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  • CLASSES

    Other Systemic Antivirals

    DEA CLASS

    Rx

    DESCRIPTION

    Oral antiviral agent; prodrug for penciclovir
    Indicated for tx of acute herpes zoster, tx or suppression of recurrent genital herpes in immunocompetent patients, acute tx of recurrent herpes labialis in immunocompetent patients, and tx of recurrent mucocutaneous herpes simplex infection in HIV patients
    Similar spectrum of activity to acyclovir but longer duration of action

    COMMON BRAND NAMES

    Famvir

    HOW SUPPLIED

    Famciclovir/Famvir Oral Tab: 125mg, 250mg, 500mg

    DOSAGE & INDICATIONS

    For the treatment of herpes zoster (shingles) infection.
    Oral dosage

    NOTE: The efficacy of famciclovir has not been studied in ophthalmic zoster or disseminated zoster.

    Adults

    500 mg PO every 8 hours 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. For HIV-infected patients with localized infection, the HIV guidelines recommend treating for 7—10 days; a longer duration of therapy may be required if lesions are slow to resolve. For HIV-infected patients with extensive cutaneous lesions or visceral involvement, the guidelines recommend as stepdown therapy after IV acyclovir to complete a 10—14 day course. The treatment of acute herpes zoster (shingles) with famciclovir will significantly decrease the incidence and duration of postherpetic neuralgia.

    Adolescents

    For localized infection in HIV-infected patients, the HIV guidelines recommend 500 mg PO 3 times daily for 7—10 days; a longer duration of therapy may be required if lesions are slow to resolve. For patients with extensive cutaneous lesions or visceral involvement, the guidelines recommend as stepdown therapy after IV acyclovir to complete a 10—14 day course.

    For the treatment of herpes simplex virus infection including recurrent herpes genitalis and herpes labialis.
    For acute treatment of recurrent episodes of herpes genitalis.
    Oral dosage
    Adults

    In immunocompetent patients, 1000 mg PO twice daily for 1 day at the first sign or symptom. The CDC recommends either: 125 mg PO twice daily for 5 days; 1000 mg PO twice daily for 1 day; or 500 mg PO once then 250 mg PO twice daily for 2 days beginning during the prodrome or within 1 day of lesion onset. In HIV-infected patients, 500 mg PO twice daily for 7 days. Guidelines recommend treating for 5—14 days in HIV-infected patients. Efficacy has not been established when treatment is initiated more than 6 hours after onset of symptoms or lesion formation.

    Adolescents†

    500 mg PO twice daily for 5—14 days in HIV-infected patients is recommended by the HIV guidelines.

    For treatment of a first episode† of herpes genitalis.
    Oral dosage
    Adults

    The CDC recommends 250 mg PO 3 times daily for 7—10 days or until clinically resolved. In HIV-infected patients, 500 mg PO twice daily for 5—14 days is recommended by the HIV guidelines.

    Adolescents

    The American Academy of Pediatrics (AAP) recommends 250 mg PO 3 times daily for 7—10 days. In HIV-infected patients, 500 mg PO twice daily for 5—14 days is recommended by the HIV guidelines.

    For acute treatment of recurrent episodes of herpes labialis in immunocompetent patients or orolabial herpes in HIV-infected patients.
    Oral dosage
    Adults

    In immunocompetent patients, 1500 mg PO as a single dose at the first sign or symptom of a cold sore (e.g., tingling, itching, or burning). In HIV-infected patients, 500 mg PO twice daily for 7 days. Guidelines recommend treating for 5—10 days in HIV-infected patients.

    Adolescents†

    In HIV-infected patients, HIV guidelines recommend 500 mg PO twice daily for 5—10 days. 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. Within 24 hours of symptom onset, 43 pediatric patients were administered a single 1500 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 herpes genitalis prophylaxis.
    Oral dosage
    Adults

    In immunocompetent patients, 250 mg PO twice daily for up to 1 year for herpes genitalis is recommended. In HIV-infected patients, guidelines recommend 500 mg PO twice daily. Safety and efficacy beyond 1 year of treatment have not been established.

    Adolescents†

    In HIV-infected patients, 500 mg PO twice daily is recommended by the HIV guidelines.

