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famciclovir 125 mg tablet

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Uses

Oral famciclovir is used for the treatment of acute, localized herpes zoster (shingles, zoster). Oral famciclovir also is used for the treatment of genital herpes infections and for the suppression of recurrent episodes of genital herpes in immunocompetent adults. The drug also is used for the treatment of recurrent mucocutaneous herpes simplex virus (HSV) infections in adults with human immunodeficiency virus (HIV) infection. In addition, oral famciclovir is used for the episodic treatment of herpes labialis (perioral herpes, cold sores, fever blisters) in immunocompetent adults.

Genital Herpes

Treatment of First Episodes

Although the manufacturer states that efficacy of famciclovir for the treatment of initial episodes of genital herpes simplex virus (HSV) infection has not been established, famciclovir is considered a drug of choice for the treatment of initial episodes of genital herpes. Because many patients with first episodes of genital herpes present with mild clinical symptoms but later develop severe or prolonged symptoms, the US Centers for Disease Control and Prevention (CDC) states that most patients with initial genital herpes should receive antiviral therapy. The CDC and some clinicians recommend that first episodes of genital herpes be treated with a regimen of oral acyclovir (400 mg 3 times daily or 200 mg 5 times daily for 7-10 days), oral famciclovir (250 mg 3 times daily given for 7-10 days), or oral valacyclovir (1 g twice daily given for 7-10 days).

Studies have been initiated to compare the relative efficacy of oral famciclovir and oral acyclovir for the treatment of initial episodes of genital herpes in immunocompetent adults, and preliminary results indicate that oral famciclovir (125, 250, 500, or 750 mg 3 times daily) is as effective as oral acyclovir (200 mg 5 times daily) in terms of time to complete healing of lesions, resolution of symptoms, and time to cessation of viral shedding.

Episodic Treatment of Recurrent Episodes

Oral famciclovir is used in the treatment of recurrent episodes of genital herpes in immunocompetent adults. Antiviral therapy for recurrent genital herpes can be given episodically to ameliorate or shorten the duration of lesions or can be given continuously as suppressive therapy to reduce the frequency of recurrences. For episodic treatment of recurrent genital herpes, the CDC and some clinicians recommend oral acyclovir (400 mg 3 times daily for 5 days, 800 mg twice daily for 5 days, or 800 mg 3 times daily for 2 days), oral famciclovir (125 mg twice daily for 5 days or 1 g twice daily for 1 day), or oral valacyclovir (500 mg twice daily for 3 days or 1 g once daily for 5 days). Episodic antiviral therapy should be initiated within 1 day of lesion onset or during the prodrome that precedes some outbreaks. The manufacturer states that patients should be advised to initiate oral famciclovir at the first sign or symptom of an episode and that there are no data on the effectiveness of the drug initiated more than 6 hours after the onset of signs and symptoms of a recurrent episode.

Efficacy of oral famciclovir for the episodic treatment of recurrent genital herpes has been evaluated in randomized double-blind, placebo-controlled studies. In one study involving 329 immunocompetent adults who self-initiated treatment within 6 hours of appearance of lesions or onset of symptoms of recurrence, the median time to lesion healing of nonaborted lesions and resolution of all symptoms was 4.3 and 3.3 days, respectively, in patients who received oral famciclovir (1 g twice daily for 1 day) compared with 6.1 and 5.4 days, respectively, in those who received placebo. The proportion of patients with aborted lesions (no development beyond erythema) was larger in the famciclovir group than in the placebo group (23 versus 13%).

Combined data from 2 studies involving 626 otherwise healthy adults who self-initiated treatment within 6 hours of appearance of lesions or onset of symptoms of recurrence indicate that the median time to lesion healing and cessation of viral shedding was 4 and 1.8 days, respectively, in patients who received oral famciclovir (125 mg twice daily for 5 days) compared with 5 and 3.4 days, respectively, in those who received placebo. The median time to resolution of all symptoms was 3.2 days in those who received famciclovir versus 3.8 days in placebo-treated patients. There is no evidence that higher dosages of famciclovir (i.e., 250 or 500 mg twice daily) provide additional benefit in terms of time to lesion healing or relief of symptoms in immunocompetent adults.

