|| See TERMINOLOGY & ABBREVIATIONS ||
J05AB09 - famciclovir; Belongs to the class of nucleosides and nucleotides excluding reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
S01AD07 - famciclovir; Belongs to the class of antiinfectives, antivirals. Used in the treatment of eye infections.
Immunocompetent Adult Patients
Herpes labialis (cold sores): is indicated for the treatment of recurrent herpes labialis.
Recurrent episodes: is indicated for the treatment of recurrent episodes of genital herpes. The efficacy of when initiated more than 6 hours after onset of symptoms or lesions has not been established.
Suppressive therapy: is indicated for chronic suppressive therapy of recurrent episodes of genital herpes. The efficacy and safety of for the suppression of recurrent genital herpes beyond 1 year have not been established.
Herpes zoster (shingles): is indicated for the treatment of herpes zoster. The efficacy of when initiated more than 72 hours after onset of rash has not been established.
HIV-Infected Adult Patients
Recurrent orolabial or genital herpes: is indicated for the treatment of recurrent episodes of orolabial or genital herpes in HIV-infected adults. The efficacy of when initiated more than 48 hours after onset of symptoms or lesions has not been established.
Limitation of Use
The efficacy and safety of have not been established for:
|Dosage & Administration||
Dosing Recommendation in Patients with Renal Impairment
Dosage recommendations for adult patients with renal impairment are provided in Table 1
FAMCICLOVIR is contraindicated in patients with known hypersensitivity to the product, its components, or DenavirÂ® (penciclovir cream).
|Warnings & 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 for their level of renal function. Dosage reduction is recommended when administering to patients with renal impairment.|
|Adverse Drug Reaction(s)||
Acute renal failure is discussed in greater detail in other sections of the label.
The most common adverse events reported in at least 1 indication by >10% of adult patients treated with are headache and nausea.
Adverse reactions from Post-marketing Experience
The adverse events listed below have been reported during postapproval use of . 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:
Potential for 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.
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 pretreatment 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.
|Pregnancy Category (FDA) and use in Specific Population||
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 embryofetal 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.
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 in infants. should not be used in nursing mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment.
The efficacy of has not been established in pediatric patients. The pharmacokinetic profile and safety of famciclovir (experimental granules mixed with OraSweetÂ® or tablets) were studied in 3 open-label studies.
Study 1 was a single-dose pharmacokinetic and safety study in infants 1 month to <1 year of age who had an active herpes simplex virus (HSV) infection or who were at risk for HSV infection. Eighteen subjects were enrolled and received a single dose of famciclovir experimental granules mixed with OraSweet based on the patientâ€™s body weight (doses ranged from 25 mg to 175 mg). These doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. The efficacy and safety of famciclovir have not been established as suppressive therapy in infants following neonatal HSV infections. In addition, the efficacy cannot be extrapolated from adults to infants because there is no similar disease in adults. Therefore, famciclovir is not recommended in infants.
Study 2 was an open-label, single-dose pharmacokinetic, multiple-dose safety study of famciclovir experimental granules mixed with OraSweet in children 1 to <12 years of age with clinically suspected HSV or varicella zoster virus (VZV) infection. Fifty-one subjects were enrolled in the pharmacokinetic part of the study and received a single body weight adjusted dose of famciclovir (doses ranged from 125 mg to 500 mg). These doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. Based on the pharmacokinetic data observed with these doses in children, a new weight-based dosing algorithm was designed and used in the multiple-dose safety part of the study. Pharmacokinetic data were not obtained with the revised weight-based dosing algorithm.
A total of 100 patients were enrolled in the multiple-dose safety part of the study; 47 subjects with active or latent HSV infection and 53 subjects with chickenpox. Patients with active or latent HSV infection received famciclovir twice a day for 7 days. The daily dose of famciclovir ranged from 150 mg to 500 mg twice daily depending on the patientâ€™s body weight. Patients with chickenpox received famciclovir three times daily for 7 days. The daily dose of famciclovir ranged from 150 mg to 500 mg three times daily depending on the patientâ€™s body weight. The clinical adverse events and laboratory test abnormalities observed in this study were similar to these seen in adults. The available data are insufficient to support the use of famciclovir for the treatment of children 1 to <12 years of age with chickenpox or infections due to HSV for the following reasons:
Chickenpox: The efficacy of famciclovir for the treatment of chickenpox has not been established in either pediatric or adult patients. Famciclovir is approved for the treatment of herpes zoster in adult patients. However, extrapolation of efficacy data from adults with herpes zoster to children with chickenpox would not be appropriate. Although chickenpox and herpes zoster are caused by the same virus, the diseases are different.
Genital herpes: Clinical information on genital herpes in children is limited. Therefore, efficacy data from adults cannot be extrapolated to this population. Further, famciclovir has not been studied in children 1 to <12 years of age with recurrent genital herpes. None of the children in Study 2 had genital herpes.
Herpes labialis: There are no pharmacokinetic and safety data in children 1 to <12 years of age to support a famciclovir dose that provides penciclovir systemic exposures comparable to the penciclovir systemic exposures in adults after a single dose administration of 1500 mg. Moreover, no efficacy data have been obtained in children 1 to <12 years of age with recurrent herpes labialis.
