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Famciclovir: An overview

Famciclovir: An overview
Literature review current through: Jan 2024.
This topic last updated: Apr 29, 2022.

INTRODUCTION — Famciclovir is an oral prodrug that is converted by first-pass metabolism to the antiviral drug penciclovir [1,2].

MECHANISM OF ACTION — Penciclovir, upon intracellular uptake, is monophosphorylated by virally-encoded thymidine kinase and subsequently converted to a triphosphate by cellular enzymes. Penciclovir triphosphate preferentially inhibits the DNA polymerase of susceptible viruses; at clinically relevant levels, there is no substantial effect upon cellular DNA polymerase, thereby minimizing side effects to the host [2].

This mechanism is similar to that described for acyclovir; however, compared with acyclovir triphosphate, penciclovir triphosphate has a lower affinity for viral DNA polymerase but a longer intracellular half-life [2]. (See "Acyclovir: An overview".)

Spectrum of activity — Penciclovir is active against herpes simplex virus (HSV) types 1 and 2, and varicella zoster virus (VZV). Epstein-Barr virus is also susceptible in vitro [2].

Mechanism of resistance — The mechanisms of resistance to penciclovir are similar to those described for acyclovir [3]. Three mechanisms have been shown to endow herpes simplex viruses with resistance to acyclovir, a phenomenon rare in the immunocompetent host [4]:

Reduced or absent thymidine kinase

Altered thymidine kinase activity resulting in decreased acyclovir phosphorylation

Altered viral DNA polymerase with decreased affinity for acyclovir triphosphate

(See "Acyclovir: An overview", section on 'Mechanism of resistance'.)

Most acyclovir-resistant strains of HSV and VZV exhibit cross-resistance to penciclovir; reduced or absent viral thymidine kinase is the primary mechanism [2,5]. However, some acyclovir-resistant and foscarnet-resistant isolates remain susceptible to penciclovir. These strains demonstrate altered thymidine kinase and DNA polymerase substrate specificity [2,5,6].

BASIC PHARMACOKINETICS — Famciclovir is well absorbed, featuring an oral bioavailability of 77 percent [7]. Prompt first-pass metabolism in the intestine and liver results in conversion to penciclovir. A 500 mg dose of famciclovir yields peak penciclovir levels of 2.7 to 4 mg/L, with a plasma half-life of 2.1 to 2.7 hours. Food has no clinically important effect upon these levels [2].

A key feature of penciclovir is a prolonged intracellular half-life of penciclovir triphosphate: 10 to 20 hours in herpes simplex virus-infected cells, and 7 to 14 hours in varicella zoster virus-infected cells. In comparison, the intracellular half-life of acyclovir triphosphate is one hour or less [2]. As a result, famciclovir requires less frequent dosing.

Excretion is primarily renal, and dose reduction is recommended in patients with impaired renal function (creatinine clearance under 60 mL/min) [1,2]. Penciclovir is removed by hemodialysis [1]. Well-compensated chronic liver disease does not require dose modification, but pharmacokinetic studies in patients with poorly compensated hepatic insufficiency have not been performed [1].

TOXICITY — Famciclovir is very well tolerated, with a side effect profile similar to those of placebo and oral acyclovir, although long-term safety data are unavailable [1] (see "Acyclovir: An overview"). A review of over 1600 patients receiving famciclovir for herpes zoster or genital herpes revealed an adverse event profile not significantly different from placebo [8].

USE IN PREGNANCY — Available data from pharmacovigilance reports have found no association between famciclovir and increased risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal studies also suggest safety. In order to monitor the outcomes of pregnancies exposed to this drug, providers are encouraged to report cases to the Novartis Adverse Event reporting line at 1-888-NOW-NOVA (669-6682) [9].

USE DURING BREASTFEEDING — Animal studies show that penciclovir is present in the milk of lactating rats. However, no data are available regarding the presence of famciclovir or penciclovir in human breast milk, the impact of these drugs on milk production, or the safety of breastfed infants if the mother is taking famciclovir. Thus, the decision to use famciclovir in mothers who are breastfeeding must balance the benefits of breastfeeding with the mother's clinical need for famciclovir and the potential (albeit unknown) adverse effects on the breastfed infant [9].

USE OF FAMCICLOVIR IN IMMUNOCOMPETENT PATIENTS — Famciclovir is one possible treatment option for patients with acute herpes zoster [10,11] and those with primary and recurrent genital herpes infection [12-14]. The management and treatment of these infections is discussed elsewhere. (See "Treatment of herpes zoster" and "Treatment of genital herpes simplex virus infection".)

