Professional Information
Famciclovir (Systemic)
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VA CLASSIFICATION
Primary: AM820
Commonly used brand name(s): Famvir.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antiviral (systemic)—
Indications
Accepted
Herpes genitalis, recurrent episodes ( suppression 1 or treatment)—Famciclovir is indicated in the suppression or treatment of recurrent episodes of genital herpes {01}. Treatment of recurrent episodes is most effective when started within 6 hours of the onset of symptoms or lesions {01}.
Herpes simplex, HIV-associated (treatment)—Famciclovir is indicated in the treatment of recurrent mucocutaneous (orolabial and genital) herpes simplex infections in HIV-infected patients.{13}
Herpes zoster (treatment)—Famciclovir is indicated in the treatment of herpes zoster infections (shingles) caused by varicella-zoster virus (VZV) {01}. Famciclovir has been found to decrease the duration of post-herpetic neuralgia (defined as pain at or following healing) when compared to placebo (55 to 62 days versus 128 days, respectively). Famciclovir has also been found to be equivalent to acyclovir in decreasing the duration of acute pain {09}. Therapy is most effective when started within 48 hours of the onset of rash {01}.
Unaccepted
The efficacy of famciclovir has not been established in the treatment of initial episodes of genital herpes infection, ophthalmic zoster, disseminated zoster, or in immunocompromised patients with herpes zoster {01}{13}.
1 Not included in Canadian product labeling.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
321.3 {01}
Mechanism of action/Effect:
Famciclovir is a pro-drug; it is the diacetyl 6-deoxy analog of the active antiviral compound, penciclovir. Penciclovir is phosphorylated by viral thymidine kinase to penciclovir monophosphate, which is then converted to penciclovir triphosphate by cellular kinases. Penciclovir inhibits herpes viral DNA synthesis, and, therefore, replication. Penciclovir does not inhibit DNA synthesis in uninfected cells because it is phosphorylated only in herpes-infected cells. {01}
Penciclovir has antiviral activity against herpes simplex virus type 1 (HSV-1), HSV-2, varicella-zoster virus (VZV), and Epstein-Barr virus {01} {09}. In vitro studies have shown that penciclovir triphosphate has greater intracellular stability in HSV-2–infected cells than does acyclovir triphosphate {02}. Also, unlike acyclovir, the antiviral activity of penciclovir persists in the absence of extracellular drug {07} {10}.
Absorption:
Famciclovir is absorbed in the upper intestine and rapidly converted in the intestinal wall to the active compound, penciclovir {09}. The bioavailability of peniciclovir after oral administration of famciclovir is approximately 77% {01} {09}.
Famciclovir may be taken without regard to meals; although a decrease in the time to peak serum concentration and peak serum concentration of penciclovir was seen when famciclovir was taken with food or after a meal, there was no decrease in the extent of systemic availability {01} {03}.
Distribution:
The steady-state volume of distribution of penciclovir is approximately 1 liter per kilogram (L/kg) {01}.
Protein binding:
Low (20 to 25%) {01} {07}.
Biotransformation:
Famciclovir is deacetylated, and then oxidized to form the active agent, penciclovir {01} {10}. Little or no famciclovir is detected in the plasma or urine. Inactive metabolites include 6-deoxypenciclovir, monoacetylated penciclovir, and monoacetylated 6-deoxypenciclovir, all of which account for < 1.5% of the dose {01} {07}.
Half-life:
Normal renal function:
2.1 to 3 hours {01} {03} {04} {05} {06} {11}.
Severe renal failure (creatinine clearance < 30 mL/min [0.33 mL/sec]):
10 to 13 hours {01} {07}.
Intracellular half-life of penciclovir triphosphate:
In HSV-1–infected cells—Approximately 10 hours {01}.
In HSV-2–infected cells—Approximately 20 hours {01} {08}.
In VZV-infected cells—Approximately 7 hours {01} {08}.
Time to peak plasma concentration
0.7 to 0.9 hours {01} {03} {04} {05} {06} {11}.
