Famciclovir: Package Insert and Label Information (Page 3 of 4)

12.4 Virology

Mechanism of action: Famciclovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown.

Antiviral activity: In cell culture studies, penciclovir is inhibitory to the following herpes viruses: HSV-1, HSV-2 and VZV. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV and 10 days postinfection for VZV. The median EC50 values of penciclovir against laboratory and clinical isolates of HSV-1, HSV-2, and VZV were 2 μM (range 1.2 to 2.4 μM, n = 7), 2.6 μM (range 1.6 to 11 μM, n = 6), and 34 μM (range 6.7 to 71 μM, n = 6), respectively.

Resistance: Penciclovir-resistant mutants of HSV and VZV can result from mutations in the viral thymidine kinase (TK) and DNA polymerase genes. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). The median EC50 values observed in a plaque reduction assay with penciclovir resistant HSV-1, HSV-2, and VZV were 69 μM (range 14 to 115 μM, n = 6), 46 μM (range 4 to > 395 μM, n = 9), and 92 μM (range 51 to 148 μM, n = 4), respectively. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.

Cross-resistance: Cross-resistance has been observed among HSV DNA polymerase inhibitors. The most commonly encountered acyclovir resistant mutants that are TK negative are also resistant to penciclovir.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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 4.5 x the human systemic exposure at the recommended total daily oral dose ranging between 500 mg and 2000 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 2.7 x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.3 to 1.2 x 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 (5000 mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat dominant lethal study (5000 mg/kg). Famciclovir induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage (1200 mcg/mL). Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation (1000 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 5.7 x 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 0.6 x 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 1.2 x the human AUC) and 150 mg/kg/day (1.3 to 5.1 x the human AUC), respectively.

Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg/day (2.7 to 10.8 x the human AUC).

Two placebo-controlled studies in a total of 130 otherwise healthy men with a normal sperm profile over an 8 week baseline period and recurrent genital herpes receiving oral famciclovir (250 mg twice daily) (n = 66) or placebo (n = 64) therapy for 18 weeks showed no evidence of significant effects on sperm count, motility or morphology during treatment or during an 8 week follow-up.

13.2 Animal Toxicology and/or Pharmacology

Juvenile toxicity study in rats: In juvenile rats, famciclovir was administered daily at doses of 0, 40, 125, or 400 mg/kg/day for 10 weeks beginning on post-partum Day 4. There were no treatment related deaths or clinical observations. The toxicity of famciclovir was not enhanced in juvenile rats compared to that in the adult animals.

14 CLINICAL STUDIES

14.1 Herpes 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 1500 mg as a single dose (n = 227), famciclovir 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 1500 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 1500 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 or placebo: 33% for famciclovir 1500 mg single dose and 34% for placebo. The median time to loss of pain and tenderness was 1.7 days in famciclovir 1500 mg single dose-treated patients versus 2.9 days in placebo-treated patients.

14.2 Genital 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 1000 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) versus 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 1000 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 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 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 6.

Table 6: 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%

Famciclovir-treated patients had approximately 1/5 the median number of recurrences as compared to placebo-treated patients. Higher doses of famciclovir were not associated with an increase in efficacy.

14.3 Recurrent Orolabial or Genital Herpes in HIV-Infected Patients

A randomized, double-blind trial 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 orolabial or genital herpes 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.

14.4 Herpes Zoster (Shingles)

Two randomized, double-blind trials, 1 placebo-controlled and 1 active-controlled, were conducted in 964 immunocompetent adults with uncomplicated herpes zoster. Treatment was initiated within 72 hours of first lesion appearance and was continued for 7 days.

In the placebo-controlled trial, 419 patients were treated with either famciclovir 500 mg three times daily (n = 138), famciclovir 750 mg three times daily (n = 135) or placebo (n = 146). The median time to full crusting was 5 days among famciclovir 500 mg-treated patients as 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 famciclovir 500 mg-treated patients than for placebo-treated patients in the overall study population. The effects of famciclovir were greater when therapy was initiated within 48 hours of rash onset; it was also more profound in patients 50 years of age or older. Among the 65.2% of patients with at least 1 positive viral culture, famciclovir 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 famciclovir- 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 developed postherpetic neuralgia, the median duration of postherpetic neuralgia was shorter in patients treated with famciclovir 500 mg than in those treated with placebo (63 days and 119 days, respectively). No additional efficacy was demonstrated with higher dose of famciclovir.

In the active-controlled trial, 545 patients were treated with one of three doses of famciclovir three times daily or with acyclovir 800 mg five times daily. 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 famciclovir and acyclovir-treated groups.

16 HOW SUPPLIED/STORAGE AND HANDLING

Famciclovir tablets are supplied as follows:

500 mg – White, capsule-shaped, film-coated tablets, debossed with “8119” on one side and “93” on the other side; available in

Bottles of 3 NDC 54868-5905-2
Bottles of 10 NDC 54868-5905-3
Bottles of 20 NDC 54868-5905-0
Bottles of 21 NDC 54868-5905-1
Bottles of 30 NDC 54868-5905-4

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Patient Information)

There is no evidence that famciclovir will affect the ability of a patient to drive or to use machines. However, patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking famciclovir should refrain from driving or operating machinery.

17.1 Herpes Labialis (Cold Sores)

Patients should be advised to initiate treatment at the earliest sign or symptom of a recurrence of cold sores (e.g., tingling, itching, burning, pain, or lesion). Patients should be instructed that treatment for cold sores should not exceed 1 dose. Patients should be informed that famciclovir is not a cure for cold sores.

17.2 Genital Herpes

Patients should be informed that famciclovir is not a cure for genital herpes. There are no data evaluating whether famciclovir will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices.

If episodic therapy for recurrent genital herpes is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.

There are no data on safety or effectiveness of chronic suppressive therapy of longer than one year duration.

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