Famciclovir 500 mg Tablet, Film Coated, 30-count — NDC 60505-3247-3 (Billing 60505-3247-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Famciclovir is an orally administered prodrug of the anti-alpha herpes viral agent penciclovir [see Microbiology ( 12.4 )] .

12.3Pharmacokinetics Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir. Following oral administration famciclovir undergoes rapid and extensive metabolism to penciclovir and little or no famciclovir is detected in plasma or urine. Penciclovir is predominantly eliminated unchanged by the kidney.

Therefore, the dose of famciclovir tablets needs to be adjusted in patients with different degrees of renal impairment [see Dosage and Administration ( 2.3 )] . Pharmacokinetics in adults Absorption and Bioavailability The absolute bioavailability of penciclovir 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 1,000 mg administered as a single dose.

Table 5 shows the mean pharmacokinetic parameters of penciclovir after single administration of famciclovir to healthy male volunteers. Table 5 Mean Pharmacokinetic Parameters of Penciclovir in Healthy Adult Subjects* Dose AUC (0-inf ) † (mcg hr/mL) C max ‡ (mcg/mL) t max § (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 1,000 mg 17.9 6.6 0.9 *Based on pharmacokinetic data from 17 studies † AUC (0-inf) (mcg hr/mL)=area under the plasma concentration-time profile extrapolated to infinity. ‡ C max (mcg/mL)=maximum observed plasma concentration. §t t max (h)= time to C max .

Following oral single-dose administration of 500 mg famciclovir to 7 patients with herpes zoster, the AUC (mean ± SD), C max , and t max 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 2 groups.

There is no accumulation of penciclovir after the administration of 500 mg famciclovir three times daily for 7 days. Penciclovir C max decreased approximately 50% and t max 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 C max and a delay in t max 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, famciclovir tablets can be taken without regard to meals. Distribution The volume of distribution (Vdβ) 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 less than 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%, less than 0.5% and less than 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. Cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir in vivo [see Drug Interactions ( 7.2 )] . Elimination Approximately 94% of administered radioactivity w… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Famciclovir is an orally administered prodrug of the anti-alpha herpes viral agent penciclovir [see Microbiology ( 12.4 )] .

12.3Pharmacokinetics Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir. Following oral administration famciclovir undergoes rapid and extensive metabolism to penciclovir and little or no famciclovir is detected in plasma or urine. Penciclovir is predominantly eliminated unchanged by the kidney.

Therefore, the dose of famciclovir tablets needs to be adjusted in patients with different degrees of renal impairment [see Dosage and Administration ( 2.3 )] . Pharmacokinetics in adults Absorption and Bioavailability The absolute bioavailability of penciclovir 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 1,000 mg administered as a single dose.

Table 5 shows the mean pharmacokinetic parameters of penciclovir after single administration of famciclovir to healthy male volunteers. Table 5 Mean Pharmacokinetic Parameters of Penciclovir in Healthy Adult Subjects* Dose AUC (0-inf ) † (mcg hr/mL) C max ‡ (mcg/mL) t max § (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 1,000 mg 17.9 6.6 0.9 *Based on pharmacokinetic data from 17 studies † AUC (0-inf) (mcg hr/mL)=area under the plasma concentration-time profile extrapolated to infinity. ‡ C max (mcg/mL)=maximum observed plasma concentration. §t t max (h)= time to C max .

Following oral single-dose administration of 500 mg famciclovir to 7 patients with herpes zoster, the AUC (mean ± SD), C max , and t max 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 2 groups.

There is no accumulation of penciclovir after the administration of 500 mg famciclovir three times daily for 7 days. Penciclovir C max decreased approximately 50% and t max 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 C max and a delay in t max 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, famciclovir tablets can be taken without regard to meals. Distribution The volume of distribution (Vdβ) 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 less than 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%, less than 0.5% and less than 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. Cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir in vivo [see Drug Interactions ( 7.2 )] . 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 3… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Herpes Labialis (Cold Sores) A randomized, double-blind, placebo-controlled trial was conducted in 701 immunocompetent adults with recurrent herpes labialis. Patients self-initiated therapy within 1 hour of first onset of signs or symptoms of a recurrent herpes labialis episode with famciclovir tablets 1,500 mg as a single dose (n=227), famciclovir tablets 750 mg twice daily (n=220) or placebo (n=254) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.4 days in the famciclovir 1,500 mg single-dose group (n=152) as compared to 6.2 days in the placebo group (n=168).