Peak plasma concentration
3.3 to 4.2 mcg/mL [10.3 to 13.1 micromoles/L] after a single oral dose (fasting) of 500 mg {01} {03} {05} {06} {11}.
Elimination:
Renal (glomerular filtration and tubular secretion) {02}; 60 to 65% of an oral dose is recovered as penciclovir in the urine {03} {04} {05} {06} {11}; 27% in the feces over 72 hours {01}.
In dialysis—It is not known if hemodialysis removes penciclovir from the blood {01}.
Precautions to Consider
Carcinogenicity
Dietary carcinogenicity studies of famciclovir were conducted in rats and mice at the doses listed below for approximately 1.5 years. A significant increase in the incidence of mammary adenocarcinoma was seen in female rats receiving 600 mg per kg (mg/kg) per day (1.5 times the human systemic exposure at 500 mg three times a day, based on the area under the plasma concentration–time curve [AUC] for penciclovir). Marginal increases in the incidence of subcutaneous tissue fibrosarcomas or squamous cell carcinomas of the skin were seen in female rats and male mice dosed at 600 mg/kg per day (0.4 times the human exposure, based on AUC for penciclovir). There was no increase in tumor incidence reported in male rats treated with doses of up to 240 mg/kg per day (0.9 times the human AUC), or in female mice treated with doses of up to 600 mg/kg per day (0.4 times the human AUC). {01}
Mutagenicity
Famciclovir and penciclovir were negative in in vitro tests for gene mutations in bacteria ( S. typhimurium and E. coli ) and unscheduled DNA synthesis in mammalian HeLa 83 cells. Famciclovir was also negative in the L5178Y mouse lymphoma assay, the in vivo mouse micronucleus test, and rat dominant lethal study. Famciclovir induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage.
Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation. In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation. Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow, but not when administered orally. {01}
Pregnancy/Reproduction
Fertility—
Testicular toxicity was observed in rats, mice, and dogs following repeated administration of famciclovir or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm count, and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of dosing at 500 mg/kg per day (1.9 times the human AUC). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26 weeks) at doses of 600 mg/kg per day (0.4 times the human AUC) and 150 mg/kg per day (107 times the human AUC), respectively. {01}
Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg per day (3.6 times the human AUC). {01}
Pregnancy—
No adequate and well-controlled studies have been done in pregnant women. {01}
No adverse effects were observed on embryo-fetal development in rats and rabbits given oral famciclovir at doses of up to 1000 mg/kg per day (approximately 3.6 and 1.8 times the human exposure based on AUC, respectively), and intravenous doses of 360 mg/kg per day in rats (2 times the human exposure based on body surface area [BSA]) and 120 mg/kg per day in rabbits (1.5 times the human exposure based on BSA). Also, no adverse effects were observed after intravenous administration of penciclovir to rats given 80 mg/kg per day (0.4 times the human exposure based on BSA), and rabbits given 60 mg/kg per day (0.7 times the human exposure based on BSA){01}. Physicians are encouraged to register patients in the Famvir® Pregnancy Registry maintained by SmithKline Beecham by calling (800)366–8900, ext.5231{13}.
FDA Pregnancy Category B {01}.
Breast-feeding
Following oral administration of famciclovir, it is not known whether penciclovir is distributed into breast milk {01}.
However, it has been found to pass into the milk of lactating rats at concentrations higher than those seen in the plasma. Also, because of the tumorigenicity seen in rats, it is recommended that either breast-feeding or administration of famciclovir to the mother be discontinued. {01}
Pediatrics
Safety and efficacy have not been established in children up to 18 years of age {01}.
