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Famciclovir (FAMVIR(R))

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Famciclovir (FAMVIR(R)) Infectious Diseases in Obstetrics and Gynecology 5:3-7 (1997) (C) 1997 Wiley-Liss, Inc. Famciclovir (FAMVIR(R)) Stephen L. Sacks* Department of Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada Viridae Clinical Sciences, Inc., Vancouver, British Columbia, Canada ABSTRACT Famciclovir is an antiviral with efficacy and safety comparable to aciclovir, but famciclovir's more favorable pharmacokinetic profile enables a less frequent dosing regimen. Future trials will likely determine famciclovir's role in the suppression of HBV. Infect. Dis. Obstet. Gynecol, 5:3-7, 1997. (C) 1997 Wiley-Liss, Inc. amciclovir (Famvir (R), SmithKlinc Beecham, firmed that, after oral dosing with famciclovir, more Crawley, UK) is a prodrug of the antiviral than half the dose is absorbed. nucleoside analog penciclovir. It is currently ap- proved worldwide for the treatment of varicella MECHANISM OF ACTION zoster (VCV) and herpes simplex virus (HSV-1 and Penciclovir freely enters both virus-infected and HSV-2) infections. Famciclovir is characterized by uninfected cells. However, antiherpesviral selectiv- its high rate of absorption and rapid conversion to ity relies on rapid phosphorylation to the active the active compound, penciclovir. In the U.S.., the form, penciclovir triphosphate, in virus-infected currently approved dosing regimen of famciclovir cells only. Viral thymidine kinase (TK) is respon- for the treatment of herpes zoster (shingles) is 500 sible for the critical rate-limiting initial phosphor- mg rid for 7 days; for recurrent genital herpes it is ylation to penciclovir monophosphate. Metabolism 125 mg bid for 5 days. This treatment is also ef- to the diphosphate and active triphosphate forms fective for treatment of first episode genital herpes occur via other cellular enzymes, z at a dose of 250 mg rid for 5 days and chronic Penciclovir triphosphate accumulates to high suppression of recurrences at a dose of 250 mg bid. concentrations in virus-infected cells and interacts However, the last two indications are still pending with viral DNA polymerase to inhibit viral DNA approval by U.S. regulatory authorities. synthesis. 3 Although penciclovir is phosphorylated in uninfected cells as well, conversion to penciclo- STRUCTURE AND DERIVATION vir monophosphate is much more readily achieved Famciclovir (2- [2-(2-amino-9H-purin-9-yl)ethyl]- by viral than by human TK. Thus, concentrations 1,3-propanediol diacetate) is the diacetyl ester of of penciclovir triphosphate remain low in unin- 6-deoxy penciclovir (a synthetic acyclic guanine fected cells and have minimal effect on human derivative). Whereas penciclovir itself is very DNA. z poorly absorbed orally, it was found in animal stud- ies that its dipropionyl and diacetyl 6-deoxy deriva- PHARMACOKINETICS tives (BRL 43599 and famciclovir, respectively) After oral administration, famciclovir undergoes gave much improved blood levels of penciclovir. rapid and extensive absorption in the upper intes- Furthermore, famciclovir was found to be much tine and is rapidly metabolized in the intestinal more stable than B RL 43599.1 Human studies con- wall and liver to the active compound penciclo- *Correspondence: Dr. Stephen L. Sacks, Viridae Clinical Sciences, Inc., 1134 Burrard Street, Vancouver, B.C. V6Z 1Y8, Canada. Received 15 November 1996 Antimicrobial Symposium Accepted 14 January 1997 FAMCICLOVIR (FAMVIR (R)) SACKS vir. 4,s Little or no famciclovir is detected in plasma of patients in both famciclovir and placebo groups. or urine. Inactive metabolites formed include 6- Serious adverse events were no more frequent than deoxy penciclovir, monoacetylated penciclovir, and placebo and none were classified as related to or 6-deoxy monoacetylated penciclovir. 6 Unlike aci- probably related to famciclovir. 7 clovir, which has a 10-20% bioavailability, 7 the bio- In a recent dose-finding trial of twice-daily oral availability of penciclovir after oral administration famciclovir for recurrent genital herpes, 19 there of famciclovir is about 77%. 4,8,9 Compared to aci- were no significant differences in adverse events or clovir, penciclovir is preferentially taken up and withdrawals between the famciclovir (125,250, and phosphorylated by HSV- and VZV-infected cells. 500 mg twice-daily) and placebo groups. Most fre- Furthermore, penciclovir triphosphate has a very quent adverse effects reported for both groups prolonged intracellular half-life in infected cells (7 were headache, nausea, and dizziness. to 20 hours versus 0.7 to hour for aciclovir tri- A recent double-blind placebo-controlled study phosphate), z Penciclovir is not metabolized but is in which 34 men with recurrent genital herpes re- eliminated unchanged in the urine. 