Suppressive Therapy of Recurrent Episodes

Famciclovir is used for chronic suppressive therapy of recurrent genital herpes in immunocompetent adults. The CDC states that suppressive antiviral therapy can reduce the frequency of genital herpes recurrences by 70-80% in patients who have frequent recurrences (i.e., 6 or more per year) and many patients report no symptomatic outbreaks during such therapy. For chronic suppressive therapy of recurrent genital herpes, the CDC and some clinicians recommend a regimen of oral acyclovir (400 mg twice daily), oral famciclovir (250 mg twice daily), or oral valacyclovir (500 mg or 1 g once daily). The CDC states that data suggest that therapy with famciclovir or valacyclovir is as effective as acyclovir in terms of clinical outcome, although the 500 mg once-daily valacyclovir regimen might be less effective than acyclovir or other valacyclovir regimens in patients who have very frequent recurrences (i.e., 10 or more episodes per year).

In a study of patients with frequent recurrences of genital herpes infections (6 or more per year), 39 or 29% of those receiving famciclovir suppressive therapy (250 mg twice daily) were free of recurrences at 6 or 12 months, respectively, and 10 or 6% of those receiving placebo were free of recurrences at these time points. Safety and efficacy of oral famciclovir for suppressive therapy of recurrent genital herpes infections have been established in patients receiving daily therapy for up to 1 year.

HIV-Infected Individuals

Immunocompromised individuals may have prolonged or severe episodes of genital, perianal, or oral herpes; HSV lesions are common in those with human immunodeficiency virus (HIV) infection and may be severe, painful, and atypical.(See Uses: Mucocutaneous Herpes Simplex Virus Infections.)

The CDC states that episodic treatment or suppressive therapy with oral antiviral agents often is beneficial in HIV-infected individuals with genital herpes. While the drugs of choice for episodic treatment or suppressive therapy of genital herpes in HIV-infected individuals are the same as those in immunocompetent adults, higher dosages and/or more prolonged therapy may be necessary. For episodic treatment of recurrences of genital herpes in HIV-infected individuals, the CDC recommends a 5- to 10-day regimen of oral acyclovir (400 mg 3 times daily), oral famciclovir (500 mg twice daily), or oral valacyclovir (1 g twice daily). For daily suppressive therapy of recurrent genital herpes in HIV-infected individuals, the CDC recommends oral acyclovir (400-800 mg 2-3 times daily), oral famciclovir (500 mg twice daily), or oral valacyclovir (500 mg twice daily).

Patient Counseling and Management of Sexual Partners

Counseling of infected individuals and their sex partners is critical to management of genital herpes. The goals of such counseling are to help patients understand and cope with the infection and to prevent sexual and perinatal transmission of the virus. Antiviral therapy offers clinical benefit to most symptomatic patients and is the mainstay of management; however, genital herpes is a recurrent, life-long viral infection. Although antiviral therapy can be used to control the symptoms and signs of genital herpes episodes, it cannot eradicate latent HSV or affect the risk, frequency, or severity of recurrences of genital herpes when antiviral therapy is discontinued.

The majority of genital herpes infections are transmitted by individuals unaware that they have the infection or by individuals who are asymptomatic when transmission occurs. Patients should be advised that famciclovir is not a cure for genital herpes, and there are no data evaluating whether famciclovir prevents transmission of HSV to others. Because genital herpes is a sexually transmitted disease, patients should be advised to avoid sexual contact with uninfected partners when lesions and/or prodromal symptoms are present. In addition, patients should be advised that sexual transmission of the virus can occur during asymptomatic periods and that suppressive antiviral therapy reduces, but does not eliminate, subclinical viral shedding.

Sex partners of individuals with genital herpes should be advised that they may be infected even if they have no symptoms. Asymptomatic partners of patients with genital herpes should be questioned regarding a history of genital lesions, educated to recognize symptoms of genital herpes, and offered type-specific serologic testing to determine whether risk for HSV acquisition exists. Antiviral therapy is not recommended for sexual partners who do not have clinical manifestations of infection, but symptomatic sex partners of individuals with genital herpes should be evaluated and treated.

