Famciclovir is an oral antiviral agent. It is the diacetyl 6-deoxy analog of the active antiviral agent penciclovir. Penciclovir itself is marketed as a topical and intravenous antiviral agent. Penciclovir has a similar spectrum of activity to acyclovir but has a longer duration of action due to a longer intracellular half-life. Thus, famciclovir can be dosed less frequently than oral acyclovir. Twice daily dosing of oral famciclovir has been shown effective in suppressing HSV-2 infection in HIV-positive patients. Despite the bioavailability and duration of action advantages for famciclovir/penciclovir, acyclovir possesses a higher affinity for the target enzyme than penciclovir. Famciclovir was originally FDA-approved on June 30, 1994. Famciclovir is FDA-approved for treatment of acute herpes zoster (shingles), treatment or suppression of recurrent genital herpes in immunocompetent patients, acute treatment of recurrent herpes labialis (cold sores) in immunocompetent patients, and treatment of recurrent mucocutaneous herpes simplex infection in HIV-infected patients.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Famciclovir may be administered without regard to meals.
During clinical trials, episodes of headache and migraine were experienced by 8.5 to 39.3% and 0.2 to 3.1% of famciclovir recipients, respectively. Other neurologic adverse events included fatigue (0.6 to 4.8%) and paresthesias (0.9 to 2.6%). Cases of seizures, confusion, delirium, disorientation, dizziness, drowsiness, and hallucinations have been noted during the post-marketing period. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
During clinical trials for genital herpes suppression, 0.2% of famciclovir recipients and 0.3% of patients receiving placebo experienced increased serum creatinine > 1.5 x upper limits of normal. Patients with underlying renal dysfunction have developed acute renal failure (unspecified) after receiving inappropriately high doses of famciclovir. Dosage reduction is recommended for patients with preexisting renal impairment (See Indications/Dosage).
Gastrointestinal/digestive adverse events have been associated with famciclovir treatment. During clinical trials, nausea (2.2-12.5%), vomiting (0.7-5%), abdominal pain (0.2-7.9%), diarrhea (1.6-9%), and flatulence (0.2-4.8%) were reported. Additionally, cases of hyperamylasemia (> 1.5 x upper limit of normal, ULN) and elevated lipase concentrations (> 1.5 x ULN) were reported in 1.5% and 4.9% of famciclovir recipients, respectively.
During clinical trials, rash (unspecified) and pruritus were observed in 0.4 to 3.3% and 2.2 to 3.7% of famciclovir recipients, respectively. Other adverse events reported during the post-marketing period include urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, hypersensitivity vasculitis, anaphylactic shock, anaphylactoid reactions, and angioedema. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
Hematologic adverse events observed in patients receiving treatment with famciclovir for genital herpes suppression include anemia (0.1%, < 0.8 x lower limits of normal, LLN), leukopenia (1.3%, < 0.75 x LLN), and neutropenia (3.2%, < 0.8 x LLN). Cases of thrombocytopenia have been noted during the post-marketing period. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
Cases of hyperbilirubinemia (> 1.5 x upper limit of normal, ULN) and elevated hepatic enzymes (> 2 x ULN) were observed in 1.9% and 2.3-3.2%, respectively, of patients receiving famciclovir during clinical trials for genital herpes suppression. Additionally, famciclovir has been associated with the development of cholestatic jaundice during the post-marketing period. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
During clinical trials, dysmenorrhea was reported by 0.4-7.6% of famciclovir recipients and 0.6-6.3% of patients receiving placebo.
Famciclovir has been associated with the development of palpitations during the post-marketing period.
Patients who have developed famciclovir hypersensitivity or penciclovir hypersensitivity should not receive famciclovir. Because of similar chemical structures and possible cross-sensitivity, famciclovir should not be used in patients with acyclovir hypersensitivity, ganciclovir hypersensitivity, valacyclovir hypersensitivity, or valganciclovir hypersensitivity. Alternative agents such as foscarnet or cidofovir may be suitable since they are not structurally related to these antivirals.