Geriatrics
Studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of famciclovir in the elderly. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment of famciclovir dosage or of dosing interval. {01} {04}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Probenecid{01} (probenecid may compete with penciclovir for active tubular secretion, resulting in increased plasma concentrations of penciclovir)
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problem exists
» Renal function impairment{01} (because penciclovir is renally excreted, patients with renal function impairment may be at increased risk of toxicity; patients with a creatinine clearance of < 60 mL/min [1 mL/sec] require a reduction in dose)
Side/Adverse Effects
Note: No serious side effects have been noted to date with the administration of famciclovir. {01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent {01}
Headache
Incidence less frequent {01}
Dizziness
fatigue (unusual tiredness or weakness)
gastrointestinal disturbances (diarrhea; nausea; vomiting)
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Famciclovir (Systemic) .
In providing consultation, consider» emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Breast-feeding—Because of the potential for tumorigenicity seen in rats, it is recommended that either breast-feeding or the use of famciclovir be discontinued
Use in children—Safety and efficacy have not been established in children up to 18 years of age
Other medical problems, especially renal function impairment
Proper use of this medication
Initiating use of famciclovir for herpes zoster at the earliest sign or symptom; it is most effective when started within 48 hours of the onset of rash
Initiating use of famciclovir for treatment of recurrent episodes of genital herpes at the earliest sign or symptom; it is most effective when started within 6 hours of the onset of symptoms or lesions
Famciclovir may be taken with meals
» Compliance with full course of therapy; not using more often or for longer than prescribed
» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses
» Proper storage
Precautions while using this medication
Checking with physician if no improvement within a few days
Keeping affected areas as clean and dry as possible; wearing loose-fitting clothing to avoid irritation of lesions
General Dosing Information
Therapy should be initiated as soon as possible following the onset of signs and symptoms of varicella-zoster infection. Treatment was started within 72 hours of the onset of rash in clinical studies; however, famciclovir was found to be more useful if started within 48 hours. {01}
For treatment of recurrent episodes of herpes genitalis, therapy should be initiated as soon as possible following the onset of signs and symptoms. Treatment was started within 6 hours of the onset of symptoms or lesions in clinical studies. {01}
For treatment of recurrent mucocutaneous herpes simplex infections in HIV-infected patients, treatment was started within 48 hours of lesion onset in efficacy studies. {13}
In clinical trials, the effect of famciclovir on the resolution of rash was most pronounced in patients over 50 years of age. {01}
Famciclovir tablets may be taken with meals since absorption has not been shown to be significantly affected by food. {01}
Oral Dosage Forms
FAMCICLOVIR TABLETS
Usual adult dose
Genital herpes, recurrent episodes (suppression)1
Oral, 250 mg two times a day for up to one year {01}.
Genital herpes, recurrent episodes (treatment)
Oral, 125 mg two times a day for five days {01}.
Herpes simplex, HIV-associated (treatment)
Oral, 500 mg two times a day for seven days {13}.
Herpes zoster (treatment)
Oral, 500 mg every eight hours for seven days {01}.
Note: Adults with impaired renal function may require a change in dosing as follows {01}{13}:
| Indication | Creatinine clearance (mL/min)/(mL/sec) |
Dosing regimen |
|---|---|---|
| Herpes zoster | ³ 60/1 | 500 mg every 8 hours |
| 40–59/0.67–0.98 | 500 mg every 12 hours |
|
| 20–39/0.33–0.65 | 500 mg every 24 hours |
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| < 20/0.33 | 250 mg every 24 hours |
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| Treatment of recurrent genital herpes | ³ 40/0.67 | 125 mg every 12 hours |
| 20–39/0.33–0.65 | 125 mg every 24 hours |
|
| < 20/0.33 | 125 mg every 24 hours |
|
| Treatment of recurrent mucocutaneous (orolabial and genital) herpes simplex in HIV-infected patients | ³ 40/0.67 | 500 mg every 12 hours |
| 20–39/0.33–0.65 | 500 mg every 24 hours |
|
| < 20/0.33 | 250 mg every 24 hours |
|
| Suppression of recurrent genital herpes | ³ 40/0.67 | 250 mg every 12 hours |
| 20–39/0.33–0.65 | 125 mg every 12 hours |
|
| < 20/0.33 | 125 mg every 24 hours |
|
| Hemodialysis patients | The recommended dose is 250 mg (herpes zoster or treatment of recurrent mucocutaneous (orolabial and genital) herpes simplex infections in HIV-infected patients) or 125 mg (treatment or suppression of recurrent genital herpes) administered after each dialysis session. | |
Usual pediatric dose
Safety and efficacy have not been established for patients up to 18 years of age. {01}
Strength(s) usually available
U.S.—
125 mg (Rx) [Famvir (lactose)]{01}
250 mg (Rx) [Famvir (lactose)]{01}
500 mg (Rx) [Famvir (lactose)]{01}
Canada—
125 mg (Rx) [Famvir (lactose)]{12}
250 mg (Rx) [Famvir (lactose)]{12}
500 mg (Rx) [Famvir (lactose)]{12}
Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F){13}, in a well-closed container, unless otherwise specified by manufacturer.
