FAMVIR - famciclovir tablet, film coated 
Novartis Pharmaceuticals Corporation

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use FAMVIR safely and effectively. See full prescribing information for FAMVIR.
FAMVIR® (famciclovir) Tablets
Initial U.S. Approval: 1994


RECENT MAJOR CHANGES

Adverse Reactions (6.2)                         06/2009

Use in Specific Population (8.4)                         06/2009

Clinical Pharmacology (12.3)                         06/2009

Clinical Studies (14.5)                         06/2009


INDICATIONS AND USAGE

FAMVIR, a prodrug of penciclovir, is a nucleoside analogue DNA polymerase inhibitor indicated for:

Adult Patients (1.1)

  • Herpes Labialis (Cold Sores): treatment of recurrent herpes labialis in immunocompetent adults
  • Genital Herpes
    • Recurrent Episodes: treatment of recurrent episodes of genital herpes in immunocompetent adults
    • Suppressive Therapy: chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent adults

  • Mucocutaneous herpes simplex virus infections in HIV-infected patients
  • Herpes Zoster (Shingles)

DOSAGE AND ADMINISTRATION

Adult Dosage (2.1)
Herpes Labialis (Cold Sores) in immunocompetent adults1500 mg as a single dose
Herpes Labialis (Cold Sores) in HIV-infected adults500 mg twice daily for 7 days
Genital Herpes – Recurrent Episodes in immunocompetent adults1000 mg twice daily for 1 day
Genital Herpes – Recurrent Episodes in HIV-infected adults500 mg twice daily for 7 days
Genital Herpes – Suppressive Therapy 250 mg twice daily
Mucocutaneous herpes simplex virus infections in HIV-infected patients500 mg twice daily for 7 days
Herpes Zoster (Shingles)500 mg every 8 hours for 7 days

Dosage recommendations for adult patients with reduced renal function are provided in Table 1. (2.2)


DOSAGE FORMS AND STRENGTHS

Tablets: 125 mg, 250 mg, 500 mg (3)


CONTRAINDICATIONS

Known hypersensitivity to the product, its components, or Denavir® (penciclovir cream) (4)


WARNINGS AND PRECAUTIONS

Dosage adjustment is recommended when administering FAMVIR to patients with creatinine clearance values <60 mL/min. (5.1)


ADVERSE REACTIONS

The most common adverse events reported in at least one indication by >10% of adult patients are headache and nausea. (6.1)



To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


DRUG INTERACTIONS

  • Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir. (5.2, 7)
  • Raloxifene, a potent aldehyde oxidase inhibitor in vitro, could decrease the formation of penciclovir. (7)


See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 07/2009

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

1  INDICATIONS AND USAGE

1.1 Adult Patients

1.2 Limitation of use

2  DOSAGE AND ADMINISTRATION

2.1 Adult Dosing Recommendation 

2.2 Patients with Reduced Renal Function

3  DOSAGE FORMS AND STRENGTHS

4  CONTRAINDICATIONS

5  WARNINGS AND PRECAUTIONS

5.1 General 

5.2 Drug interactions

6  ADVERSE REACTIONS 

6.1 Clinical Trials Experience in Adult Patients 

6.2 Clinical Trials Experience in Pediatric Patients 

6.3 Postmarketing Experience 

7  DRUG INTERACTIONS

8  USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 

8.3 Nursing mothers 

8.4 Pediatric use

8.5 Geriatric use

8.6 Renal Insufficiency

8.7 Hepatic Insufficiency

10  OVERDOSAGE

11  DESCRIPTION

12  CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal toxicology: Juvenile toxicity study in rats

14 CLINICAL STUDIES

14.1 Herpes Labialis (Cold Sores)

14.2 Genital Herpes

14.3 Mucocutaneous herpes simplex virus infections in HIV-infected patients

14.4 Herpes Zoster (Shingles)

14.5 Pediatric Studies

16  HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Herpes Labialis (Cold Sores)

17.2 Genital Herpes

17.3 Herpes Zoster (Shingles)

FDA-APPROVED PATIENT LABELING

PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL


FULL PRESCRIBING INFORMATION

1  INDICATIONS AND USAGE

1.1 Adult Patients

Herpes Labialis (Cold Sores): FAMVIR is indicated for the treatment of recurrent herpes labialis in immunocompetent adults.

Genital Herpes: Recurrent Episodes: FAMVIR is indicated for the treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of FAMVIR when initiated more than 6 hours after onset of symptoms or lesions has not been established.

