FAMCICLOVIR

Golden State Medical Supply, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use FAMCICLOVIR Tablets safely and effectively. See full prescribing information for FAMCICLOVIR Tablets. FAMCICLOVIR TabletsInitial U.S. Approval: 1994 INDICATIONS AND USAGEFamciclovir, a prodrug of penciclovir, is a nucleoside analogue DNA polymerase inhibitor indicated for:  Immunocompetent Adult Patients (1.1) Herpes labialis (cold sores) Genital herpes Treatment of recurrent episodes Suppressive therapy of recurrent episodes HIV-Infected Adult Patients (1.2) Treatment of recurrent episodes of orolabial or genital herpes Limitation of Use (1.3) The efficacy and safety of Famciclovir have not been established for: Patients 10% of adult patients are headache and nausea. (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Drug Information Service at 1-800-667-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONSProbenecid: May increase penciclovir levels. Monitor for evidence of penciclovir toxicity (7.2)USE IN SPECIFIC POPULATIONSNursing mothers: Famciclovir tablets should not be used in nursing mothers unless the potential benefits outweigh the potential risks associated with treatment (8.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 FAMCICLOVIR INDICATIONS AND USAGE
  • 1.1 Immunocompetent Adult Patients
  • 1.2 HIV-Infected Adult Patients
  • 1.3 Limitation of Use
• 2 FAMCICLOVIR DOSAGE AND ADMINISTRATION
  • 2.1 Dosing Recommendation in Immunocompetent Adult Patients
  • 2.2 Dosing Recommendation in HIV-Infected Adult Patients
  • 2.3 Dosing Recommendation in Patients with Renal Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 FAMCICLOVIR CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
• 6 FAMCICLOVIR ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience in Adult Patients
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Potential for Famciclovir Tablets to Affect Other Drugs
  • 7.2 Potential for Other Drugs to Affect Penciclovir
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Patients with Renal Impairment
  • 8.7 Patients with Hepatic Impairment
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.1 Controlled Substance
  • 9.2 Abuse
  • 9.3 Dependence
• 10 OVERDOSAGE
• 11 FAMCICLOVIR DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.4 Virology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology and/or Pharmacology
  • 13.2 Animal Toxicology
• 14 CLINICAL STUDIES
  • 14.1 Herpes Labialis (Cold Sores) 
  • 14.2 Genital Herpes
  • 14.3 Recurrent Orolabial or Genital Herpes in HIV-Infected Patients 
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Herpes Labialis (Cold Sores)
  • 17.2 Genital Herpes
• PRINCIPAL DISPLAY PANEL - 125 MG BOTTLE LABEL
• PRINCIPAL DISPLAY PANEL - 250 MG BOTTLE LABEL
• PRINCIPAL DISPLAY PANEL - 500 MG BOTTLE LABEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Immunocompetent Adult Patients

Herpes labialis (cold sores): Famciclovir tablets are indicated for the treatment of recurrent herpes labialis.  

Genital herpes:

Recurrent episodes: Famciclovir tablets are indicated for the treatment of recurrent episodes of genital herpes. The efficacy of famciclovir tablets when initiated more than 6 hours after onset of symptoms or lesions has not been established.

Suppressive therapy: Famciclovir tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes. The efficacy and safety of famciclovir tablets for the suppression of recurrent genital herpes beyond 1 year have not been established.

1.2 HIV-Infected Adult Patients

Recurrent orolabial or genital herpes:  Famciclovir tablets are indicated for the treatment of recurrent episodes of orolabial or genital herpes in HIV-infected adults. The efficacy of famciclovir tablets when initiated more than 48 hours after onset of symptoms or lesions has not been established.

1.3 Limitation of Use

The efficacy and safety of famciclovir tablets have not been established for:

• Patients <18 years of age
• Patients with first episode of genital herpes
• Patients with ophthalmic zoster
• Immunocompromised patients other than for the treatment of recurrent orolabial or genital herpes in HIV-infected patients

2 DOSAGE AND ADMINISTRATION

Famciclovir may be taken with or without food.

2.1 Dosing Recommendation in Immunocompetent Adult Patients

Herpes labialis (cold sores): The recommended dosage of famciclovir tablets for the treatment of recurrent herpes labialis is 1500 mg as a single dose. Therapy should be initiated at the first sign or symptom of herpes labialis (e.g., tingling, itching, burning, pain, or lesion).

Genital Herpes:

Recurrent episodes: The recommended dosage of famciclovir tablets for the treatment of recurrent episodes of genital herpes is 1000 mg twice daily for 1 day. 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 famciclovir tablets for chronic suppressive therapy of recurrent episodes of genital herpes is 250 mg twice daily.