The risk for neonatal HSV infection should be discussed with all genital herpes patients, including men. Pregnant women and women of childbearing age who have genital herpes should inform their providers who care for them during pregnancy as well as those who will care for their neonates.

Information to assist patients and clinicians in counseling regarding genital herpes is available at http://www.ashastd.org and http://www.ihmf.org. For further information on treatment of initial or recurrent episodes of genital herpes or suppression of recurrent infections, .

Herpes Labialis

Famciclovir is used for the episodic treatment of herpes labialis (perioral herpes, cold sores, fever blisters) in immunocompetent adults.

Efficacy of a 1-day regimen of famciclovir was evaluated in healthy adults with a history of recurrent cold sores. Patients were randomized to famciclovir 1.5 g as a single dose, famciclovir 750 mg twice daily for 1 day, or placebo; patients self-initiated therapy within 1 hour of symptom onset. The median time to lesion healing of nonaborted lesions and resolution of symptoms (pain and tenderness) was 4.4 and 1.7 days, respectively, in patients who received the single-dose oral famciclovir regimen compared with 6.2 and 2.9 days, respectively, in those who received placebo. There was no difference between the famciclovir-treated and placebo-treated patients in aborted lesions (no development beyond the papular stage).

Mucocutaneous Herpes Simplex Virus Infections

Oral famciclovir is used for the treatment of recurrent mucocutaneous HSV infections (HSV-1 and HSV-2) in HIV-infected adults. The CDC, National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), and other experts state that orolabial HSV infections in HIV-infected individuals may be treated with oral acyclovir, oral famciclovir, or oral valacyclovir. IV acyclovir usually is indicated for initial treatment of moderate to severe mucocutaneous HSV infections in HIV-infected individuals but may be switched to oral antiviral therapy (acyclovir, famciclovir, valacyclovir) after lesions begin to regress. If acyclovir-resistant HSV is suspected, IV foscarnet or IV cidofovir is recommended for treatment.

In a comparative study in HIV-infected patients (40% had CD4 T-cell counts below 200/mm) with recurrent mucocutaneous HSV infections (54% with anogenital lesions, 35% with orolabial lesions) who initiated therapy within 48 hours of the onset of lesions, oral famciclovir (500 mg twice daily for 7 days) was as effective as oral acyclovir (400 mg 5 times daily for 7 days) in reducing formation of new lesions and time to complete healing.(See HIV-infected Individuals under Uses: Genital Herpes.)

Famciclovir also has been recommended for chronic suppressive or maintenance therapy (secondary prophylaxis) against HSV disease in HIV-infected adults or adolescents with frequent or severe recurrences. In patients with advanced HIV infection, reactivation of HSV frequently occurs and can result in chronic, persistent mucocutaneous disease that may be severe. The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) has established guidelines for the prevention of opportunistic infections in HIV-infected individuals that include recommendations concerning prevention of exposure to opportunistic pathogens, prevention of first disease episodes, and prevention of disease recurrence. The USPHS/IDSA does not recommend primary prophylaxis against initial episodes of HSV infection in HIV-infected adults, adolescents, or children. In addition, the USPHS/IDSA does not recommend routine chronic suppressive or maintenance therapy (secondary prophylaxis) against HSV disease in HIV-infected individuals since acute episodes of mucocutaneous disease generally can be treated successfully with acyclovir. However, these and other experts state that long-term prophylaxis against recurrence of HSV disease can be considered for HIV-infected adults, adolescents, and children who have frequent or severe recurrences. If secondary prophylaxis is indicated in HIV-infected adults or adolescents, the USPHS/IDSA, CDC, NIH, IDSA, and other experts recommend use of oral acyclovir, oral famciclovir, or oral valacyclovir. If indicated in infants and children, the USPHS/IDSA and other experts recommend use of oral acyclovir.

Herpes Zoster (Shingles, Zoster)

Oral famciclovir is used for the treatment of acute, localized herpes zoster (shingles, zoster) in immunocompetent adults. Some clinicians suggest that the drugs of choice for the treatment of herpes zoster in immunocompetent adults are oral acyclovir, oral famciclovir, or oral valacyclovir.