Suppressive Therapy: FAMVIR is indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent adults. The efficacy and safety of FAMVIR for the suppression of recurrent genital herpes beyond 1 year have not been established.

Mucocutaneous herpes simplex virus infections in HIV-infected patients: FAMVIR is indicated for the treatment of recurrent mucocutaneous herpes simplex virus infections in HIV-infected adults.

Herpes Zoster (Shingles): FAMVIR is indicated for the treatment of herpes zoster. The efficacy of FAMVIR when initiated more than 72 hours after rash onset has not been established.      

1.2 Limitation of use

The efficacy of FAMVIR has not been established in patients <18 years of age.      

2  DOSAGE AND ADMINISTRATION

FAMVIR may be taken without regard to food.

2.1 Adult Dosing Recommendation 

Herpes Labialis (Cold Sores): The recommended dosage of FAMVIR for the treatment of recurrent herpes labialis in immunocompetent adults is 1500 mg as a single dose. In HIV-infected patients the recommended dosage is 500 mg twice daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes labialis (e.g. tingling, itching, burning, pain, or lesion).

Genital Herpes: Recurrent Episodes: The recommended dosage of FAMVIR for the treatment of recurrent episodes of genital herpes in immunocompetent adults is 1000 mg twice daily for 1 day. In HIV-infected patients the recommended dosage is 500 mg twice daily for 7 days. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g. tingling, itching, burning, pain, or lesion).

Suppressive Therapy: The recommended dosage of FAMVIR for chronic suppressive therapy of recurrent episodes of genital herpes is 250 mg twice daily.

Mucocutaneous herpes simplex virus infections in HIV-infected patients: The recommended dosage of FAMVIR for the treatment of recurrent mucocutaneous herpes simplex virus infections in HIV-infected patients is 500 mg twice daily for 7 days. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g. tingling, itching, burning, pain, or lesion).

Herpes Zoster (Shingles): The recommended dosage of FAMVIR for the treatment of herpes zoster is 500 mg every 8 hours for 7 days. Therapy should be initiated promptly as soon as herpes zoster is diagnosed.

2.2 Patients with Reduced Renal Function

Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 

Table1 Dosage Recommendations for Adult Patients with Reduced Renal Function
Indication and Normal Dosage
Regimen
Creatinine Clearance
(mL/min.)
Adjusted Dosage
Regimen Dose (mg)
Dosing Interval
Single-Day Dosing Regimens
Recurrent Genital Herpes
1000 mg every 12 hours for 1 day
≥601000every 12 hours for 1 day
40-59500every 12 hours for 1 day
20-39500single dose
<20250single dose
HD*250single dose following
dialysis
Recurrent Herpes Labialis
1500 mg single dose
≥601500single dose
40-59750single dose
20-39500single dose
<20250single dose
HD*250single dose following
dialysis
Multiple-Day Dosing Regimens
Herpes Zoster
500 mg every 8 hours
≥60500every 8 hours
40-59500every 12 hours
20-39500every 24 hours
<20250every 24 hours
HD*250following each dialysis
Suppression of Recurrent
Genital Herpes
250 mg every 12 hours
≥40250every 12 hours
20-39125every 12 hours
<20125every 24 hours
HD*125following each dialysis
Recurrent Orolabial
and Genital Herpes
Simplex Infection in
HIV-Infected Patients
500 mg every 12 hours
≥40500every 12 hours
20-39500every 24 hours
<20250every 24 hours
HD*250following each dialysis

*Hemodialysis

3  DOSAGE FORMS AND STRENGTHS

FAMVIR Tablets are available in three strengths:

4  CONTRAINDICATIONS

FAMVIR is contraindicated in patients with known hypersensitivity to the product, its components, or Denavir® (penciclovir cream).

5  WARNINGS AND PRECAUTIONS

5.1 General 

The efficacy of FAMVIR has not been established for initial episode genital herpes infection, ophthalmic zoster, disseminated zoster or in immunocompromised patients with herpes zoster.

Dosage adjustment is recommended when administering FAMVIR to patients with creatinine clearance values <60 mL/min. [see Dosage and Administration (2.2)]. In patients with underlying renal disease who have received inappropriately high doses of FAMVIR for their level of renal function, acute renal failure has been reported.

FAMVIR 125 mg, 250 mg and 500 mg tablets contain lactose (26.9 mg, 53.7 mg and 107.4 mg, respectively). Patients with rare hereditary problems of galactose intolerance, a severe lactase deficiency or glucose-galactose malabsorption should not take FAMVIR 125 mg, 250 mg and 500 mg tablets.

5.2 Drug interactions

Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir.