Renal clearance of penciclovir (the active metabolite of famciclovir) is decreased in patients with renal impairment. Lower doses of famciclovir are suggested for patients with creatinine clearance values less than 60 ml/min, including patients with renal failure receiving dialysis. Acute renal failure has been reported in patients receiving inappropriately high doses of famciclovir for their level of renal function. Geriatric patients over age 65 years may also have reduced rates of clearance which, in part, may be due to changes in renal function.
Safe use of famciclovir in neonates, infants, children, and adolescents under the age of 18 years has not been established.
The efficacy of famciclovir in other herpes infection such as ophthalmic zoster, disseminated zoster (varicella), or immunocompromised patients with herpes zoster has not been determined.
Available data from pharmacovigilance reports have not associated use of famciclovir during pregnancy with any increased risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. Similarly, animal reproduction studies have not identified any evidence of teratogenicity. Although there are fetal risks associated with untreated herpes simplex virus during pregnancy, famciclovir should only be used during pregnancy when the benefits to the mother outweigh risks to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to famciclovir, health care providers are encouraged to register patients in the Famvir Pregnancy Registry by calling 888-669-6682.
According to the manufacturer, famciclovir should only be used in nursing mothers if the potential benefits to the mother outweigh the potential risks to the infant. It is not known if penciclovir, a metabolite of famciclovir, is excreted into human milk and there is no published experience with famciclovir during breast-feeding; thus, other agents may be preferred. Acyclovir and valacyclovir may be potential alternatives to consider during breast-feeding. However, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
This drug may also have activity against the following microorganisms: Epstein-Barr virus
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.
For the treatment of herpes zoster (shingles) infection:
NOTE: The efficacy of famciclovir has not been studied in ophthalmic zoster or disseminated zoster.
-for the treatment of herpes zoster (shingles) infection in immunocompetent patients:
Oral dosage:
Adults: 500 mg PO 3 times daily for 7 days, beginning as soon as possible after diagnosis, preferably within 48 hours of rash onset. Efficacy of therapy initiated more than 72 hours after rash onset has not been studied. The treatment of acute herpes zoster (shingles) with famciclovir will significantly decrease the incidence and duration of postherpetic neuralgia.
Adolescents*: 500 mg PO 3 times daily for 7 days. Initiate as soon as possible after diagnosis, preferably within 48 hours of rash onset. Efficacy of therapy initiated more than 72 hours after rash onset has not been studied.
-for the treatment of herpes zoster (shingles) infection in persons living with HIV*:
Oral dosage:
Adults: 500 mg PO 3 times daily for 7 to 10 days for localized infection; a longer duration of therapy may be required if lesions are slow to resolve. For those with extensive cutaneous lesions or visceral involvement, use as stepdown therapy after IV acyclovir to complete a 10- to 14-day course.
Adolescents: 500 mg PO 3 times daily for 7 to 10 days for localized infection; a longer duration of therapy may be required if lesions are slow to resolve. For those with extensive cutaneous lesions or visceral involvement, use as stepdown therapy after IV acyclovir to complete a 10- to 14-day course.
For the treatment of herpes simplex virus infection including herpes genitalis and herpes labialis:
-for the treatment of initial episode* of herpes genitalis in immunocompetent patients:
Oral dosage:
Adults: 250 mg PO 3 times daily for 7 to 10 days or until clinical resolution.
Children weighing 45 kg or more and Adolescents: 250 mg PO 3 times daily for 7 to 10 days or until clinical resolution.
-for the treatment of initial episode* of herpes genitalis in persons living with HIV:
Oral dosage:
Adults: 500 mg PO twice daily for 7 to 10 days or until clinical resolution.
Adolescents: 500 mg PO twice daily for 7 to 10 days or until clinical resolution.
