Famciclovir

Famciclovir (INN) (pronounced /pɛnˈsaɪkloʊvɪr/) is a guanine analogue antiviral drug used for the treatment of various herpesvirus infections, most commonly for herpes zoster (shingles). It is a prodrug form of penciclovir with improved oral bioavailability. Famciclovir is marketed under the trade name Famvir (Novartis).

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Pharmacology

Pharmacokinetics

Absorption and Bioavailability: Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir. Following oral administration, little or no famciclovir is detected in plasma or urine.

The absolute bioavailability of famciclovir is 77± 8% as determined following the administration of a 500-mg famciclovir oral dose and a 400-mg penciclovir intravenous dose to 12 healthy male subjects.

Penciclovir concentrations increased in proportion to dose over a famciclovir dose range of 125 mg to 750 mg administered as a single dose. Single oral-dose administration of 125-mg, 250-mg or 500-mg famciclovir to healthy male volunteers across 17 studies gave the following pharmacokinetic parameters:

Table 2

Dose AUC (0-inf)† (mcg hr/mL) Cmax† (mcg/mL) Tmax§ (h) 125 mg 2.24 0.8 0.9 250 mg 4.48 1.6 0.9 500 mg 8.95 3.3 0.9

†AUC (0-inf) (mcg hr/mL)=area under the plasma concentration-time profile extrapolated to infinity. †Cmax (mcg/mL)=maximum observed plasma concentration. § Tmax (h)= time to Cmax.

Following single oral-dose administration of 500-mg famciclovir to seven patients with herpes zoster, the mean ± SD AUC, Cmax, and Tmax were 12.1± 1.7 mcg hr/mL, 4.0± 0.7 mcg/mL, and 0.7± 0.2 hours, respectively. The AUC of penciclovir was approximately 35% greater in patients with herpes zoster as compared to healthy volunteers. Some of this difference may be due to differences in renal function between the two groups.

There is no accumulation of penciclovir after the administration of 500-mg famciclovir t.i.d. for 7 days.

Penciclovir Cmax decreased approximately 50% and Tmax was delayed by 1.5 hours when a capsule formulation of famciclovir was administered with food (nutritional content was approximately 910 Kcal and 26% fat). There was no effect on the extent of availability (AUC) of penciclovir. There was an 18% decrease in Cmax and a delay in Tmax of about 1 hour when famciclovir was given 2 hours after a meal as compared to its administration 2 hours before a meal. Because there was no effect on the extent of systemic availability of penciclovir, it appears that Famvir® (famciclovir) can be taken without regard to meals.

Distribution: The volume of distribution (Vdb ) was 1.08± 0.17 L/kg in 12 healthy male subjects following a single intravenous dose of penciclovir at 400 mg administered as a 1-hour intravenous infusion.

Penciclovir is <20% bound to plasma proteins over the concentration range of 0.1 to 20 mcg/mL. The blood/plasma ratio of penciclovir is approximately 1.

Metabolism: Following oral administration, famciclovir is deacetylated and oxidized to form penciclovir. Metabolites that are inactive include 6-deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated penciclovir (5%, <0.5% and <0.5% of the dose in the urine, respectively). Little or no famciclovir is detected in plasma or urine.

An in vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in famciclovir metabolism. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase.

Elimination: Approximately 94% of administered radioactivity was recovered in urine over 24 hours (83% of the dose was excreted in the first 6 hours) after the administration of 5 mg/kg radiolabeled penciclovir as a 1-hour infusion to three healthy male volunteers. Penciclovir accounted for 91% of the radioactivity excreted in the urine.

Following the oral administration of a single 500-mg dose of radiolabeled famciclovir to three healthy male volunteers, 73% and 27% of administered radioactivity were recovered in urine and feces over 72 hours, respectively. Penciclovir accounted for 82% and 6-deoxy penciclovir accounted for 7% of the radioactivity excreted in the urine. Approximately 60% of the administered radiolabeled dose was collected in urine in the first 6 hours.

After intravenous administration of penciclovir in 48 healthy male volunteers, mean ± S.D. total plasma clearance of penciclovir was 36.6± 6.3 L/hr (0.48± 0.09 L/hr/kg). Penciclovir renal clearance accounted for 74.5± 8.8% of total plasma clearance.

Renal clearance of penciclovir following the oral administration of a single 500-mg dose of famciclovir to 109 healthy male volunteers was 27.7± 7.6 L/hr.