2.2 Dosing Recommendation in HIV-Infected Adult Patients

Recurrent orolabial or genital herpes: The recommended dosage of famciclovir tablets for the treatment of recurrent orolabial or genital herpes 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).

2.3 Dosing Recommendation in Patients with Renal Impairment

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

Table 1 Dosage Recommendations for Adult Patients with Renal Impairment

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	≥60	1000	every 12 hours for 1 day
	40-59	500	every 12 hours for 1 day
	20-39	500	single dose
	<20	250	single dose
	HDHemodialysis	250	single dose following dialysis
Recurrent Herpes Labialis 1500 mg single dose	≥60	1500	single dose
	40-59	750	single dose
	20-39	500	single dose
	<20	250	single dose
	HDHemodialysis	250	single dose following dialysis
Multiple-Day Dosing Regimens
Suppression of Recurrent Genital Herpes 250 mg every 12 hours	≥40	250	every 12 hours
	20-39	125	every 12 hours
	<20	125	every 24 hours
	HDHemodialysis	125	following each dialysis
Recurrent Orolabial or Genital Herpes in HIV-Infected Patients 500 mg every 12 hours	≥40	500	every 12 hours
	20-39	500	every 24 hours
	<20	250	every 24 hours
	HDHemodialysis	250	following each dialysis

3 DOSAGE FORMS AND STRENGTHS

Famciclovir tablets are available in three strengths:

• 125 mg: Famciclovir 125 mg tablets are white, round, biconvex, film-coated tablets, engraved “APO” on one side and “FAM” over “125” on the other side.
• 250 mg: Famciclovir 250 mg tablets are white, round, biconvex, film-coated tablets engraved “APO” on one side and “FAM” over “250” on the other side.
• 500 mg: Famciclovir 500 mg tablets are white, oval, biconvex film-coated tablets, engraved “APO” on one side and “FAM500” on the other side.

4 CONTRAINDICATIONS

Famciclovir is contraindicated in patients with known hypersensitivity to the product, its components, or Denavir^{¥ ®} (penciclovir cream).

5 WARNINGS AND PRECAUTIONS

Acute renal failure: Cases of acute renal failure have been reported in patients with underlying renal disease who have received inappropriately high doses of famciclovir tablets for their level of renal function. Dosage reduction is recommended when administering famciclovir tablets to patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

6 ADVERSE REACTIONS

Acute renal failure is discussed in greater detail in other sections of the label [see Warnings and Precautions (5)].

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

6.1 Clinical Trials Experience in Adult Patients

Because clinical trials are conducted under widely varying conditions, adverse reaction 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 famciclovir has been evaluated in active- and placebo-controlled clinical studies involving 163 famciclovir-treated patients with recurrent genital herpes (famciclovir, 1000 mg twice daily); 1,197 patients with recurrent genital herpes treated with famciclovir as suppressive therapy (125 mg once daily to 250 mg three times daily) of which 570 patients received famciclovir (open-labeled and/or double-blind) for at least 10 months; and 447 famciclovir-treated patients with herpes labialis (famciclovir, 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 Famciclovir TrialsPatients may have entered into more than one clinical trial.

Incidence
	Recurrent Genital Herpes1 day of treatment		Genital Herpes- Suppressiondaily treatment		Herpes LabialisPatients may have entered into more than one clinical trial.
Event	Famciclovir (n=163) %	Placebo(n=166)%	Famciclovir (n=458) %	Placebo (n=63) %	Famciclovir (n=447) %	Placebo(n=254) %
Nervous System
Headache	13.5	5.4	39.3	42.9	8.5	6.7
Paresthesia	0.0	0.0	0.9	0.0	0.0	0.0
Migraine	0.6	0.6	3.1	0.0	0.2	0.0
Gastrointestinal
Nausea	2.5	3.6	7.2	9.5	2.2	3.9
Diarrhea	4.9	1.2	9.0	9.5	1.6	0.8
Vomiting	1.2	0.6	3.1	1.6	0.7	0.0
Flatulence	0.6	0.0	4.8	1.6	0.2	0.0
Abdominal Pain	0.0	1.2	7.9	7.9	0.2	0.4
Body as a Whole
Fatigue	0.6	0.0	4.8	3.2	1.6	0.4
Skin and Appendages
Pruritus	0.0	0.6	2.2	0.0	0.0	0.0
Rash	0.0	0.0	3.3	1.6	0.0	0.0
Reproductive (Female)
Dysmenorrhea	1.8	0.6	7.6	6.3	0.4	0.0

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

Table 3 Selected Laboratory Abnormalities in Genital Herpes suppression StudiesPercentage of patients with laboratory abnormalities that were increased or decreased from baseline and were outside of specified ranges.