The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme and/or inhibiting this enzyme could potentially occur [see Drug Interactions (7)].

6  ADVERSE REACTIONS 

The most common adverse events reported in at least 1 indication by >10% of adult patients treated with FAMVIR are headache and nausea.

6.1 Clinical Trials Experience in Adult Patients 

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Immunocompetent Patients: The safety of FAMVIR has been evaluated in clinical studies involving 816 FAMVIR-treated patients with herpes zoster (FAMVIR, 250 mg three times daily to 750 mg three times daily); 163 FAMVIR-treated patients with recurrent genital herpes (FAMVIR, 1000 mg twice daily); 1,197 patients with recurrent genital herpes treated with FAMVIR as suppressive therapy (125 mg once daily to 250 mg three times daily) of which 570 patients received FAMVIR (open-labeled and/or double-blind) for at least 10 months; and 447 FAMVIR-treated patients with herpes labialis (FAMVIR, 1500 mg once or 750 mg twice daily). Table 2 lists selected adverse events.

Table 2 Selected Adverse Events (all grades and without regard to causality) Reported by ≥2% of Patients in Placebo-controlled Famvir Trials*
Incidence
Herpes ZosterRecurrent
Genital Herpes
Genital Herpes-
Suppression§
Herpes Labialis
Famvir®PlaceboFamvir®PlaceboFamvir®PlaceboFamvir®Placebo
500 mg1 gram250 mg1500 mg
three times daily*twice daily*twice daily*single dose*
(n=273)(n=146)(n=163)(n=166)(n=458)(n=63)(n=227)(n=254)
Events%%%%%%%%
Nervous System
 Headache22.717.813.55.439.342.99.76.7
 Paresthesia2.60.00.00.00.90.00.00.0
 Migraine0.70.70.60.63.10.00.00.0
Gastrointestinal
Nausea12.511.62.53.67.29.52.23.9
 Diarrhea7.74.84.91.29.09.51.80.8
Vomiting4.83.41.20.63.11.60.00.0
Flatulence1.50.70.60.04.81.60.00.0
 Abdominal Pain1.13.40.01.27.97.90.00.4
Body as a Whole
Fatigue4.43.40.60.04.83.21.30.4
Skin and Appendages
 Pruritus3.72.70.00.62.20.00.00.0
 Rash0.40.70.00.03.31.60.00.0
Reproductive Female
 Dysmenorrhea0.00.71.80.67.66.30.90.0

*Patients may have entered into more than one clinical trial.

7 days of treatment

1 day of treatment

§daily treatment

Table 3 lists selected laboratory abnormalities in genital herpes suppression trials.

Table 3        Selected Laboratory Abnormalities in Genital Herpes Suppression Studies*
ParameterFamvir®
(n = 660)
%
Placebo
(n = 210)
%
Anemia (<0.8 x NRL)0.10.0
Leukopenia (<0.75 x NRL)1.30.9
Neutropenia (<0.8 x NRL)3.21.5
AST (SGOT) (>2 x NRH)2.31.2
ALT (SGPT) (>2 x NRH)3.21.5
Total Bilirubin (>1.5 x NRH)1.91.2
Serum Creatinine (>1.5 x NRH)0.20.3
Amylase (>1.5 x NRH)1.51.9
Lipase (>1.5 x NRH)4.94.7

*Percentage of patients with laboratory abnormalities that were increased or decreased from baseline and were outside of specified ranges.

n values represent the minimum number of patients assessed for each laboratory parameter.

NRH = Normal Range High.

NRL = Normal Range Low.

HIV-infected Patients: In HIV-infected patients, the most frequently reported adverse events for FAMVIR (500 mg twice daily; n=150) and acyclovir (400 mg, 5x/day; n=143), respectively, were headache (16.7% vs. 15.4%), nausea (10.7% vs. 12.6%), diarrhea (6.7% vs. 10.5%), vomiting (4.7% vs. 3.5%), fatigue (4.0% vs. 2.1%), and abdominal pain (3.3% vs. 5.6%).

6.2 Clinical Trials Experience in Pediatric Patients 

The safety profile of FAMVIR has been studied in 169 pediatric patients 1 month to ≤12 years of age. One hundred of these pediatric patients, 1 to ≤12 years of age, were treated with FAMVIR experimental formulation (oral granules) either twice (47 patients with herpes simplex virus infections) or three times (53 patients with chicken pox) daily for 7 days. The remaining 69 pediatric patients, 1 month to ≤12 years of age, participated in single-dose pharmacokinetic and safety studies using the experimental oral granules. The frequency, intensity, and nature of clinical adverse events and laboratory abnormalities were similar to those seen in adults.