Study 3 was an open-label, single-arm study to evaluate the pharmacokinetics, safety, and antiviral activity of a single 1500 mg dose (three 500 mg tablets) of famciclovir in children 12 to <18 years of age with recurrent herpes labialis. A total of 53 subjects were enrolled in the study; 10 subjects in the pharmacokinetic part of the study and 43 subjects in the non-pharmacokinetic part of the study. All enrolled subjects weighed â‰¥40 kg. The 43 subjects enrolled in the non-pharmacokinetic part of the study had active recurrent herpes labialis and received a single 1500 mg dose of famciclovir within 24 hours after the onset of symptoms (median time to treatment initiation was 21 hours). The safety profile of famciclovir observed in this study was similar to that seen in adults. The median time to healing of patients with non-aborted lesions was 5.9 days.
In a phase 3 trial in adults in which patients received a single 1500 mg dose of famciclovir or placebo, the median time to healing among patients with non-aborted lesions was 4.4 days in the famciclovir 1500 mg single-dose group and 6.2 days in the placebo group. Of note, in the adult study treatment was initiated by patients within 1 hour after the onset of symptoms. Based on the efficacy results in Study 3, famciclovir is not recommended in children 12 to <18 years of age with recurrent herpes labialis.
Of 816 patients with herpes zoster in clinical studies who were treated with , 248 (30.4%) were â‰¥65 years of age and 103 (13%) were â‰¥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 , 26 (4.3%) were >65 years of age and 7 (1.1%) were >75 years of age. Clinical studies of in patients with recurrent genital herpes did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to 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 in elderly patients reflecting the greater frequency of decreased renal function and concomitant use of other drugs.
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 (CLCR 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
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.
Patients with Hepatic Impairment
Mild or moderate hepatic impairment (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 (Cmax) and the time to maximum plasma concentration (tmax) was increased by 0.75 hours in patients with hepatic impairment compared to normal volunteers. No dosage adjustment is recommended for patients with mild or moderate hepatic impairment. The pharmacokinetics of penciclovir has not been evaluated in patients with severe hepatic impairment. Conversion of famciclovir to the active metabolite penciclovir may be impaired in these patients resulting in a lower penciclovir plasma concentrations, and thus possibly a decrease of efficacy of famciclovir.
Black and African American Patients
In a randomized, double-blind, placebo-controlled trial conducted in 304 immunocompetent black and African American adults with recurrent genital herpes there was no difference in median time to healing between patients receiving or placebo. In general, the adverse reaction profile was similar to that observed in other clinical trials for adult patients. The relevance of these study results to other indications in black and African American patients is unknown.
Mechanism of Action
Famciclovir is an orally administered prodrug of the antiviral agent penciclovir.
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 needs to be adjusted in patients with different degrees of renal impairment .
Pharmacokinetics in adults:
Absorption and Bioavailability: The absolute bioavailability of penciclovir is 77 Â± 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.
Following oral single-dose administration of 500 mg famciclovir to 7 patients with herpes zoster, the AUC (mean Â± SD), Cmax, and tmax were 12.1Â±1.7 mcg hr/mL, 4.0Â±0.7 mcg/mL, and 0.7Â±0.2 hours, respectively. The AUC of penciclovir was approximately 35% greater in patients with herpes zoster as compared to healthy volunteers. Some of this difference may be due to differences in renal function between the 2 groups.
There is no accumulation of penciclovir after the administration of 500 mg famciclovir three times daily for 7 days.
Penciclovir 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, can be taken without regard to meals.
Distribution: The volume of distribution (VdÎ²) was 1.08Â±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 .
Elimination: Approximately 94% of administered radioactivity was recovered in urine over 24 hours (83% of the dose was excreted in the first 6 hours) after the administration of 5 mg/kg radiolabeled penciclovir as a 1-hour infusion to 3 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 3 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 Â± SD total plasma clearance of penciclovir was 36.6Â±6.3 L/hr (0.48Â±0.09 L/hr/kg). Penciclovir renal clearance accounted for 74.5Â±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 27.7Â±7.6 L/hr. Active tubular secretion contributes to the renal elimination of penciclovir.
The plasma elimination half-life of penciclovir was 2.0Â±0.3 hours after intravenous administration of penciclovir to 48 healthy male volunteers and 2.3Â±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 2.8Â±1.0 hours and 2.7Â±1.0 hours after single and repeated doses, respectively.
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 2 groups. No famciclovir dosage adjustment based on age is recommended unless renal function is impaired.
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 .
Patients with hepatic impairment: Mild or moderate hepatic impairment had no effect on the extent of availability (AUC) of penciclovir [see Use in Specific Populations (8.7)]. No dosage adjustment is recommended for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of penciclovir has not been evaluated.
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 9.3Â±1.9 mcg hr/mL and 11.1Â±2.1 mcg hr/mL in males and females, respectively. Penciclovir renal clearance was 28.5Â±8.9 L/hr and 21.8Â±4.3 L/hr, respectively. These differences were attributed to differences in renal function between the 2 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 of renal impairment (single and repeat dose) and a study in subjects with hepatic impairment (single dose) did not indicate any significant differences in the pharmacokinetics of penciclovir between black and Caucasian subjects.
|| See FDA approved Prescribing Information from Brand Manufacturer |||Manufacturer's|
| | Latest mph edition: 22 Dec 2013 |
||| Back to top ||