Parameter	Famciclovir (n = 660)n values represent the minimum number of patients assessed for each laboratory parameter. %	Placebo (n = 210)Percentage of patients with laboratory abnormalities that were increased or decreased from baseline and were outside of specified ranges. %
Anemia (<0.8 x NRL)	0.1	0.0
Leukopenia (<0.75 x NRL)	1.3	0.9
Neutropenia (<0.8 x NRL)	3.2	1.5
AST (SGOT) (>2 x NRH)	2.3	1.2
ALT (SGPT) (>2 x NRH)	3.2	1.5
Total Bilirubin (>1.5 x NRH)	1.9	1.2
Serum Creatinine (>1.5 x NRH)	0.2	0.3
Amylase (>1.5 x NRH)	1.5	1.9
Lipase (>1.5 x NRH)	4.9	4.7

NRH = Normal Range High.

NRL = Normal Range Low.

HIV-infected patients: In HIV-infected patients, the most frequently reported adverse event for famciclovir (500 mg twice daily; n=50) and acyclovir (400 mg; 5x/day; n=143), respectively, were headache (17% vs. 15%), nausea (11% vs. 13%), diarrhea (7% vs. 11%), vomiting (5% vs. 4%), fatigue (4% vs. 2%), and abdominal pain (3% vs. 6%)

6.2 Postmarketing Experience

 The adverse events listed below have been reported during post-approval use of famciclovir tablets. 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:

Blood and lymphatic system disorders: Thrombocytopenia

Hepatobiliary disorders: Abnormal liver function tests, cholestatic jaundice

Nervous system disorders: Dizziness, somnolence

Psychiatric disorders: Confusion (including delirium, disorientation, and confusional state occurring predominantly in the elderly), hallucinations

Skin and subcutaneous tissue disorders: Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

7 DRUG INTERACTIONS

7.1 Potential for Famciclovir Tablets to Affect Other 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 coadministered with zidovudine or emtricitabine.

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

7.2 Potential for Other Drugs to Affect 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.  

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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy category B: After oral administration, famciclovir (prodrug) is converted to penciclovir (active drug). There are no adequate and well-controlled studies of famciclovir or penciclovir use in pregnant women. No adverse effects on embryo fetal development were observed in animal reproduction studies using famciclovir and penciclovir at doses higher than the maximum recommended human dose (MRHD) and human exposure. Because animal reproduction studies are not always predictive of human response, famciclovir should be used during pregnancy only if needed.

In animal reproduction studies, pregnant rats and rabbits received oral famciclovir at doses (up to 1000 mg/kg/day) that provided 2.7 to 10.8 times (rats) and 1.4 to 5.4 times (rabbits) the human systemic exposure based on AUC. No adverse effects were observed on embryo-fetal development. In other studies, pregnant rats and rabbits received intravenous famciclovir at doses (360 mg/kg/day) 1.5 to 6 times (rats) and (120 mg/kg/day) 1.1 to 4.5 times (rabbits) or penciclovir at doses (80/mg/kg/day) 0.3 to 1.3 times (rats) and (60 mg/kg/day) 0.5 to 2.1 times (rabbits) the MRHD based on body surface area comparisons. No adverse effects were observed on embryo-fetal development.

8.2 Labor and Delivery

8.3 Nursing Mothers

It is not known whether famciclovir (prodrug) or penciclovir (active drug) are excreted in human milk. Following oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. There are no data on the safety of famciclovir in infants. Famciclovir tablets 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

8.5 Geriatric Use

8.4 Pediatric Use

The efficacy and safety of famciclovir tablets have not been established in pediatric patients. Labeling describing additional clinical pharmacokinetic studies in pediatric patients (ages of 1 month to < 12 years) is approved for Novartis Pharmaceuticals Corporation’s Famvir® Tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, a description of those clinical pharmacokinetic studies is not approved for this famciclovir tablet product.

8.5 Geriatric Use

Of 610 patients with recurrent herpes simplex (type 1 or type 2) in clinical studies who were treated with famciclovir, 26 (4.3%) were >65 years of age and 7 (1.1%) were >75 years of age. Clinical studies of famciclovir in patients with recurrent genital herpes did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

No famciclovir dosage adjustment based on age is recommended unless renal function is impaired [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. In general, appropriate caution should be exercised in the administration and monitoring of famciclovir tablets in elderly patients reflecting the greater frequency of decreased renal function and concomitant use of other drugs.

