Famciclovir

Famciclovir is a white to pale yellow solid. It is freely soluble in acetone and methanol, and sparingly soluble in ethanol and isopropanol. At 25°C famciclovir is freely soluble (>25% w/v) in water initially, but rapidly precipitates as the sparingly soluble (2% to 3% w/v) monohydrate. Famciclovir is not hygroscopic below 85% relative humidity. Partition coefficients are: octanol/water (pH 4.8) P=1.09 and octanol/phosphate buffer (pH 7.4) P=2.08.

Each Famciclovir Tablet for oral administration contains 125 mg, 250 mg or 500 mg of famciclovir, together with the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polydextrose, povidone, sodium starch glycolate, titanium dioxide, and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Famciclovir is an orally administered prodrug of the antiviral agent penciclovir [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

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 needs to be adjusted in patients with different degrees of renal impairment [see Dosage and Administration (2.3) ].

Pharmacokinetics in Adults

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 1000 mg administered as a single dose. Table 5 shows the mean pharmacokinetic parameters of penciclovir after single administration of famciclovir tablets to healthy male volunteers.

Table 5: Mean Pharmacokinetic Parameters of Penciclovir in Healthy Adult SubjectsBased on pharmacokinetic data from 17 studies

Dose	AUC (0-inf) AUC (0-inf) (mcg hr/mL)=area under the plasma concentration-time profile extrapolated to infinity. (mcg hr/mL)	Cmax C max (mcg/mL)=maximum observed plasma concentration (mcg/mL)	Tmax T max (h)=time to C 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
1000 mg	17.9	6.6	0.9

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.

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 <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.

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. 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)].

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. Active tubular secretion contributes to the renal elimination of penciclovir.

The plasma elimination half-life of penciclovir was 2±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.

Special Populations

Based on cross study comparison, penciclovir AUC was 40% higher and penciclovir renal clearance was 22% lower in elderly subjects (N=18, age 65 to 79 years) as compared with younger subjects. Some of this difference may be due to differences in renal function between the two groups. No famciclovir dosage adjustment based on age is recommended unless renal function is impaired [see Dosage and Administration (2.3), Use in Specific Populations (8.5)].

In subjects with varying degrees of renal impairment, apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function, after both single and repeated dosing [see Use in Specific Populations (8.6)]. A dosage adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3)].

Mild or moderate hepatic impairment had no effect on the extent of availability (AUC) of penciclovir [see Use in Specific Populations (8.7)]. No dosage adjustment is recommended for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of penciclovir has not been evaluated.

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

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.

A retrospective evaluation was performed to compare the pharmacokinetic parameters obtained in Black and Caucasian subjects after single and repeat once-daily, twice-daily, or three times-daily administration of famciclovir 500 mg. Data from a study in healthy volunteers (single dose), a study in subjects with varying degrees of renal impairment (single and repeat dose) and a study in subjects with hepatic impairment (single dose) did not indicate any significant differences in the pharmacokinetics of penciclovir between Black and Caucasian subjects.

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). In cells infected with HSV-1 and HSV-2, 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- and 20 hours in HSV-2-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 and HSV-2. 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. The median EC₅₀ values of penciclovir against laboratory and clinical isolates of HSV-1 and HSV-2 were 2 μM (range 1.2 to 2.4 μM, N=7), 2.6 μM (range 1.6 to 11 μM, N=6), respectively.

Resistance

Penciclovir-resistant mutants of HSV 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 and HSV-2 were 69 μM (range 14 to 115 μM, N=6) and 46 μM (range 4 to >395 μM, N=9), 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 4.5x 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 2.7x 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 (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 5.7x 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 1000 mg/kg/day (2.7 to 10.8x 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 tablets (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

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 tablets 1500 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 tablets 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 tablets 1500 mg treated groups was 1.3 days (95% CI: 0.6 to 2.). 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 1500 mg single dose and 34% for placebo. The median time to loss of pain and tenderness was 1.7 days in famciclovir tablets 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 tablets 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 tablets-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 tablets-treated groups was 1.2 days (95% CI: 0.5 to 2.0). Twenty-three percent of famciclovir tablets-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 tablets-treated patients vs. 5.4 days in placebo-treated patients.

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 6.

Famciclovir tablets-treated patients had approximately 1/5 the median number of recurrences as compared to placebo-treated patients. Higher doses of famciclovir tablets 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Famciclovir Tablets are supplied as tablets for oral administration. The 125 mg tablet is a round, white to off-white, film-coated, biconvex tablet, debossed with product identification "54 127" on one side and plain on the other side. The 250 mg tablet is a round, white to off-white, film-coated, biconvex tablet, debossed with product identification "54 315" on one side and plain on the other side. The 500 mg tablet is an oval, white to off-white, film-coated, biconvex tablet, debossed with product identification "54 225" on one side and plain on the other side.