-for the treatment of recurrent herpes genitalis in immunocompetent patients:
Oral dosage:
Adults: 1,000 mg PO twice daily for 1 day; 500 mg PO once, then 250 mg PO twice daily for 2 days; or 125 mg PO twice daily for 5 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset. Efficacy has not been established when treatment is initiated more than 6 hours after onset of symptoms or lesion formation.
Children* weighing 45 kg or more and Adolescents*: 1,000 mg PO twice daily for 1 day; 500 mg PO once, then 250 mg PO twice daily for 2 days; or 125 mg PO twice daily for 5 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset. Efficacy has not been established when treatment is initiated more than 6 hours after onset of symptoms or lesion formation.
-for the treatment of recurrent herpes genitalis in persons living with HIV:
Oral dosage:
Adults: 500 mg PO twice daily for 5 to 10 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset. Efficacy has not been established when treatment is initiated more than 48 hours after onset of symptoms or lesion formation.
Adolescents*: 500 mg PO twice daily for 5 to 10 days. Treatment should begin at the first sign or symptom, either during the prodrome or within 1 day of lesion onset. Efficacy has not been established when treatment is initiated more than 48 hours after onset of symptoms or lesion formation.
-for the treatment of recurrent herpes labialis in immunocompetent patients:
Oral dosage:
Adults: 1,500 mg PO as a single dose at the first sign or symptom of a cold sore.
Adolescents*: 1,500 mg PO as a single dose at the first sign or symptom of a cold sore.
Children 12 years*: Not approved for use in patients younger than 18 years of age. Safety and efficacy for the treatment of recurrent herpes labialis in children was evaluated during an open-label, single-arm study. Pediatric patients were enrolled if between the ages of 12 and 17 years and weighed 40 kg or more. Within 24 hours of symptom onset, 43 pediatric patients were administered a single 1,500 mg dose (median time to initiation was 21 hours). Comparing the study results with an adult study found the safety profiles to be similar; however, efficacy (defined as the median time to healing) was lower in the pediatric population. In pediatric patients, the median time to healing of non-aborted lesions was 5.9 days compared with 4.4 days for adult. It is important to note that in the adult study, treatment was initiated within 1 hours of symptom onset.
-for the treatment of recurrent herpes labialis in persons living with HIV:
Oral dosage:
Adults: 500 mg PO twice daily for 5 to 10 days at the first sign or symptom of a cold sore. Efficacy has not been established when treatment is initiated more than 48 hours after onset of symptoms or lesion formation.
Adolescents*: 500 mg PO twice daily for 5 to 10 days at the first sign or symptom of a cold sore. Efficacy has not been established when treatment is initiated more than 48 hours after onset of symptoms or lesion formation.
For herpes genitalis prophylaxis or secondary genital herpes simplex infection prophylaxis (i.e., long-term suppressive therapy) in patients with frequent or severe recurrences:
-for long-term suppressive therapy of recurrent herpes genitalis in immunocompetent patients:
Oral dosage:
Adults: 250 mg PO twice daily. The safety and efficacy beyond 1 year has not been established.
Children* weighing 45 kg or more and Adolescents*: 250 mg PO twice daily. The safety and efficacy beyond 1 year has not been established.
-for long-term suppressive therapy of recurrent herpes genitalis in persons living with HIV*:
Oral dosage:
Adults: 500 mg PO twice daily. Although safety and efficacy beyond 1 year have not been established, guidelines suggest suppressive therapy may be continued indefinitely (without regard to CD4 count). A review of the continued need should be conducted annually.
Children weighing 45 kg or more and Adolescents: 500 mg PO twice daily. Although safety and efficacy beyond 1 year have not been established, guidelines suggest suppressive therapy may be continued indefinitely (without regard to CD4 count). A review of the continued need should be conducted annually.