8.6 Patients with Renal Impairment

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 impairment (CL_CR ranged from 6.4 to 138.8 mL/min), the following results were obtained (Table 4):

Table 4 Pharmacokinetic Parameters of Penciclovir in Subjects with Different Degrees of Renal Impairment

Parameter (mean ± S.D.)	CLCR CLCR is measured creatinine clearance. ≥60 (mL/min.) (n=15)	CLCR 40-59 (mL/min.) (n=5)	CLCR 20-39 (mL/min.) (n=4)	CLCR <20 (mL/min.) (n=3)
CLCR (mL/min)	88.1 ± 20.6	49.3 ± 5.9	26.5 ± 5.3	12.7 ± 5.9
CLR (L/hr)	30.1 ± 10.6	13.0 ± 1.3n=4.	4.2 ± 0.9	1.6 ± 1.0
CL/FCL/F consists of bioavailability factor and famciclovir to penciclovir conversion factor.(L/hr)	66.9 ± 27.5	27.3 ± 2.8	12.8 ± 1.3	5.8 ± 2.8
Half-life (hr)	2.3 ± 0.5	3.4 ± 0.7	6.2 ± 1.6	13.4 ± 10.2

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 impairment [see Dosage and Administration (2.3)]. 

8.7 Patients with Hepatic Impairment

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 (C_max) and the time to maximum plasma concentration (t_max) was increased by 0.75 hours in patients with hepatic impairment 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.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

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

11 DESCRIPTION

The active ingredient in Famciclovir 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 is a white to off-white powder. 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.

Famciclovir tablets contain 125 mg, 250 mg or 500 mg of famciclovir, together with the following inactive ingredients: hypromellose, poloxamer, stearic acid, polyethylene glycol, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

Pharmacokinetics in adults:

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

Penciclovir concentrations increased in proportion to dose over a famciclovir dose range of 125 mg to 1000 mg administered as a single dose. Table 5 shows the mean pharmacokinetic parameters of penciclovir after single administration of famciclovir to healthy male volunteers.

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

Dose	AUC (0-inf) (mcg hr/mL)AUC (0-inf) (mcg hr/mL)=area under the plasma concentration-time profile extrapolated to infinity.	Cmax(mcg/mL) Cmax (mcg/mL)=maximum observed plasma concentration.	Tmax Tmax (h)= time to Cmax (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 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 (7.2)].

Elimination: Approximately 94% of administered radioactivity was recovered in urine over 24 hours (83% of the dose was excreted in the first 6 hours) after the administration of 5 mg/kg radiolabeled penciclovir as a 1-hour infusion to 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 ± SD 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.

Special populations:

Geriatric patients: Based on cross study comparison, penciclovir AUC was 40% higher and penciclovir renal clearance was 22% lower in elderly subjects (n=18, age 65-79 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)].  

Patients with renal impairment: 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)].

Patients with hepatic impairment: 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: 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 or 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, 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-1and 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-1and HSV-2 were 2 μM (range 1.2 to 2.4 μM, n = 7) and 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-1and 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-resistence: 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 and/or Pharmacology

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 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 – 2.0). No differences in proportion of patients with aborted lesions (not progressing beyond the papule stage) were observed between patients receiving famciclovir tablets or placebo: 33% for famciclovir tablets 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-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 – 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.

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.

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%
RecurrencesBased on patient reported data; not necessarily confirmed by a physician.	47%	74%	53%	78%
Lost to follow-upPatients recurrence-free at time of last contact prior to withdrawal.	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.

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

Famciclovir Tablets are supplied as follows:

Famciclovir 125 mg tablets are white, round, biconvex, film-coated tablets, engraved “APO” on one side and “FAM” over “125” on the other side 

• Bottles of 30------NDC 60429-359-30

Famciclovir 250 mg tablets are white, round, biconvex, film-coated tablets engraved “APO” on one side and “FAM” over “250” on the other side. 

• Bottles of 30s-----NDC 60429-360-30 

Famciclovir 500 mg tablets are white, oval, biconvex film-coated tablets, engraved “APO” on one side and “FAM500” on the other side. 

• Bottles of 30s-----NDC 6042-361-30 

Store at 20°C to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59° to 86°F) [see USP controlled room temperature].

Dispense in a tight container [see USP].

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.

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 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.

^¥Denavir is a registered trademark of Novartis.

Manufactured by: Apotex Inc., Toronto, Ontario, Canada, M9L 1T9

Manufacturer for: Apotex Corp., Weston, Florida 33326, USA

Revision 3

March 2011

PRINCIPAL DISPLAY PANEL - 125 MG BOTTLE LABEL

GSMS, Inc. NDC 60429-359-30

FAMCICLOVIR Tablets

125 mg

Rx only

30 Tablets

PRINCIPAL DISPLAY PANEL - 250 MG BOTTLE LABEL

GSMS, Inc. NDC 60429-360-30

FAMCICLOVIR Tablets

250 mg

Rx only

30 Tablets

PRINCIPAL DISPLAY PANEL - 500 MG BOTTLE LABEL

GSMS, Inc. NDC 60429-361-30

FAMCICLOVIR Tablets

500 mg

Rx only

30 Tablets