Efficacy of famciclovir in the treatment of acute, localized herpes zoster has been evaluated in a randomized, double-blind, placebo-controlled trial in immunocompetent adults and in a dose-ranging, double-blind trial in immunocompetent adults who were randomized to receive oral famciclovir (250, 500, or 750 mg 3 times daily for 7 days) or oral acyclovir (800 mg every 4 hours 5 times daily for 7 days). Results of these studies indicate that famciclovir may prevent the appearance of new lesions, decrease the duration of viral shedding, decrease the duration of pain, and promote healing and crusting of lesions in immunocompetent adults with localized herpes zoster when given within 72 hours of the onset of rash, particularly if initiated within 48 hours of rash onset. Like acyclovir, famciclovir does not appear to prevent the development of postherpetic neuralgia; the drug significantly decreases the median duration of neuralgia, particularly in patients older than 50 years of age. In comparative studies, 7 days of oral therapy with famciclovir (250-750 mg 3 times daily) was comparably effective to 7 days of oral therapy with acyclovir (800 mg 5 times daily). There were no statistically significant differences in the duration of postherpetic neuralgia between famciclovir- and acyclovir-treated patients.

Oral famciclovir has been used in a limited number of patients for the treatment of ophthalmic herpes zoster or disseminated herpes zoster or for the treatment of herpes zoster in immunocompromised patients; however, the manufacturer states that efficacy of famciclovir for the treatment of these infections has not been established. The CDC and other experts state that oral famciclovir or oral valacyclovir is the treatment of choice for localized dermatomal herpes zoster in HIV-infected adults or adolescents.

Hepatitis B Virus Infection

Famciclovir has been used for the management of chronic hepatitis B virus (HBV) infection in a limited number of patients. The drug also has been evaluated for the control of HBV recurrence in organ or bone marrow transplant recipients. While there is some evidence suggesting that famciclovir (250-500 mg 3 times daily) is effective for the management of HBV infection, further study is needed to establish safety and efficacy.

The CDC, NIH, IDSA, and other experts state that famciclovir is not recommended for the treatment of HBV infection in HIV-infected individuals since the drug is less active than lamivudine against HBV and is not active against lamivudine-resistant HBV.

Dosage and Administration

Administration

Famciclovir is administered orally without regard to meals. Food does not affect the systemic bioavailability or elimination of famciclovir.

Dosage

Genital Herpes

Treatment of First Episodes

If oral famciclovir is used for the treatment of initial episodes of genital herpes simplex virus (HSV) infection in immunocompetent adults or adolescents, the US Centers for Disease Control and Prevention (CDC) and other clinicians recommend that adults receive 250 mg 3 times daily for 7-10 days. The CDC states that the duration of treatment may be extended if healing is incomplete after 10 days of therapy.

In HIV-infected individuals, the CDC and other clinicians recommend a dosage of 500 mg twice daily for 7-14 days for the treatment of initial episodes of genital HSV infection.

Episodic Treatment of Recurrent Episodes

For the episodic treatment of recurrent genital herpes in immunocompetent adults, the dosage of oral famciclovir recommended by the manufacturer is 1 g twice daily for 1 day. The CDC and other clinicians recommend a dosage of 1 g twice daily for 1 day or 125 mg twice daily for 5 days.

In HIV-infected individuals, the CDC and other clinicians recommend a dosage of 500 mg twice daily for 5-10 days for the episodic treatment of recurrent genital herpes; alternatively, this dosage can be given for 7-14 days.

Patients should be advised to initiate famciclovir therapy at the first sign or symptom of an episode. Data are not available concerning efficacy of oral famciclovir initiated more than 6 hours after the onset of signs or symptoms of a recurrent episode of genital herpes.

Suppressive Therapy of Recurrent Episodes

For chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent adults, the recommended dosage of oral famciclovir is 250 mg every 12 hours.

In HIV-infected individuals, the CDC recommends a dosage of 500 mg twice daily for suppressive therapy of recurrent episodes of genital herpes. The manufacturer states that chronic suppressive therapy with oral famciclovir may be given for up to 1 year. Because the frequency of recurrent episodes diminishes over time in many patients, the CDC recommends that suppressive antiviral therapy be discontinued periodically (e.g., once yearly) to assess the need for continued therapy.