Pediatric Patients 1 to ≤12 Years of Age (Multiple-dose Safety): Adverse events reported in >2% of 100 patients receiving FAMVIR either twice daily (n = 47) or three time daily (n = 53) for 7 days included diarrhea (10%), vomiting (10%), headache (6%), pyrexia (6%), nausea (5%), upper abdominal pain (3%), cough (3%), and pruritus (3%).

Pediatric Patients 1 Month to ≤12 Years of Age (Single-dose Safety): Adverse events reported in more than 1 subject across the single-dose pharmacokinetic and safety studies in 69 pediatric patients 1 month to ≤12 years of age were vomiting (4%), diarrhea (3%), pyrexia (3%), and dehydration (3%).

6.3 Postmarketing Experience 

The adverse reactions listed below have been reported during post-approval use of FAMVIR. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: urticaria, serious skin reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), cholestatic jaundice, abnormal liver function tests, thrombocytopenia, hallucinations, dizziness, somnolence and confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly).

7  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, zidovudine, promethazine, when given shortly after an antacid (magnesium and aluminum hydroxide), or concomitantly with emtricitabine. No clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose (three times daily) administration of famciclovir (500 mg) with multiple doses of digoxin.

Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir [see Warnings and Precautions (5.2)].

The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme and/or inhibiting this enzyme could potentially occur. Clinical interaction studies of famciclovir with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir. Raloxifene, a potent aldehyde oxidase inhibitor in vitro, could decrease the formation of penciclovir. However, a clinical drug-drug interaction study to determine the magnitude of interaction between penciclovir and raloxifene has not been conducted [see Warnings and Precautions (5.2)].

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 three times daily). No clinically significant effect on the pharmacokinetics of zidovudine, its metabolite zidovudine glucuronide or emtricitabine was observed following a single oral dose of 500 mg famciclovir co-administered with zidovudine or emtricitabine.

An in vitro study using human liver microsomes suggests that famciclovir is not an inhibitor of CYP3A4 enzymes.

8  USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 

Teratogenic Effects–Pregnancy Category B

Famciclovir was tested for effects on embryo-fetal development in rats and rabbits at oral doses up to 1000 mg/kg/day (approximately 2.7 to 10.8x and 1.4 to 5.4x the human systemic exposure to penciclovir based on AUC comparisons for the rat and rabbit, respectively) and intravenous doses of 360 mg/kg/day in rats (1.5 to 6x the human dose based on body surface area [BSA] comparisons) or 120 mg/kg/day in rabbits (1.1 to 4.5x the human dose [BSA]). No adverse effects were observed on embryo-fetal development. Similarly, no adverse effects were observed following intravenous administration of penciclovir to rats (80 mg/kg/day, 0.3 to 1.3x the human dose [BSA]) or rabbits (60 mg/kg/day, 0.5 to 2.1x the human dose [BSA]). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, famciclovir should be used during pregnancy only if the benefit to the patient clearly exceeds the potential risk to the fetus.

Pregnancy Exposure Reporting

To monitor maternal-fetal outcomes of pregnant women exposed to FAMVIR, Novartis Pharmaceuticals Corporation maintains a FAMVIR Pregnancy Reporting system. Physicians are encouraged to report their patients by calling 1-888-669-6682.

8.3 Nursing mothers 

Following oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. It is not known whether it is excreted in human milk. There are no data on the safety of FAMVIR in infants. Famciclovir should not be used in nursing mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment.

8.4 Pediatric use

Efficacy in children under the age of 18 years has not been established.

Penciclovir pharmacokinetics have been evaluated in a total of 68 pediatric patients 1 month to ≤12 years of age following single dose administration of FAMVIR (experimental oral granules mixed with OraSweet®). Doses were based on patient’s body weight and ranged from 25 mg (up to a body weight of 5.4 kg) to 500 mg (body weight ≥40 kg), in steps of 25 mg. Doses in mg/kg and pharmacokinetic parameters are provided in Table 4 by age cohort. In the patients 6 months to ≤12 years of age, the average systemic exposure to penciclovir was similar or slightly lower than in adults receiving a 500 mg dose of famciclovir (adult AUC=8.95 mcg•hr/mL, adult Cmax=3.3 mcg/mL, [see Clinical Pharmacology (12.3)]. In the patients 1 month to <6 months of age, with the doses used in this study, AUC and Cmax of penciclovir were about 3- to 5-fold lower than in adults receiving a 500 mg dose of famciclovir. Higher doses of famciclovir have not been studied in pediatric patients. 