0054-0196-13 125 mg, bottle of 30

0054-0197-13 250 mg, bottle of 30

0054-0198-13 500 mg, bottle of 30

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Patient Information)

There is no evidence that famciclovir tablets 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 tablets should refrain from driving or operating machinery.

Because famciclovir tablets contains lactose (famciclovir tablets 125 mg, 250 mg and 500 mg tablets contain lactose 37 mg, 74 mg and 148 mg, respectively), patients with rare hereditary problems of galactose intolerance, a severe lactase deficiency or glucose-galactose malabsorption should be advised to discuss with their healthcare provider before taking famciclovir tablets.

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 tablets are not a cure for cold sores.

17.2 Genital Herpes

Patients should be informed that famciclovir tablets are not a cure for genital herpes. There are no data evaluating whether famciclovir tablets 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.

Patient Information

Famciclovir Tablets

Read this Patient Information before you start taking famciclovir tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What are famciclovir tablets?

Famciclovir tablets are a prescription antiviral medicine used to:

• •treat outbreaks of cold sores (fever blisters) in healthy adults
• •treat outbreaks of genital herpes in healthy adults
• •decrease the number of outbreaks of genital herpes in healthy adults
• •treat outbreaks of herpes simplex lesions in or around the mouth, genitals, and anal area in people infected with HIV

It is not known if famciclovir tablets are safe and effective in children younger than 18 years of age.

Famciclovir is not a cure for herpes. It is not known if famciclovir tablets can stop the spread of herpes to others. If you are sexually active, you can pass herpes to your partner even if you are taking famciclovir tablets. Herpes can be transmitted even if you do not have active symptoms. You should continue to practice safer sex to lower the chances of spreading genital herpes to others. Do not have sexual contact with your partner during an outbreak of genital herpes or if you have any symptoms of genital herpes. Use a condom made of latex or polyurethane when you have a sexual contact. Ask your healthcare provider for more information about safer sex practices.

Who should not take famciclovir tablets?

Do not take famciclovir tablets if you are allergic to any of its ingredients or to penciclovir cream. See the end of this Patient Information leaflet for a complete list of ingredients in famciclovir tablets.

What should I tell my healthcare provider before taking famciclovir tablets?

Before you start taking famciclovir tablets, tell your healthcare provider if you:

• •have kidney or liver problems
• •have a rare genetic problem with galactose intolerance, a severe lactase deficiency or you do not absorb glucose-galactose (malabsorption)
• •are pregnant or planning to become pregnant. It is not known if famciclovir tablets will harm your unborn baby
• •are breast-feeding or plan to breast-feed.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take:

• •any other medicines and products you use to treat herpes outbreaks
• •probenecid (Probalan®*)

Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist every time you get a new medicine.

How should I take famciclovir tablets?

• •Take famciclovir tablets exactly as prescribed
• •Your healthcare provider will tell you how many famciclovir tablets to take and when to take them. Your dose of famciclovir tablets and how often you take it may be different depending on your condition
• •Famciclovir tablets can be taken with or without food
• •It is important for you to finish all of the medicine as prescribed, even if you begin to feel better
• •Your symptoms may continue even after you finish all of your famciclovir tablets. This does not mean that you need more medicine, since you have already finished a full course of famciclovir tablets and it will continue to work in your body. Talk to your healthcare provider if you have any questions about your condition and your treatment

What are the possible side effects of famciclovir tablets?

The most common side effects of famciclovir tablets include:

• •headache
• •nausea

Talk to your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of famciclovir tablets. Ask your healthcare provider or pharmacist for more information.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store famciclovir tablets?

• •Store famciclovir tablets at room temperature between 59° to 86°F (15° to 30°C.)

Keep famciclovir tablets and all medicines out of reach from children.

General information about famciclovir tablets

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use famciclovir tablets for a condition for which it was not prescribed. Do not give famciclovir tablets to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about famciclovir tablets. If you would like more information, talk with your healthcare provider. Your healthcare provider or pharmacist can give you information about famciclovir tablets that is written for health professionals. For more information, go to www.roxane.com or call 1-800-962-8364.

What are the ingredients in famciclovir tablets?

Active ingredient: famciclovir  

Inactive ingredients:  colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polydextrose, povidone, sodium starch glycolate, titanium dioxide, and triacetin.

*Probalan® is a registered trademark of Lannett Company, Inc.

10005663/05 Revised April 2013

©RLI, 2013

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

Roxane Laboratories, Inc.

Famciclovir Tablets, 125 mg

NDC 0054-0196-13