Herpes Labialis

For the treatment of herpes labialis (perioral herpes, cold sores, fever blisters) in immunocompetent adults, the recommended dosage of oral famciclovir is 1.5 g given as a single dose.

Treatment should be initiated at the first prodromal symptom of a cold sore (e.g., tingling, itching, burning).

Mucocutaneous Herpes Simplex Virus Infections

For the treatment of recurrent mucocutaneous HSV infections (i.e., orolabial or anogenital lesions) in adults with human immunodeficiency virus (HIV) infection, the usual dosage of oral famciclovir is 500 mg every 12 hours for 7 days. Some experts recommend a duration of 7-14 days.

If oral famciclovir is used for chronic suppressive or maintenance prophylaxis (secondary prophylaxis) of HSV in HIV-infected adults and adolescents who have frequent or severe recurrences of HSV disease, a dosage of 250 mg twice daily has been recommended by the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA).

Herpes Zoster

For the treatment of acute, localized herpes zoster (shingles, zoster) in immunocompetent adults, the recommended dosage of oral famciclovir is 500 mg every 8 hours for 7 days.

For the treatment of local dermatomal herpes zoster in HIV-infected adults, the CDC and other experts recommend 500 mg of famciclovir three times daily for 7-10 days.

Therapy should be initiated promptly after herpes zoster is diagnosed. Efficacy of famciclovir initiated more than 72 hours after rash onset has not been established.

Dosage in Renal and Hepatic Impairment

Dosage in Renal Impairment

Famciclovir is eliminated mainly by the kidneys via tubular secretion and glomerular filtration. In patients with moderately or severely impaired renal function, the frequency of administration of famciclovir should be decreased in response to the degree of impairment as indicated by creatinine clearance.

Because penciclovir (the active metabolite) is readily removed from plasma during hemodialysis, famciclovir should be administered after each hemodialysis session when the drug is used for the treatment of herpes zoster, treatment of recurrent mucocutaneous HSV infections in HIV-infected patients, or suppression of recurrent genital herpes. Famciclovir is administered once as a single dose after a hemodialysis session when the drug is used for the treatment of recurrent genital herpes or treatment of recurrent herpes labialis. The manufacturer recommends that a famciclovir dose (250 mg for patients with herpes zoster, 250 mg for HIV-infected patients with recurrent mucosal or cutaneous HSV infection, or 125 mg for patients receiving the drug for suppression of recurrent genital herpes) be administered following each hemodialysis session. The manufacturer recommends that a famciclovir dose (250 mg for patients with recurrent genital herpes, 250 mg for patients with recurrent herpes labialis) be administered once as a single dose after a hemodialysis session.

Genital Herpes

For episodic treatment of recurrent genital herpes in immunocompetent adults, the manufacturer states that patients with creatinine clearances of 60 mL/minute or greater may receive the usual oral famciclovir dosage of 1 g every 12 hours for 1 day. However, those with creatinine clearances of 40-59 mL/minute should receive 500 mg every 12 hours for 1 day, those with clearances of 20-39 mL/minute should receive 500 mg given as a single dose, and those with creatinine clearances less than 20 mL/minute should receive 250 mg given as a single dose.

For chronic suppressive therapy of recurrent genital herpes in immunocompetent adults with impaired renal function, the manufacturer states that patients with a creatinine clearance of 40 mL/minute or greater may receive the usual oral famciclovir dosage of 250 mg every 12 hours; those with creatinine clearances of 20-39 mL/minute or less than 20 mL/minute should receive 125 mg every 12 or 24 hours, respectively.

Herpes Labialis

For episodic treatment of recurrent herpes labialis in immunocompetent adults, the manufacturer states that patients with creatinine clearances of 60 mL/minute or greater may receive the usual oral famciclovir dosage of 1.5 g given as a single dose. However, those with creatinine clearances of 40-59 mL/minute should receive a single 750-mg dose, those with clearances of 20-39 mL/minute should receive a single 500-mg dose, and those with creatinine clearances less than 20 mL/minute should receive a single 250-mg dose.