Table 4 Penciclovir Exposure (mean (± SD)) in Pediatric Patients Following a Single Dose of Famciclovir Adjusted According to Patient’s Body Weight
Study in pediatric patients 1 to ≤12 months of ageStudies in pediatric patients 1 to ≤12 years of age
Age cohort1 to <3 months
(n=7)
3 to <6 months
(n=5)
6 to ≤12 months
(n=5)
1 to <2
years
(n=10)
2 to <6 years
(n=24)
6 to ≤12 years
(n=17)
Dose (mg/kg) 6.6
(± 1.4)
9.4
(± 2.1)
13.5
(± 2.0)
13.0
(± 0.8)
12.8
(± 1.3)
12.2
(± 1.3)

AUC +
(mcg hr/mL)
2.22
(± 1.23)
3.16
(± 0.68)
8.77
(± 2.14)
7.16
(± 2.75)
7.23 §
(± 1.90)
9.33
(± 1.84)
Cmax ++
(mcg/mL)
0.69
(± 0.41)
0.74
(± 0.17)
3.24
(± 1.01)
3.06
(± 1.06)
2.78
(± 0.93)
3.41
(± 0.96)

+ Area under the plasma concentration-time profile, up to 6 hr post dose for patients ≤12 months of age, and extrapolated to infinity for patients between 1 and ≤12 years of age

++ Maximum observed plasma concentration

§ n=20

8.5 Geriatric use

Of 816 patients with herpes zoster in clinical studies who were treated with FAMVIR, 248 (30.4%) were ≥65 years of age and 103 (13%) were ≥75 years of age. No overall differences were observed in the incidence or types of adverse events between younger and older patients. Of 610 patients with recurrent herpes simplex (type 1 or type 2) in clinical studies who were treated with FAMVIR, 26 (4.3%) were >65 years of age and 7 (1.1%) were >75 years of age. Clinical studies of FAMVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of FAMVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 

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. No famciclovir dosage adjustment based on age is recommended unless renal function is impaired [see Dosage and Administration(2.2)].

8.6 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 6):

Table 5 Penciclovir Pharmacokinetics in Dependence on Renal Function
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 ± 20.649.3 ± 5.926.5 ± 5.312.7 ± 5.9
CLR (L/hr)30.1 ± 10.613.0 ± 1.34.2 ± 0.91.6 ± 1.0
CL/F§ (L/hr)66.9 ± 27.527.3 ± 2.812.8 ± 1.35.8 ± 2.8
Half-life (hr)2.3 ± 0.53.4 ± 0.76.2 ± 1.613.4 ± 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 (2.2)].

8.7 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.

10  OVERDOSAGE

Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by hemodialysis.

11  DESCRIPTION

The active ingredient in FAMVIR Tablets is famciclovir, an orally administered prodrug of the antiviral agent penciclovir. Chemically, famciclovir is known as 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate. Its molecular formula is C14H19N5O4; its molecular weight is 321.3. It is a synthetic acyclic guanine derivative and has the following structure

Famciclovir chemical structure.

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%-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.

FAMVIR Tablets contain 125 mg, 250 mg or 500 mg of famciclovir, together with the following inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycols, sodium starch glycolate and titanium dioxide.

12  CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Famciclovir is an orally administered prodrug of the antiviral agent penciclovir.

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. The absolute bioavailability of penciclovir is on average 77%. Penciclovir is predominantly eliminated unchanged by the kidney and has an elimination half-life between 2.0 h and 2.8 h. Renal insufficiency affects the pharmacokinetics of penciclovir requiring dose adjustment.

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 1000 mg administered as a single dose. Single oral-dose administration of 125 mg, 250 mg, 500 mg, or 1000 mg famciclovir to healthy male volunteers across 17 studies gave the following pharmacokinetic parameters (Table 7):

Table 6 Mean Pharmacokinetic Parameters of Penciclovir in Healthy Adult Subjects
DoseAUC (0-inf) (mcg hr/mL)Cmax (mcg/mL)Tmax§ (h)
125 mg2.240.80.9
250 mg4.481.60.9
500 mg8.953.30.9
1000 mg17.96.60.9

 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 oral single-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 three times daily 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 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 <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. 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)].

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

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 17 patients with herpes zoster was 2.8±1.0 hours and 2.7±1.0 hours after single and repeated doses, respectively.