Auxiliary labeling:
• Continue medicine for full time of treatment.
Developed: 11/28/1994
Revised: 04/04/2000
References
- Famvir package insert (SmithKline Beecham—US), New 6/94, Rec 7/94; Rev 9/97, Rec 10/97.
- Fowles SE, Pierce DM, Prince WT, et al. The tolerance to and pharmacokinetics of penciclovir (BRL 39123A), a novel antiherpes agent, administered by intravenous infusion to healthy subjects. Eur J Clin Pharmacol 1992; 43: 513-6.
- Fowles SE, Pierce DM, Prince WT, et al. Effect of food on the bioavailability and pharmacokinetics of penciclovir, a novel antiherpes agent, following oral administration of the pro-drug, famciclovir [abstract]. Br J Clin Pharmacol 1990; 29(5): 620P-621P.
- Fowles SE, Pue MA, Peirce D, et al. Pharmacokinetics of penciclovir in healthy elderly subjects following a single oral administration of 750 mg famciclovir [abstract]. Br J Clin Pharmacol 1992; 34(5): 450P.
- Pratt SK, Fairless AJ, Pue MA, et al. Linearity of the pharmacokinetics of penciclovir following oral administration of famciclovir over the therapeutic dose range 125 to 750 mg [abstract]. Br J Clin Pharmacol 1993; 35(10): 80P-81P.
- Pratt SK, Pue MA, Fairless AJ, et al. Lack of an effect of gender on the pharmacokinetics of penciclovir following single oral doses of famciclovir [abstract]. Br J Clin Pharmacol 1994; 37(5): 493P.
- Boike SC, Pue MA, Freed MI, et al. Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment. Clin Pharmacol Ther 1994; 55: 418-26.
- Earnshaw DL, Bacon TH, Darlison SJ, et al. Mode of antiviral action of penciclovir in MRC-5 cells infected with herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus. Antimicrob Agents Chemother 1992; 36(12): 2747-57.
- Gnann JW. New antivirals with activity against varicella-zoster virus. Ann Neurol 1994; 35: S69-S74.
- Harrell AW, Wheeler SM, Pennick M, et al. Evidence that famciclovir (BRL 42810) and its associated metabolites do not inhibit the 6-beta-hydroxylation of testosterone in human liver microsomes. Drug Metab Dispos 1993; 21(1): 18-23.
- Pue MA, Pratt SK, Fairless AJ, et al. Linear pharmacokinetics of penciclovir following administration of single oral doses of famciclovir 125, 250, 500 and 750 mg to healthy volunteers. J Antimicrob Chemother 1994; 33: 119-27.
- Famciclovir (Famvir, SmithKline Beecham). In: CPS Compendium of pharmaceuticals and specialties. 32nd ed. Ottawa, Ontario, Canada: Canadian Pharmaceutical Association; 1997. p. 569-70.
- Product Information: Famvir®, famciclovir tablets. Physicians' Desk Reference (electronic version), MICROMEDEX, Inc, Englewood, CO, 2000.
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