Mucocutaneous Herpes Simplex Virus Infections

For the treatment of recurrent mucocutaneous HSV infections in HIV-infected adults with impaired renal function, the manufacturer states that patients with creatinine clearances of 40 mL/minute or greater may receive the usual oral famciclovir dosage of 500 mg every 12 hours; however those with creatinine clearances of 20-39 mL/minute should receive 500 mg once every 24 hours, and those with creatinine clearances less than 20 mL/minute should receive 250 mg once every 24 hours.

Herpes Zoster

For the treatment of localized herpes zoster in immunocompetent adults, the manufacturer states that patients with creatinine clearances of 60 mL/minute or greater may receive the usual oral famciclovir dosage of 500 mg every 8 hours. However, those with creatinine clearances of 40-59 mL/minute should receive 500 mg every 12 hours, those with creatinine clearances of 20-39 mL/minute should receive 500 mg once every 24 hours, and those with creatinine clearances less than 20 mL/minute should receive 250 mg once every 24 hours.

Dosage in Hepatic Impairment

Famciclovir is metabolized mainly in the liver to the active drug penciclovir. In patients with well-compensated chronic liver disease such as chronic hepatitis, chronic alcohol abuse, or primary biliary cirrhosis, bioavailability of penciclovir was not affected. Therefore, modification of famciclovir dosage is not necessary in patients with well-compensated liver disease. The manufacturer does not make specific recommendations for patients with uncompensated hepatic impairment, since the pharmacokinetics of famciclovir has not been evaluated in these patients.

Cautions

Famciclovir is well tolerated in immunocompetent patients with herpes zoster, genital herpes, or herpes labialis with an adverse effect profile similar to that of placebo. The most common adverse effects of the drug in both types of patients are headache, nausea, and diarrhea, and adverse effects usually are mild or moderate in severity. In controlled clinical trials in immunocompetent patients with herpes zoster, less than 1% of patients discontinued famciclovir as a result of severe adverse effects.

Similar adverse effects have been reported when famciclovir was used in patients with human immunodeficiency virus (HIV) infection, and the most frequent adverse effects in these patients are headache, nausea, and diarrhea.

Nervous System Effects

The most common adverse effect of famciclovir is headache, which occurred in approximately 23% of patients receiving the drug (versus in 18% of placebo recipients) in a large, controlled clinical trial for herpes zoster. Headache resulted in discontinuance of famciclovir in less than 1% of patients in clinical trials for herpes zoster or genital herpes. Fatigue was reported in 4.4% of patients receiving the drug (versus in 3.4% of placebo recipients) in a large, controlled clinical trial for herpes zoster. Dizziness, fever, paresthesia, and somnolence have occurred in patients receiving famciclovir in this clinical trial for herpes zoster.

Headache or fatigue occurred in 16 or 4%, respectively, of HIV-infected patients receiving famciclovir in clinical studies.

GI Effects

The most frequent adverse GI effect of famciclovir is nausea which occurred in approximately 13% of patients receiving the drug (versus in 11.6% in placebo recipients) in a large, controlled clinical trial for herpes zoster. Nausea resulted in discontinuance of famciclovir in less than 1% of patients in clinical trials for herpes zoster or genital herpes. Diarrhea was reported in approximately 8% of patients (5% of placebo recipients) and vomiting in approximately 5% of patients (3.4% of placebo recipients) in a large, controlled clinical trial for herpes zoster. Vomiting only rarely resulted in discontinuance of famciclovir in clinical trials for herpes zoster or genital herpes. Constipation, anorexia, abdominal pain, flatulence, and dyspepsia have occurred in patients receiving famciclovir in clinical trials for herpes zoster. Acute necroticohemorrhagic pancreatitis resulting in death has been reported following famciclovir administration for severe hepatitis B virus infection in a kidney graft recipient who was receiving cyclosporine concomitantly; a causal relationship to famciclovir was not established.

Nausea, diarrhea, vomiting, or abdominal pain has been reported in 11, 7, 5, or 3%, respectively, of HIV-infected patients receiving famciclovir in clinical studies.