The plasma elimination half-life of penciclovir was 2.0± 0.3 hours after intravenous administration of penciclovir to 48 healthy male volunteers and 2.3± 0.4 hours after oral administration of 500-mg famciclovir to 124 healthy male volunteers. The half-life in seven patients with herpes zoster was 3.0± 1.1 hours.

HIV-Infected Patients: Following oral administration of a single dose of 500-mg famciclovir (the oral prodrug of penciclovir) to HIV-positive patients, the pharmacokinetic parameters of penciclovir were comparable to those observed in healthy subjects.

Renal Insufficiency: Apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function. After the administration of a single 500-mg famciclovir oral dose (n=27) to healthy volunteers and to volunteers with varying degrees of renal insufficiency (CLCR ranged from 6.4 to 138.8 mL/min.), the following results were obtained (Table 3):

Table 3

Parameter (mean ± S.D.) CLCR† =60 (mL/min.) (n=15) CLCR 40-59 (mL/min.) (n=5) CLCR 20-39 (mL/min.) (n=4) CLCR <20 (mL/min.) (n=3) CLCR (mL/min) 88.1 ± 20.6 49.3 ± 5.9 26.5 ± 5.3 12.7 ± 5.9 CLR (L/hr) 30.1 ± 10.6 13.0 ± 1.3† 4.2 ± 0.9 1.6 ± 1.0 CL/F§ (L/hr) 66.9 ± 27.5 27.3 ± 2.8 12.8 ± 1.3 5.8 ± 2.8 Half-life (hr) 2.3 ± 0.5 3.4 ± 0.7 6.2 ± 1.6 13.4 ± 10.2

† CLCR is measured creatinine clearance. † n=4. § CL/F consists of bioavailability factor and famciclovir to penciclovir conversion factor.

In a multiple-dose study of famciclovir conducted in subjects with varying degrees of renal impairment (n=18), the pharmacokinetics of penciclovir were comparable to those after single doses.

A dosage adjustment is recommended for patients with renal insufficiency (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: Well-compensated chronic liver disease (chronic hepatitis [n=6], chronic ethanol abuse [n=8], or primary biliary cirrhosis [n=1]) had no effect on the extent of availability (AUC) of penciclovir following a single dose of 500-mg famciclovir. However, there was a 44% decrease in penciclovir mean maximum plasma concentration and the time to maximum plasma concentration was increased by 0.75 hours in patients with hepatic insufficiency compared to normal volunteers. No dosage adjustment is recommended for patients with well-compensated hepatic impairment. The pharmacokinetics of penciclovir have not been evaluated in patients with severe uncompensated hepatic impairment.

Elderly Subjects: Based on cross-study comparisons, mean penciclovir AUC was 40% larger and penciclovir renal clearance was 22% lower after the oral administration of famciclovir in elderly volunteers (n=18, age 65 to 79 years) compared to younger volunteers. Some of this difference may be due to differences in renal function between the two groups.

Gender: The pharmacokinetics of penciclovir were evaluated in 18 healthy male and 18 healthy female volunteers after single-dose oral administration of 500-mg famciclovir. AUC of penciclovir was 9.3± 1.9 mcg hr/mL and 11.1± 2.1 mcg hr/mL in males and females, respectively. Penciclovir renal clearance was 28.5± 8.9 L/hr and 21.8± 4.3 L/hr, respectively. These differences were attributed to differences in renal function between the two groups. No famciclovir dosage adjustment based on gender is recommended.

Pediatric Patients: The pharmacokinetics of famciclovir or penciclovir have not been evaluated in patients <18 years of age.

Race: The pharmacokinetics of famciclovir or penciclovir with respect to race have not been evaluated.

Drug Interactions

Effects on penciclovir

No clinically significant alterations in penciclovir pharmacokinetics were observed following single-dose administration of 500-mg famciclovir after pre-treatment with multiple doses of allopurinol, cimetidine, theophylline, or zidovudine. No clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose (t.i.d.) administration of famciclovir (500 mg) with multiple doses of digoxin.

Effects of famciclovir on co-administered drugs

The steady-state pharmacokinetics of digoxin were not altered by concomitant administration of multiple doses of famciclovir (500 mg t.i.d.). No clinically significant effect on the pharmacokinetics of zidovudine or zidovudine glucuronide was observed following a single oral dose of 500-mg famciclovir.