The median difference in time to healing between the placebo and famciclovir tablets 1,500 mg treated groups was 1.3 days (95% CI: 0.6 to 2.0). No differences in proportion of patients with aborted lesions (not progressing beyond the papule stage) were observed between patients receiving famciclovir tablets or placebo: 33% for famciclovir tablets 1,500 mg single dose and 34% for placebo. The median time to loss of pain and tenderness was 1.7 days in famciclovir tablets 1,500 mg single dose-treated patients vs.

2.9days in placebo-treated patients.

14.2Genital Herpes Recurrent episodes A randomized, double-blind, placebo-controlled trial was conducted in 329 immunocompetent adults with recurrent genital herpes. Patients self-initiated therapy within 6 hours of the first sign or symptom of a recurrent genital herpes episode with either famciclovir tablets 1,000 mg twice daily (n=163) or placebo (n=166) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.3 days in famciclovir-treated patients (n=125) as compared to 6.1 days in placebo-treated patients (n=145).

The median difference in time to healing between the placebo and famciclovir-treated groups was 1.2 days (95% CI: 0.5 to 2.0). Twenty-three percent of famciclovir-treated patients had aborted lesions (no lesion development beyond erythema) vs. 13% in placebo-treated patients.

The median time to loss of all symptoms (e.g., tingling, itching, burning, pain, or tenderness) was 3.3 days in famciclovir-treated patients vs. 5.4 days in placebo-treated patients. A randomized (2:1), double-blind, placebo-controlled trial was conducted in 304 immunocompetent black and African American adults with recurrent genital herpes.

Patients self-initiated therapy within 6 hours of the first sign or symptom of a recurrent genital herpes episode with either famciclovir 1,000 mg twice daily (n=206) or placebo (n=98) for 1 day. The median time to healing among patients with non-aborted lesions was 5.4 days in famciclovir-treated patients (n=152) as compared to 4.8 days in placebo-treated patients (n=78). The median difference in time to healing between the placebo and famciclovir-treated groups was -0.26 days (95% CI: -0.98 to 0.40).

Suppressive therapy Two randomized, double-blind, placebo-controlled, 12-month trials were conducted in 934 immunocompetent adults with a history of 6 or more recurrences of genital herpes episodes per year. Comparisons included famciclovir tablets 125 mg three times daily, 250 mg twice daily, 250 mg three times daily, and placebo. At 12 months, 60% to 65% of patients were still receiving famciclovir tablets and 25% were receiving placebo treatment.

Recurrence rates at 6 and 12 months in patients treated with the 250 mg twice daily dose are shown in Table 8. Table 8 Recurrence Rates at 6 and 12 Months in Adults with Recurrent Genital Herpes on Suppressive Therapy Recurrence Rates at 6 Months Recurrence Rates at 12 Months Famciclovir 250 mg twice daily (n=236) Placebo (n=233) Famciclovir 250 mg twice daily (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 co… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year dietary carcinogenicity studies with famciclovir were conducted in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in animals of this strain) was seen in female rats receiving the high dose of 600 mg/kg/day (1.1 to 4.5x the human systemic exposure at the recommended total daily oral dose ranging between 500 mg and 2,000 mg, based on area under the plasma concentration curve comparisons [24 hr AUC] for penciclovir).

No increases in tumor incidence were reported in male rats treated at doses up to 240 mg/kg/day (0.7 to 2.7x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.3 to 1.2x the human AUC). Mutagenesis Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential in a battery of in vitro and in vivo assays. 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 (at doses up to 10,000 and 5,000 mcg/plate, respectively).

Famciclovir was also negative in the L5178Y mouse lymphoma assay (5,000 mcg/mL), the in vivo mouse micronucleus test (4,800 mg/kg), and rat dominant lethal study (5,000 mg/kg). Famciclovir induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage (1,200 mcg/mL). Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation (1,000 mcg/mL).

In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation (250 mcg/mL). Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow (500 mg/kg), but not when administered orally. Impairment of 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 to male reproduction was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of dosing at 500 mg/kg/day (1.4 to 5.7x the human AUC).

The no observable effect level for sperm and testicular toxicity in rats following chronic administration (26 weeks) was 50 mg/kg/day (0.15 to 0.6x the human systemic exposure based on AUC comparisons). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26 weeks) at doses of 600 mg/kg/day (0.3 to 1.2x the human AUC) and 150 mg/kg/day (1.3 to 5.1x the human AUC), respectively. Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1,000 mg/kg/day (2.7 to 10.8x the human AUC). .