Hepatic Effects

Increased serum concentrations of ALT (SGPT) occurred in 1.4-2.4% of patients receiving famciclovir in clinical trials for herpes zoster or genital herpes. Increased serum concentrations of alkaline phosphatase, total bilirubin, and albumin each occurred rarely in patients receiving the drug in clinical trials for herpes zoster or genital herpes.

Other Adverse Effects

Pruritus occurred in approximately 4% of patients (versus in about 3% of placebo recipients) receiving famciclovir in a large, controlled clinical trial for herpes zoster. Worsening of herpes zoster manifestations or complications has been reported in patients receiving the drug. Pharyngitis, sinusitis, injury, generalized pain, rigors, back pain, and arthralgia have occurred in patients receiving famciclovir in this clinical trial for herpes zoster. Increased serum phosphate concentrations occurred in 1.6% of patients receiving famciclovir in a large, placebo-controlled clinical trial for herpes zoster, and increased serum sodium or potassium concentrations and abnormal leukocyte counts each occurred rarely in patients receiving the drug in clinical trials for herpes zoster or genital herpes. Purpura has been reported rarely.

Acute renal failure has been reported in patients with renal disease who received doses of famciclovir that were inappropriately high for their level of renal function.

Precautions and Contraindications

Famciclovir is contraindicated in patients with known hypersensitivity to the drug.

The manufacturer recommends that the dosage interval of famciclovir be adjusted carefully in patients with impaired renal function to prevent drug accumulation while maintaining adequate plasma concentrations of penciclovir, the active metabolite of famciclovir.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Concomitant administration of famciclovir and probenecid or other drugs that are excreted extensively by active renal tubular secretion may result in increased plasma concentrations of penciclovir.

Each 125-, 250-, or 500-mg tablet of famciclovir contains 26.9, 53.7, or 107.4 mg of lactose, respectively. Patients with a history of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption should not be given famciclovir tablets.

Pediatric Precautions

Safety and efficacy of famciclovir in children younger than 18 years of age have not been established.

Geriatric Precautions

Safety and efficacy of famciclovir in geriatric patients have not been specifically studied to date; however, in clinical studies of famciclovir for the treatment of herpes zoster involving over 800 patients, approximately 56% of the patients were 50 years of age or older, 30% were 65 years of age or older, and 13% were 75 years of age and older. As in the overall population of patients, headache and nausea were the most frequently reported adverse effects among geriatric patients. Although no overall differences were observed between geriatric and younger patients in the type or frequency of adverse effects in clinical studies, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. Based on comparisons from different studies of the oral administration of famciclovir, the mean renal clearance of penciclovir (the active metabolite of famciclovir) was 22% lower and the area under the plasma concentration-time curve (AUC) for penciclovir was 40% higher in healthy geriatric individuals 65-79 years of age than in healthy younger individuals.

Clinical studies of famciclovir for the treatment of recurrent herpes simplex did not include a sufficient number of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults

Caution is advised when famciclovir is used in geriatric patients. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly should be considered.

Mutagenicity and Carcinogenicity

Famciclovir and penciclovir (the active metabolite of famciclovir) did not show evidence of genotoxicity in in vitro tests for gene mutations in bacteria (Salmonella typhimurium and Escherichia coli) or unscheduled DNA synthesis in mammalian HeLa 83 cells at doses up to 10,000 and 5000 mcg/plate, respectively. Famciclovir was not mutagenic in the L5178Y mouse lymphoma assay at a concentration of 5000 mcg/mL, in the in vivo mouse micronucleus test at a dose of 4.8 g/kg, or in the rat dominant lethal study at a dose of 5 g/kg. Famciclovir caused increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage at a concentration of 1200 mcg/mL. Penciclovir was mutagenic in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation at a concentration of 1000 mcg/mL. In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation at a concentration of 250 mcg/mL. Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered IV at a dose highly toxic to bone marrow (500 mg/kg) but not when administered orally.