CLINICAL TRIALS

Herpes Zoster

Famvir® (famciclovir) was studied in a placebo-controlled, double-blind trial of 419 immunocompetent adults with uncomplicated herpes zoster. Comparisons included Famvir 500 mg t.i.d., Famvir 750 mg t.i.d., or placebo. Treatment was begun within 72 hours of initial lesion appearance and therapy was continued for 7 days.

The median time to full crusting in Famvir-treated patients was 5 days 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 Famvir 500 mg-treated patients than for placebo-treated patients in the overall study population. The effects of Famvir were greater when therapy was initiated within 48 hours of rash onset; it was also more pronounced in patients 50 years of age or older. Among the 65.2% of patients with at least one positive viral culture, Famvir-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 Famvir- 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 did develop postherpetic neuralgia, the median duration of postherpetic neuralgia was shorter in patients treated with Famvir 500 mg than in those treated with placebo (63 days and 119 days, respectively). No additional efficacy was demonstrated with higher doses of Famvir.

A double-blind controlled trial in 545 immunocompetent adults with uncomplicated herpes zoster treated within 72 hours of initial lesion appearance compared three doses of Famvir to acyclovir 800 mg 5 times per day. 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 Famvir- and acyclovir-treated groups.

Herpes Simplex Infections

Recurrent Genital Herpes: In two placebo-controlled trials, 626 immunocompetent adults with a recurrence of genital herpes were treated with Famvir 125 mg b.i.d. (n=160), Famvir 250 mg b.i.d. (n=169), Famvir 500 mg b.i.d. (n=154) or placebo (n=143) for 5 days. Treatment was initiated within 6 hours of either symptom onset or lesion appearance. In the two studies combined, the median time to healing in Famvir 125 mg-treated patients was 4 days compared to 5 days in placebo-treated patients and the median time to cessation of viral shedding was 1.8 vs. 3.4 days in Famvir 125-mg and placebo-recipients, respectively. The median time to loss of all symptoms was 3.2 days in Famvir 125 mg-treated patients vs. 3.8 days in placebo-treated patients. No additional efficacy was demonstrated with higher doses of Famvir.

Suppression of Recurrent Genital Herpes: 934 immunocompetent adults with a history of 6 or more recurrences per year were randomized into two double-blind, 1-year, placebo-controlled trials. Comparisons included Famvir 125 mg t.i.d., 250 mg b.i.d., 250 mg t.i.d. and placebo. At one year, 60% to 65% of patients were still receiving Famvir and 25% were receiving placebo treatment. Patient reported recurrence rates for the 250 mg b.i.d. dose at 6 and 12 months are shown in Table 4.

Table 4

  Recurrence Rates

at 6 Months Recurrence Rates at 12 Months Famvir® 250 mg b.i.d. (n = 236) Placebo (n=233) Famvir® 250 mg b.i.d. (n=236) Placebo (n=233) Recurrence-free 39% 10% 29% 6% Recurrences† 47% 74% 53% 78% Lost to Follow-up† 14% 16% 17% 16%

† Based on patient reported data; not necessarily confirmed by a physician. † Patients recurrence-free at time of last contact prior to withdrawal.

Famvir-treated patients had approximately 1/5 the median number of recurrences as compared to placebo-treated patients.

Higher doses of Famvir were not associated with an increase in efficacy.

Recurrent Mucocutaneous Herpes Simplex Infection in HIV-Infected Patients: A randomized, double-blind, multicenter study compared famciclovir 500 mg twice daily for 7 days (n=150) with oral acyclovir 400 mg 5 times daily for 7 days (n=143) in HIV-infected patients with recurrent mucocutaneous HSV infection treated within 48 hours of lesion onset. Approximately 40% of patients had a CD4 count below 200 cells/mm3, 54% of patients had anogenital lesions and 35% had orolabial lesions. Famciclovir therapy was comparable to oral acyclovir in reducing new lesion formation and in time to complete healing.

Pharmacokinetics

Clinical use

Indications

Dosage forms

Famciclovir comes as a tablet to take by mouth. It is usually taken every 8 hours (three times a day) for 7 days to treat shingles. To treat genital herpes it is usually taken twice a day for 5 days.^[1] It is also sometimes given in one single large dose as opposed to several days of scheduled small doses. Among other side effects, Famciclovir may cause an upset stomach. Take famciclovir with food or milk.^[1]

Adverse effects

Side effects: mild to extreme stomach upset, headaches, mild fever.

See also

• Penciclovir