Special Populations

Pediatric Patients

In children 6 months to 12 years of age given FAMVIR experimental pediatric formulation based on body weight (12.2 to 13.5 mg/kg), the average systemic exposure (AUC, Cmax) to penciclovir was similar or slightly lower than in adults given a 500 mg tablet dose. In children 1 month to <6 months of age given famciclovir doses of 6.6 to 9.4 mg/kg, AUC and Cmax of penciclovir were about 3- to 5-fold lower than in adults given a 500 mg dose. Higher doses of famciclovir have not been studied in pediatric patients [see Use in Specific Populations (8.4)].

Geriatric Patients

In elderly subjects, penciclovir AUC was 40% larger and penciclovir renal clearance was 22% lower than in younger subjects [see Use in Specific Populations (8.5)]. 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 (2.2)].  

Renal Insufficiency

In subjects with varying degrees of renal insufficiency, apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function, both after single and repeated dosing [see Use in Specific Populations (8.6)]. A dosage adjustment is recommended for patients with renal insufficiency [see Dosage and Administration (2.2)].

Hepatic Insufficiency

Well-compensated chronic liver disease 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 well-compensated hepatic impairment.

HIV-infected patients

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.

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.

Race

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

12.4 Microbiology

Mechanism of Antiviral Action

Famciclovir undergoes rapid biotransformation to the active antiviral compound 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 to penciclovir triphosphate by cellular kinases. In vitro 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 is unknown.

Antiviral Activity

In cell culture studies, penciclovir is inhibitory to the following herpes viruses (listed in decreasing order of potency): HSV-1, HSV-2 and VZV. Sensitivity test results, expressed as the concentration of the drug required to inhibit the growth of the virus by 50% (EC50) or 99% (EC99) in cell culture, vary greatly depending upon a number of factors, including the assay protocols, and in particular the cell type used (Table 8).

Table 7 Antiviral Activity of Penciclovir Against VZV, HSV-1 and HSV-2.
Method of AssayVirus TypeCell TypeEC50EC99
(mcg/mL)
Plaque ReductionVZV (c.i.)MRC-55.0 ± 3.0
VZV (c.i.)Hs680.9 ± 0.4
HSV-1 (c.i.)MRC-50.2 – 0.6
HSV-1 (c.i.)WISH0.04 – 0.5
HSV-2 (c.i.)MRC-50.9 – 2.1
HSV-2 (c.i.)WISH0.1 – 0.8
Virus YieldHSV-1 (c.i.)MRC-50.4 – 0.5
     ReductionHSV-2 (c.i.)MRC-50.6 – 0.7
DNA SynthesisVZV (Ellen)MRC-50.1
     InhibitionHSV-1 (SC16)MRC-50.04
HSV-2 (MS)MRC-50.05

(c.i.) = clinical isolates.

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 most commonly encountered acyclovir resistant mutants that are TK negative are also resistant to penciclovir. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.

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 2000 mg and 500 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 FAMVIR (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 FAMVIR 1500 mg as a single dose (n=227), FAMVIR 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 FAMVIR 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 FAMVIR 1500 mg treated groups was 1.3 days (95% CI: 0.6 – 2.0). No differences in proportion of patients with aborted lesions (not progressing beyond the papule stage) were observed between patients receiving FAMVIR or placebo: 33% for FAMVIR 1500 mg single dose and 34% for placebo. The median time to loss of pain and tenderness was 1.7 days in FAMVIR 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 FAMVIR 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 FAMVIR-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 FAMVIR-treated groups was 1.2 days (95% CI: 0.5 – 2.0). Twenty-three percent of FAMVIR-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 FAMVIR-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 FAMVIR 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 FAMVIR 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 9.

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
Famvir®
250 mg twice daily 
(n=236)
Placebo

(n=233)
Famvir®
250 mg twice daily 
(n=236)
Placebo

(n=233)
Recurrence-free39%10%29%6%
Recurrences47%74%53%78%
Lost to Follow-up14%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.

14.3 Mucocutaneous herpes simplex virus infections 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 mucocutaneous herpes simplex virus 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.

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 FAMVIR 500 mg three times daily (n=138), FAMVIR 750 mg three times daily (n=135) or placebo (n=146). The median time to full crusting was 5 days among FAMVIR 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 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 1 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 developed 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 dose of FAMVIR.

In the active-controlled trial, 545 patients were treated with one of three doses of FAMVIR 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 FAMVIR and acyclovir-treated groups.