For the adjunctive treatment of Bell's palsy* in combination with steroids:
Oral dosage:
Adults: 250 mg PO 3 times daily for 5 to 7 days in combination with an oral corticosteroid. Clinical practice guidelines suggest an antiviral plus oral corticosteroid within 72 hours of symptom onset to modestly increase probability of functional facial nerve recovery.
For the treatment of varicella (chickenpox) infection*:
-for the treatment of uncomplicated varicella (chickenpox) infection* in immunocompromised patients:
Oral dosage:
Adults: 500 mg PO 3 times daily for 5 to 7 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours).
Adolescents: 500 mg PO 3 times daily for 5 to 7 days. Initiate therapy at the first sign of symptoms (i.e., within 24 hours).
-for the treatment of severe or complicated varicella (chickenpox) infection* in immunocompromised patients as stepdown therapy from IV acyclovir:
Oral dosage:
Adults: 500 mg PO 3 times daily for a total treatment course of 7 to 10 days.
Adolescents: 500 mg PO 3 times daily for a total treatment course of 7 to 10 days.
For the treatment of herpes simplex ocular infection*, including herpes simplex virus epithelial keratitis*, herpes simplex virus stromal keratitis*, and herpes simplex virus endothelial keratitis*:
-for the treatment of dendritic epithelial keratitis:
Oral dosage:
Adults: 250 mg PO twice daily for 7 to 10 days.
-for the treatment of geographic epithelial keratitis:
Oral dosage:
Adults: 500 mg PO twice daily for 14 to 21 days.
-for the treatment of non-necrotizing stromal keratitis:
Oral dosage:
Adults: 250 mg PO once or twice daily plus topical ophthalmic steroid for at least 10 weeks.
-for the treatment of necrotizing stromal keratitis:
Oral dosage:
Adults: 500 mg PO 2 to 3 times daily for 7 to 10 days plus topical ophthalmic steroid, then 250 mg PO twice daily for the duration of topical ophthalmic steroid use.
-for the treatment of endothelial keratitis:
Oral dosage:
Adults: 250 to 500 mg PO twice daily for 7 to 10 days plus topical ophthalmic steroid, then 250 mg PO twice daily for the duration of topical ophthalmic steroid use.
For the treatment of herpes zoster ocular infection (herpes zoster ophthalmicus), including viral conjunctivitis:
-for the treatment of herpes zoster ocular infection in immunocompetent patients:
Oral dosage:
Adults: 500 mg PO 3 times daily for 7 days. Initiate therapy within 48 to 72 hours of rash onset.
Children and Adolescents 12 to 17 years*: 500 mg PO 3 times daily for 7 days. Initiate therapy within 48 to 72 hours of rash onset.
-for the treatment of herpes zoster ocular infection in immunocompromised patients*:
NOTE: Oral therapy can be considered for those who are not severely immunosuppressed.
Oral dosage:
Adults: 500 mg PO 3 times daily for 7 to 14 days. Initiate therapy within 48 to 72 hours of rash onset.
Children and Adolescents 12 to 17 years: 500 mg PO 3 times daily for 7 to 14 days. Initiate therapy within 48 to 72 hours of rash onset.
Maximum Dosage Limits:
-Adults
2,000 mg/day PO for single-day therapy or 1,500 mg/day PO for multiple-day therapy.
-Geriatric
2,000 mg/day PO for single-day therapy or 1,500 mg/day PO for multiple-day therapy.
-Adolescents
Safety and efficacy have not been established; however, doses up to 2,000 mg/day PO for single-day therapy or 1,500 mg/day PO for multiple-day therapy have been used off-label.
-Children
weight 45 kg or more: Safety and efficacy have not been established; however, doses up to 2,000 mg/day PO for single-day therapy or 1,000 mg/day PO for multiple-day therapy have been used off-label.
weight less than 45 kg: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is recommended for patients with well-compensated hepatic impairment. The pharmacokinetics of penciclovir (the active moiety of famciclovir) have not been evaluated in patients with severe uncompensated hepatic impairment.