USE OF FAMCICLOVIR IN IMMUNOCOMPROMISED PATIENTS — Famciclovir is one potential treatment option for herpes zoster and primary and recurrent genital herpes in immunocompromised patients [14-16]. The approach to the treatment of genital herpes infections in the HIV-infected host is discussed elsewhere. (See "Treatment of drug-resistant genital herpes simplex virus infection in patients with HIV".)

SUMMARY AND RECOMMENDATIONS

Famciclovir is an oral prodrug which is converted by first-pass metabolism to the antiviral drug penciclovir. (See 'Introduction' above.)

Upon intracellular uptake, penciclovir is mono-phosphorylated by virally-encoded thymidine kinase and subsequently converted to a triphosphate by cellular enzymes. Penciclovir triphosphate preferentially inhibits the DNA polymerase of susceptible viruses. At clinically relevant levels, there is no substantial effect upon cellular DNA polymerase, thereby minimizing side effects to the host. (See 'Mechanism of action' above.)

Penciclovir is active against herpes simplex virus (HSV) types 1 and 2, and varicella-zoster virus (VZV). (See 'Spectrum of activity' above.)

The mechanisms of resistance to penciclovir are similar to those described for acyclovir. Most acyclovir-resistant strains of HSV and VZV exhibit cross-resistance to penciclovir. Resistance is rarely seen among immunocompetent hosts but has been well-documented in immunocompromised hosts, such as transplant recipients and HIV-infected patients. (See 'Mechanism of resistance' above.)

A key feature of penciclovir is a prolonged intracellular half-life of penciclovir triphosphate: 10 to 20 hours in HSV-infected cells, and 7 to 14 hours in VZV-infected cells. In comparison, the intracellular half-life of acyclovir triphosphate is one hour or less. As a result, famciclovir requires less frequent dosing. (See 'Basic pharmacokinetics' above.)

Excretion is primarily renal, and dose reduction is recommended in patients with impaired renal function (creatinine clearance under 60 mL/min). (See 'Basic pharmacokinetics' above.)

Famciclovir is very well tolerated, with a side effect profile similar to that of placebo, although long-term safety data are unavailable. (See 'Toxicity' above.)

  1. Famvir (famciclovir) prescribing information. SmithKline Beecham, 1997.
  2. Perry CM, Wagstaff AJ. Famciclovir. A review of its pharmacological properties and therapeutic efficacy in herpesvirus infections. Drugs 1995; 50:396.
  3. Drugs for non-HIV viral infections. Treat Guidel Med Lett 2007; 5:59.
  4. Chatis PA, Crumpacker CS. Resistance of herpesviruses to antiviral drugs. Antimicrob Agents Chemother 1992; 36:1589.
  5. Boyd MR, Safrin S, Kern ER. Penciclovir: A review of its spectrum of activity, selectivity, and cross-resistance pattern. Antiviral Chem Chemother 1993; 4(Suppl 1):3.
  6. Safrin S, Phan L. In vitro activity of penciclovir against clinical isolates of acyclovir-resistant and foscarnet-resistant herpes simplex virus. Antimicrob Agents Chemother 1993; 37:2241.
  7. Vere Hodge RA. Famciclovir and penciclovir: The mode of action of famciclovir including its conversion to penciclovir. Antiviral Chem Chemother 1993; 4:67.
  8. Saltzman R, Jurewicz R, Boon R. Safety of famciclovir in patients with herpes zoster and genital herpes. Antimicrob Agents Chemother 1994; 38:2454.
  9. US Food and Drug Administration. Highlights of prescribing information: Famvir (famciclovir). https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020363s050lbl.pdf (Accessed on March 25, 2019).
  10. 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 1995; 123:89.
  11. Boon RJ, Griffin DR. Efficacy of famciclovir in the treatment of herpes zoster: reduction of pain associated with zoster. Neurology 1995; 45:S76.
  12. Loveless M, Sacks SL, Harris JRW. Famciclovir in the management of first-episode genital herpes. IDCP 1997; 6:S12.
  13. Sacks SL, Aoki FY, Diaz-Mitoma F, et al. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. JAMA 1996; 276:44.
  14. Sacks SL. Management of recurrent genital herpes — episodic therapy with famciclovir. IDCP 1997; 6:S5.
  15. Frechette G, Romanowski B. Efficacy and safety of famciclovir for the treatment of HSV infection in HIV+ patients. Can J Infect Dis 1997; 8:44A.
  16. Schacker T, Hu HL, Koelle DM, et al. Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial. Ann Intern Med 1998; 128:21.
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