14.5 Pediatric Studies

The safety of FAMVIR has been evaluated in 169 pediatric patients 1 month to ≤12 years of age. One hundred of these patients were 1 to ≤12 years of age and were treated with FAMVIR experimental oral granules either twice (47 patients with herpes simplex virus infections) or three times (53 patients with chickenpox) daily for 7 days. The remaining 69 patients (18 patients 1 to ≤12 months, 51 patients 1 to ≤12 years) participated in single-dose pharmacokinetic and safety studies using FAMVIR experimental oral granules. [see Use in Specific Populations (8.4) and Adverse Reactions (6.2)].

16  HOW SUPPLIED/STORAGE AND HANDLING

FAMVIR Tablets is supplied as film-coated tablets as follows: 125 mg in bottles of 30; 250 mg in bottles of 30; 500 mg in bottles of 30 and Single Unit Packages of 50 (intended for institutional use only).

FAMVIR 125 mg tablet:

White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “125” on the other.

125 mg 30’s………………………………………………………………………………………………NDC 0078-0366-15

FAMVIR 250 mg tablet:

White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “250” on the other.

250 mg 30’s………………………………………………………………………………………………NDC 0078-0367-15

FAMVIR 500 mg tablet:

White, oval film-coated, biconvex, debossed with “FAMVIR” on one side and “500” on the other.

500 mg 30’s………………………………………………………………………………………………NDC 0078-0368-15

500 mg SUP 50’s……………………………………………………………………………...…………NDC 0078-0368-64

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

17 PATIENT COUNSELING INFORMATION

There is no evidence that FAMVIR 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 FAMVIR 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 FAMVIR is not a cure for cold sores.

17.2 Genital Herpes

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

17.3 Herpes Zoster (Shingles)

There are no data on treatment initiated more than 72 hours after onset of zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.

FDA-APPROVED PATIENT LABELING

Patient Information

FAMVIR®

(Fam’-veer)

(famciclovir) Tablets

125 mg, 250 mg, 500 mg

You must read and follow all instructions before using FAMVIR.

Read the Patient Information every time you or a family member gets FAMVIR. There may be new information. This Patient information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about FAMVIR, ask your doctor or pharmacist.

What is the most important information I should know about FAMVIR?

FAMVIR is not a cure of herpes. It is not known if FAMVIR can stop the spread of herpes to others. If you are sexually active, you can pass herpes to you partner even if you are taking FAMVIR. Herpes can be transmitted even if you do not have active symptoms. If you are taking FAMVIR to manage a recurrent herpes outbreak, you should initiate therapy at the first sign or symptom of an outbreak.

What is FAMVIR?

Famvir is a prescription antiviral medicine used to:

How does FAMVIR work?

Recurrent genital herpes. The herpes virus is most active during the prodrome when the symptoms of an oncoming outbreak are first sensed (such as tingling, burning, pain, itching, and tenderness). At this time, the virus is reproducing itself most actively. FAMVIR helps by interfering with the reproduction of the herpes virus, and can stop or minimize the outbreak, relieve pain and burning, and reduce time to healing of lesions. When used as suppressive treatment, FAMVIR can also lessen the number of outbreaks that can occur. FAMVIR is effective for treating recurrent genital herpes, even in people who have HIV.

Cold Sores. Just like in the treatment of recurrent genital herpes, FAMVIR interferes with herpes virus reproduction to help minimize cold sore pain and tenderness and heal blisters, even in people who have HIV.

Shingles. Shingles is a painful or itchy rash that occurs on the body or face. It is caused by another type of herpes virus (varicella zoster virus), the same virus that causes chicken pox. FAMVIR works to heal the rash and reduce the amount of pain that people ages 50 and over may have after the rash has healed. There is no data on effectiveness of treatment initiated after 72 hours.

Who should not use FAMVIR?

Do not use FAMVIR if you are allergic to this drug or anything in it. See the end of this Patient Information for a complete list of ingredients. FAMVIR is not indicated in people under 18 years of age. Talk to you doctor if you are younger than 18 and plan to use FAMVIR. Talk to your doctor before using FAMVIR if you are over 65 or have kidney or liver problems.

What should I tell my doctor before starting FAMVIR?

Before you start using FAMVIR, tell your doctor about all of your medical conditions, including if you:

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Tell your doctor about all the medicines and products you use to treat herpes outbreaks. Know the medicines you take. Keep a list of them with you to show to your doctor and pharmacist every time you get a new medicine.

How do I take FAMVIR?

Use FAMVIR exactly as prescribed. FAMVIR can be taken with or without food. Take the amount of FAMVIR that has been prescribed for you, even if you begin to feel better. Your symptoms may persist even after you finish all of your FAMVIR. This does not necessarily mean that you need more medication, since you have already completed a full course of FAMVIR and it will continue to work in your body.