Patients with Renal Impairment Dosing
Treatment of herpes zoster:
CrCl 60 mL/minute or more: no dosage adjustment needed.
CrCl 40 to 59 mL/minute: 500 mg PO every 12 hours.
CrCl 20 to 39 mL/minute: 500 mg PO every 24 hours.
CrCl less than 20 mL/minute: 250 mg PO every 24 hours.
Acute treatment of recurrent herpes genitalis in immunocompetent patients:
CrCl 60 mL/minute or more: no dosage adjustment needed.
CrCl 40 to 59 mL/minute: 500 mg PO every 12 hours for 1 day.
CrCl 20 to 39 mL/minute: 500 mg PO single dose.
CrCl less than 20 mL/minute: 250 mg PO single dose.
Acute treatment of recurrent herpes labialis in immunocompetent patients:
CrCl 60 mL/minute or more: no dosage adjustment needed.
CrCl 40 to 59 mL/minute: 750 mg PO single dose.
CrCl 20 to 39 mL/minute: 500 mg PO single dose.
CrCl less than 20 mL/minute: 250 mg PO single dose.
Herpes genitalis prophylaxis in immunocompetent patients:
CrCl 40 mL/minute or more: no dosage adjustment needed.
CrCl 20 to 39 mL/minute: 125 mg PO every 12 hours.
CrCl less than 20 mL/minute: 125 mg PO every 24 hours.
Recurrent orolabial and genital herpes simplex in HIV-infected patients:
CrCl 40 mL/minute or more: no dosage adjustment needed.
CrCl 20 to 39 mL/minute: 500 mg PO every 24 hours.
CrCl less than 20 mL/minute: 250 mg PO every 24 hours.
Intermittent hemodialysis
For recurrent genital herpes or herpes labialis in immunocompetent patients, give 250 mg PO as a single dose following dialysis session. For herpes genitalis prophylaxis in immunocompetent patients, give 125 mg PO after each dialysis session. For herpes zoster and recurrent herpes simplex virus infection in HIV-infected patients, give 250 mg PO after each dialysis session.
*non-FDA-approved indication
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) If possible, discontinue famciclovir at least 24 hours before administration of the varicella-zoster virus vaccine, live. Also, do not administer famciclovir for at least 14 days after vaccination. Concurrent administration of any of the varicella-zoster virus vaccines (Zostavax, Varivax, ProQuad) with antiviral medications known to be effective against varicella zoster virus has not been evaluated. Therefore, when possible, a washout period between the use of the antiviral medication and the vaccines is recommended. Refer to the most recent Center for Disease control guidance if concurrent use is necessary.
Probenecid: (Moderate) Probenecid undergoes both renal tubular secretion and renal tubular reabsorption. Concomitant administration of probenecid with famciclovir may impair clearance of the active metabolite, penciclovir. Probenecid should be avoided during therapy with famciclovir.
Probenecid; Colchicine: (Moderate) Probenecid undergoes both renal tubular secretion and renal tubular reabsorption. Concomitant administration of probenecid with famciclovir may impair clearance of the active metabolite, penciclovir. Probenecid should be avoided during therapy with famciclovir.
Talimogene Laherparepvec: (Major) Consider the risks and benefits of treatment with talimogene laherparepvec before administering acyclovir or other antivirals to prevent or manage herpetic infection. Talimogene laherparepvec is a live, attenuated herpes simplex virus that is sensitive to acyclovir; coadministration with antiviral agents may cause a decrease in efficacy.
Varicella-Zoster Virus Vaccine, Live: (Major) If possible, discontinue famciclovir at least 24 hours before administration of the varicella-zoster virus vaccine, live. Also, do not administer famciclovir for at least 14 days after vaccination. Concurrent administration of any of the varicella-zoster virus vaccines (Zostavax, Varivax, ProQuad) with antiviral medications known to be effective against varicella zoster virus has not been evaluated. Therefore, when possible, a washout period between the use of the antiviral medication and the vaccines is recommended. Refer to the most recent Center for Disease control guidance if concurrent use is necessary.