1 ceived famciclovir 250 mg twice daily for 18 weeks The pharmacokinetics of penciclovir remain reported that famciclovir did not appear to have largely unaltered in the elderly, making it unnec- significant effects on any of the sperm parameters essary to adjust the dosage in these patients. TM measured, zo In a study of patients with renal impairment, No clinically significant alterations in penciclo- urinary excretion of pcnciclovir decreased in pro- vir pharmacokinetics were observed following portion to the decrease in estimated creatine clear- single-dose administration of 500 mg famciclovir ance leading to a recommendation that the dosage after pre-treatment with multiple doses of cimeti- interval of famciclovir should be prolonged from 8 dine, allopurinol, or theophylline. 6 hours to 12 hours for patients with moderate renal impairment, and to 24 hours for patients with se- SPECTRUM OF ANTIVIRAL ACTIVITY vere renal impairment. 13 There is no evidence for Famciclovir is effective against HSV-1, HSV-2, the need to alter dosage levels of famciclovir in VCV, and the Epstein-Barr virus (EBV). Penciclo- those with well-compensated hepatic impair- vir has also been shown to inhibit viral replication merit. 4 The pharmacokinetics of famciclovir have in vitro in duck hepatocytes infected with duck not been studied in patients with severe uncom- hepatitis B virus (HBV) z,za and famciclovir has pensated hepatic impairment. been shown to inhibit HBV replication in vivo in In three studies that investigated the effects of hepatic and nonhepatic tissue of ducklings that had food on the pharmacokinetics and bioavailability of been infected in ovo with duck HBV. zz famciclovir,S-17 no clinically significant differ- ences were observed in healthy male volunteers CLINICAL APPLICATIONS who received famciclovir (250 and 500 mg single Famciclovir is currently licensed to treat VZV her- doses) 30 minutes after food compared to those pes zoster (shingles) and HSV genital herpes infec- who received famciclovir 2 hours before food. tions. When famciclovir 250 mg was administered 30 Two large clinical trials evaluated famciclovir's minutes after food, Cma was reduced by only 20%. effect on rash healing of acute herpes zoster and control of acute pain. A prospective, randomized, SIDE EFFECTS AND INTERACTIONS placebo-controlled, double-blind trial evaluated Tolerability data from trials of famciclovir for the famciclovir (500 or 750 mg three times daily for 7 treatment of genital herpes and herpes zoster indi- days) in 419 intent-to-treat immunocompetent pa- cate that famciclovir is well tolerated with an ad- tients with herpes zoster rash. z3 Famciclovir accel- verse event profile similar to placebo. e'ls In an erated the healing of skin lesions (reduced times to analysis of several trials, side effects did not corre- full crusting and loss of vesicles, ulcers, and crusts) late with increasing daily dose over a range of 125 compared to those given placebo and significantly rag/day to 2,250 rag/day. The most frequent ad- reduced duration of viral shedding and pain. More verse events reported in this analysis were head- importantly, patients receiving famciclovir lost ache, nausea, and diarrhea, which occurred in >2% post-herpetic neuralgia (PHN; defined as pain per- 4 INFECTIOUS DISEASES 1N OBSTETRICS AND GYNECOLOGY FAMCICL0VIR (FAMVIR (R)) SACKS sisting after lesion healing) a median of approxi- TABLE I. Costs of selected antiviral agents mately 60 days sooner than those on placebo. (in U.S. dollars) A double-blind, double-dummy, randomized Tablets/ study compared the safety and efficacy of famci- Cost/ course of Cost of clovir (250, 500, or 750 mg three times a day) and Product Dose dose therapy therapy aciclovir (800 mg five times a day) for 7 days in 545 Zoster Famvir 500 mg tid/ immunocompetent patients with acute herpes zos- 7 days $4.92 21 $103.32 z4 ter. For the intent-to-treat population, all doses of Aciclovir 800 mg famciclovir were equally effective as aciclovir for 5x/day healing lesions and shortening the time to loss of 7 days: $3.41 35 $119.35 10 days: $3.41 50 $170.50 acute pain. With early treatment, there was ap- Valaciclovir 1000 mg proximately 1.5-1.8-fold acceleration in loss of pain tid/7 day $4.60 42 $96.60 over aciclovir, reinforcing the potential benefit of Recurrent GH Famciclovir 125 mg bid/ early treatment. 5 days $1.85 10 $18.50 To determine the efficacy and safety of famci- Aciclovir 200 mg clovir in the episodic treatment of recurrent genital 5x/day 5 $0.90 25 $22.50 herpes, a multicenter, randomized, double-blind, days 400 mg tid/ dose-ranging, patient-initiated study was con- 5 days $1.76 15 $26.40 ducted comparing three twice-daily doses (125, Valaciclovir 500 rng bid/ 250, and 500 mg) of oral famciclovir with placebo 5 days $2.30 tO $23.00 st 18 Episode over a 5-day period. Famciclovir at all doses was GH significantly more effective than placebo at 'reduc- Famciclovir ing time to healing, time to cessation of viral shed- (under FDA 250 mg tid/ review) 5 days $2.45 15 $36.75 ding, as well as durations of lesion edema, vesicles, Aciclovir 200 mg ulcer, and crusts. Times to cessation of all symp- 5x/day/ toms and of moderate to severe lesion tenderness, 10 days $0.90 50 $45.00 pain, and burning were also reduced.
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