Your dose of FAMVIR may be different if you are infected with HIV or have kidney disease (please consult your doctor).

What are the possible side effects of FAMVIR?

The most common side effects for all doses of FAMVIR are headache, diarrhea, and nausea. Side effects tend to be mild to moderate, and usually last only a short time.

Other side effects may include vomiting, abdominal pain, or fatigue. Talk to your doctor if side effects continue or if they bother you.

These are not all the possible side effects that may occur with FAMVIR. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store FAMVIR?

General advice about FAMVIR

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Use FAMVIR only for the condition for which it was prescribed. Do not give FAMVIR to other people even if they have the same symptoms you have, as it may not be right for them.

This Patient information summarizes the most important information about FAMVIR. If you would like more information, talk with your doctor. Your doctor or pharmacist can give you information about FAMVIR that is written for health professionals. For more information, you can also visit the Novartis Internet site at www.FAMVIR.com or call the Novartis help line at 1-888-669-6682.

What are the ingredients in FAMVIR?

Active Ingredients: famciclovir

Inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycols, sodium starch glycolate, and titanium dioxide

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

REV: JUNE 2009                                                                   T2009-xx

©Novartis

PRINCIPAL DISPLAY PANEL

Package Label – 125 mg

Rx Only       NDC 0078-0366-15

FAMVIR® (famciclovir) Tablets

125 mg per tablet

30 Tablets

PRINCIPAL DISPLAY PANEL – PACKAGE LABEL – 125 MG TABLETS.

PRINCIPAL DISPLAY PANEL

Package Label – 250 mg

Rx Only       NDC 0078-0367-15

FAMVIR® (famciclovir) Tablets

250 mg per tablet

30 Tablets

PRINCIPAL DISPLAY PANEL – PACKAGE LABEL – 250 MG TABLETS.

PRINCIPAL DISPLAY PANEL

Package Label – 500 mg

Rx Only       NDC 0078-0368-15

FAMVIR® (famciclovir) Tablets

500 mg per tablet

30 Tablets

PRINCIPAL DISPLAY PANEL – PACKAGE LABEL – 500 MG TABLETS.


FAMVIR 
famciclovir   tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0078-0366
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
FAMCICLOVIR (FAMCICLOVIR) FAMCICLOVIR125 mg
Inactive Ingredients
Ingredient NameStrength
HYDROXYPROPYL CELLULOSE 
LACTOSE 
MAGNESIUM STEARATE 
POLYETHYLENE GLYCOL 
SODIUM STARCH GLYCOLATE TYPE A POTATO 
TITANIUM DIOXIDE 
Product Characteristics
ColorWHITEScore no score
ShapeROUNDSize8mm
FlavorImprint Code FAMVIR;125
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10078-0366-1530 TABLET In 1 BOTTLENone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02036306/29/1994

FAMVIR 
famciclovir   tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0078-0367
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
FAMCICLOVIR (FAMCICLOVIR) FAMCICLOVIR250 mg
Inactive Ingredients
Ingredient NameStrength
HYDROXYPROPYL CELLULOSE 
LACTOSE 
MAGNESIUM STEARATE 
POLYETHYLENE GLYCOL 
SODIUM STARCH GLYCOLATE TYPE A POTATO 
TITANIUM DIOXIDE 
Product Characteristics
ColorWHITEScore no score
ShapeROUNDSize10mm
FlavorImprint Code FAMVIR;250
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10078-0367-1530 TABLET In 1 BOTTLENone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02036306/29/1994

FAMVIR 
famciclovir   tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0078-0368
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
FAMCICLOVIR (FAMCICLOVIR) FAMCICLOVIR500 mg
Inactive Ingredients
Ingredient NameStrength
HYDROXYPROPYL CELLULOSE 
LACTOSE 
MAGNESIUM STEARATE 
POLYETHYLENE GLYCOL 
SODIUM STARCH GLYCOLATE TYPE A POTATO 
TITANIUM DIOXIDE 
Product Characteristics
ColorWHITEScore no score
ShapeOVALSize18mm
FlavorImprint Code FAMVIR;500
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10078-0368-6450 BLISTER PACK In 1 PACKAGEcontains a BLISTER PACK
11 TABLET In 1 BLISTER PACKThis package is contained within the PACKAGE (0078-0368-64)
20078-0368-1530 TABLET In 1 BOTTLENone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02036306/29/1994

Labeler - Novartis Pharmaceuticals Corporation (002147023)
Revised: 07/2009Novartis Pharmaceuticals Corporation