Penciclovir is the active antiviral compound produced by biotransformation of famciclovir. Penciclovir is a selective substrate for HSV-1, HSV-2, and varicella-zoster virus thymidine kinase (TK). Cellular kinases convert the monophosphate form of the drug to the triphosphate. In vitro studies show that penciclovir triphosphate selectively inhibits viral DNA polymerase by competing with deoxyguanosine triphosphate. Phosphorylation of penciclovir to a monophosphate form depends on viral TK, which only occurs in virus-infected cells. Inhibition of DNA synthesis of virus-infected cells inhibits viral replication. DNA synthesis in cells not infected with the virus is unaltered.
Penciclovir is active against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). The degree of antiviral activity is dependent on several factors, including the time interval between infection and treatment. Resistance of HSV and VZV to penciclovir can result from mutations in the viral TK and DNA polymerase genes. Mutations in the viral TK may lead to the complete loss of viral TK activity, reduced levels of TK activity, or alterations in the ability of viral TK to phosphorylate thymidine. The most common type of resistance is the loss of viral TK activity (TK negative isolates).
Famciclovir is administered orally.
Famciclovir undergoes almost complete deacetylation and oxidation to produce penciclovir and several inactive metabolites. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. The cytochrome P450 enzyme system appears to play little part in the metabolism of famciclovir. Penciclovir is about equally distributed in blood and plasma and < 20% bound to plasma proteins. Excretion is mostly renal, glomerular filtration and tubular secretion, with about 73% penciclovir excreted within 24 hours following oral administration and 27% excreted in the feces. Plasma elimination half-life is 2-3 hours. Reduced renal function affects clearance and indicates a dosage reduction. The intracellular half-life of penciclovir triphosphate is approximately 7 hours in VZV-infected cells, 10 hours in HSV-1 infected cells, and 20 hours in HSV-2 infected cells.
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration little or no famciclovir is detected in the plasma or urine. Famciclovir can be administered without regard to meals since the extent of systemic availability of penciclovir remains unaltered even though there may be a delay in absorption and time to peak concentration. Bioavailability of famciclovir is about 77%, much greater than that of acyclovir. Serum concentrations of penciclovir, a metabolite, are proportional to the dose of famciclovir, with no apparent accumulation over a 7 day treatment period. The time to reach maximum concentration is about 45-60 minutes.
-Special Populations
Hepatic Impairment
In patients with well-compensated chronic liver disease, there was no changes in the AUC of penciclovir (an active metabolite of famciclovir); however, there was a 44% decrease in penciclovir Cmax and the Tmax was increased by 0.75 hours as compared to normal volunteers. No dosage adjustment of famciclovir is necessary in patients with compensated liver disease. Patients with severe liver impairment may experienced decreased conversion of famciclovir to penciclovir, resulting in lower penciclovir serum concentrations and potentially diminished famciclovir efficacy. The pharmacokinetics of penciclovir have not been evaluated in patients with uncompensated liver disease.
Renal Impairment
The clearance of penciclovir, a metabolite of famciclovir, decreases linearly with reductions in renal function. Dosage adjustments for famciclovir in renal insufficiency are recommended.
Ethnic Differences
A retrospective analysis of famciclovir's pharmacokinetic parameters in Black and Caucasian adults revealed no significant differences due to race. Data for the analysis was obtained from single and repeated 500 mg doses in healthy volunteers, persons with renal impairment, and persons with hepatic impairment.
Other
Herpes Zoster Patients
The AUC of penciclovir, a famciclovir metabolite, was approximately 35% greater in patients with herpes zoster as compared to healthy individuals. Some of this difference may be due to differences in renal function between the two groups.