from those experienced with placebo. The most commonly reported adverse events were headache, nausea and diarrhea.

Conclusion

Famciclovir is a safe, convenient treatment alternative for GH and HZ. It helps to alleviate symptoms of both afflictions, to ease the pain and burning of GH and shorten the duration of PHN. Episodic and suppressive treatment of recurrent GH with famciclovir reduces genital herpes infectivity within and among individuals, reducing the number of outbreaks and delivering more days free from active disease. Lack of significant clinical interactions with commonly prescribed medications makes famciclovir an excellent treatment choice for patient populations on multiple medications, such as the elderly and those infected with HIV.

References

  1. Estimating the Burden of STIs Worldwide. In: World Health Organization. Policies and Programs on Secually Transmitted Infections: The gap between intent and action (1997) Available from: http://www.who.int/HIV_AIDS/STIgap/Chapter%201.html.
  2. Love Safely and Love Responsibly this Valentine’s Day, 14 February 2001. International Herpes Alliance Press Release. Available from: http:www.herpesalliance.org.
  3. Oliver L, Wald A, Kim M, et al. Seroprevalence of herpes simplex virus infections in a family medicine clinic. Arch Fam Med 4(3):228–32 (1995 Mar).
  4. Lafferty WE, Downey L, Celum C, Wald A. Herpes simplex virus type 1 as a cause of genital herpes: impact on surveillance and prevention. J Infect Dis 181(4):1454–7 (2000 Apr).
  5. Frequently Asked Questions about Genital Herpes. Centers for Disease Control National Center for HIV, STD and TB Prevention, Division of Sexually Transmitted Diseases. Available from: http://www.cdc.gov/nchstp/dstd/Fact_Sheets/facts_Genital_Herpes.htm.
  6. Q & As for Shingles and PHN. Varicella Zoster Virus Research Foundation. Available from: http://www.vzvfoundation.org/shinglesq&a.html and http://www.vzvfoundation.org/PHN.html.
  7. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med 123(2):89–96 (1995 Jul).
  8. Dworkin RH, Boon RJ, Griffin DR, Phung, D. Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis 178(Suppl 1):S76–80 (1998 Nov).
  9. Vere Hodge RA. Famciclovir and penciclovir: the mode of action of famciclovir, including its conversion to penciclovir. Antiviral Chem Chemother 4:67–84 (1993).
  10. Daniels S, Schentag JJ. Drug interaction studies and safety of famciclovir in healthy volunteers. Antiviral Chem Chemother 4:S57–64 (1993).
  11. Famuir® package insert. Novertis Pharmaceuticals, NJ, USA (2001).
  12. Sacks SL, Aoki FL, Diaz-Mitoma F, Sellors J, Shafran SD. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. JAMA 276(1):44–9 (1996 Jul).
  13. Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL. Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group. JAMA 280(10):887–92 (1998 Sep).
  14. Seiderer S, Scott S, Rousseau F, et al. Safe coadministration of famciclovir and zidovudine to HIV positive patients. Antiviral Res 26:A287 (1995).
  15. Romanowski B, Aoki FY, Martel AY, Lavender EA, Parsons JE, Saltzman RL. Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals. Collaborative Famciclovir HIV Study Group. AIDS 14(9):1211–7 (2000 Jun).
  16. Degreef H, Famciclovir Herpes Zoster Clinical Study Group. Famciclovir, a new oral antiherpes drug: results of the first controlled clinical study demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients. Int J Antimicrob Agents 4:241–246 (1994).
  17. Carrington D. Reducing the duration of zoster-associated pain with Famvir. Proceedings of the 1st European Congress of Chemotherapy, Glasgow, 1996; poster W114.
  18. Ashton R. Efficacy of once and twice daily famciclovir for the treatment of acute herpes zoster. Proceedings of the 1st European Congress of Chemotherapy, Glasgow, 1996; poster W107.
  19. Tyring S, Belanger R, Bezwoda W, et al. A randomized, double-blind trial of famciclovir versus acyclovir for the treatment of localized dermatomal herpes zoster in immunocompromised patients. Cancer Invest 19(1):13–22 (2001).

In this issue:

  1. Famciclovir Therapy (Famvir®) for Herpes Simplex and Herpes Zoster Infections
  2. Treatments for Chronic Palmoplantar Pustular Psoriasis
  3. Update on Drugs and Drug News - Number 12 2000