    Children†

    In HIV-infected patients, 500 mg PO twice daily is recommended by the HIV gudielines for children old enough to receive adult dosing.

    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† in HIV-infected patients.
    Oral dosage
    Adults

    500 mg PO 3 times daily for 5—7 days is recommended by the HIV guidelines for uncomplicated infections or as stepdown treatment from IV acyclovir for a total treatment course of 7—10 days in patients with complicated infections.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2000 mg/day PO for single-day therapy or 1500 mg/day PO for multiple-day therapy.

    Elderly

    2000 mg/day PO for single-day therapy or 1500 mg/day PO for multiple-day therapy.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    •Treatment of herpes zoster:
    CrCl >= 60 mL/min: no dosage adjustment needed.
    CrCl 40—59 mL/min: 500 mg PO every 12 hours.
    CrCl 20—39 mL/min: 500 mg PO every 24 hours.
    CrCl < 20 mL/min: 250 mg PO every 24 hours.
    •Acute treatment of recurrent herpes genitalis in immunocompetent patients:
    CrCl >= 60 mL/min: no dosage adjustment needed.
    CrCl 40—59 mL/min: 500 mg PO every 12 hours for 1 day.
    CrCl 20—39 mL/min: 500 mg PO single dose.
    CrCl < 20 mL/min: 250 mg PO single dose.
    •Acute treatment of recurrent herpes labialis in immunocompetent patients:
    CrCl >= 60 mL/min: no dosage adjustment needed.
    CrCl 40—59 mL/min: 750 mg PO single dose.
    CrCl 20—39 mL/min: 500 mg PO single dose.
    CrCl < 20 mL/min: 250 mg PO single dose.
    •Herpes genitalis prophylaxis in immunocompetent patients:
    CrCl >= 40 mL/min: no dosage adjustment needed.
    CrCl 20—39 mL/min: 125 mg PO every 12 hours.
    CrCl < 20 mL/min: 125 mg PO every 24 hours.
    •Recurrent orolabial and genital herpes simplex in HIV-infected patients:
    CrCl >= 40 mL/min: no dosage adjustment needed.
    CrCl 20—39 mL/min: 500 mg PO every 24 hours.
    CrCl < 20 mL/min: 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.

    ADMINISTRATION

    Oral Administration

    Famciclovir may be administered without regard to meals.

    STORAGE

    Famvir:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Acyclovir hypersensitivity, famciclovir hypersensitivity, ganciclovir hypersensitivity, penciclovir hypersensitivity, valacyclovir hypersensitivity, valganciclovir hypersensitivity

    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.

    Dialysis, geriatric, renal failure, renal impairment

    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.

    Children, infants, neonates

    Safe use of famciclovir in neonates, infants, children, and adolescents under the age of 18 years has not been established.

    Herpes infection, varicella

    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.

    Pregnancy

    Although famciclovir is classified as pregnancy category B, only animal reproduction studies have been conducted producing no evidence of teratogenicity. No safety studies have been undertaken in humans. 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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    neutropenia / Delayed / 3.2-3.2
    elevated hepatic enzymes / Delayed / 2.3-3.2
    migraine / Early / 0.2-3.1
    hyperbilirubinemia / Delayed / 1.9-1.9
    hyperamylasemia / Delayed / 1.5-1.5
    leukopenia / Delayed / 1.3-1.3
    anemia / Delayed / 0.1-0.1
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known
    delirium / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    palpitations / Early / Incidence not known

    Mild

    headache / Early / 8.5-39.3
    nausea / Early / 2.2-12.5
    diarrhea / Early / 1.6-9.0
    abdominal pain / Early / 0.2-7.9
    dysmenorrhea / Delayed / 0.4-7.6
    vomiting / Early / 0.7-5.0
    fatigue / Early / 0.6-4.8
    flatulence / Early / 0.2-4.8
    pruritus / Rapid / 2.2-3.7
    rash (unspecified) / Early / 0.4-3.3
    paresthesias / Delayed / 0.9-2.6
    drowsiness / Early / Incidence not known
    dizziness / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Although famciclovir is classified as pregnancy category B, only animal reproduction studies have been conducted producing no evidence of teratogenicity. No safety studies have been undertaken in humans. 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.

    MECHANISM OF ACTION

    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).

    PHARMACOKINETICS

    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.

    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.