Two-year dietary carcinogenicity studies of famciclovir were performed in rats and mice. After 7-8 months of drug administration, dosage was decreased from 750 to 600 mg/kg daily in female rats and in male and female mice and from 300 to 240 mg/kg daily in male rats to ensure long-term survival. An increase in the incidence of mammary adenocarcinoma was seen in female rats receiving 600 mg/kg daily (1.5-9 times the human systemic exposure at the recommended oral dosage of 500 mg 3 times daily or 125 mg twice daily based on the 24-hour AUC for penciclovir). Marginal increases in the incidence of subcutaneous tissue fibrosarcomas or squamous cell carcinomas of the skin were seen in female rats and male mice, respectively, at a dosage of 600 mg/kg daily (0.4-2.4 times the human systemic exposure based on the 24-hour AUC for penciclovir). No increases in tumor incidence occurred in male rats receiving dosages up to 240 mg/kg daily (0.9-5.4 times the human systemic exposure) or in female mice receiving dosages up to 600 mg/kg daily (0.4-2.4 times the human systemic exposure).

There currently is no evidence of mutagenicity or carcinogenicity in humans.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies using oral famciclovir dosages up to 1 g/kg daily in rats and rabbits (approximately 3.6-21.6 and 1.8-10.8 times the human systemic exposure to penciclovir, respectively, based on AUC comparisons) and IV dosages of 360 mg/kg daily in rats (2-12 times the human dose based on body surface area comparisons) or 120 mg/kg daily in rabbits (1.5-9 times the human dose based on body surface area comparisons) have not revealed evidence of adverse effects on embryofetal development. Similar studies using IV penciclovir dosages up to 80 mg/kg daily in rats (0.4-2.6 times the human dose based on body surface area comparisons) or 60 mg/kg daily in rabbits (0.7-4.2 times the human dose based on body surface area comparisons) also did not reveal evidence of adverse effects on embryofetal development. There are no adequate and well-controlled studies to date using famciclovir in pregnant women, and the drug should be used during pregnancy only when clearly needed.

To monitor maternal-fetal outcome of pregnant women exposed to famciclovir, the manufacturer maintains a Famciclovir Pregnancy Registry. The registry may be contacted by calling 888-669-6682.

Reproduction studies using famciclovir or penciclovir in rats, mice, and dogs revealed evidence of testicular toxicity following repeated oral administration of high dosages. Testicular changes, including atrophy of the seminiferous tubules, reduction in sperm count, and/or increased incidence of sperm with abnormal morphology or reduced motility, were observed. The degree of toxicity was related to dose and duration of exposure. In male rats, decreased fertility was observed following 10 weeks of dosing at 500 mg/kg daily (1.9-11.4 times the human AUC). Administration of famciclovir to male rats in dosages of 50 mg/kg daily (0.2-1.2 times the human systemic exposure based on AUC comparisons) for 26 weeks did not reveal evidence of sperm or testicular toxicity. Testicular toxicity was observed following administration of dosages of 600 mg/kg daily (0.4-2.4 times the human systemic exposure based on AUC comparisons) for 104 weeks in male mice and dosages of 150 mg/kg daily (1.7-10.2 times the human system exposure based on AUC comparisons) for 26 weeks in male dogs. No effect on spermatogenesis was observed in human males with genital herpes following oral famciclovir dosages of 250 mg twice daily for 18 weeks.

Fertility

Reproduction studies using oral famciclovir dosages up to 1 g/kg daily (3.6-21.6 times the human systemic exposure based on AUC comparisons) in female rats have not revealed evidence of impaired fertility or reproductive performance.

Lactation

It is not known whether famciclovir or penciclovir is distributed into milk in humans. Following oral administration of famciclovir to lactating rats, penciclovir was distributed into breast milk at concentrations higher than those observed in plasma. Data on safety of famciclovir in infants currently is not available.

Drug Interactions

Famciclovir not metabolized by CYP isoenzymes.

Drugs Eliminated by Renal Excretion

Potential increased plasma penciclovir concentrations when used concomitantly with other drugs eliminated by active renal tubular secretion (e.g., probenecid).

Drugs Metabolized by Aldehyde Oxidase

Potential pharmacokinetic interaction with other drugs metabolized by aldehyde oxidase.

Pharmacokinetics

Absorption

Bioavailability

Famciclovir, a prodrug of penciclovir, is rapidly and well absorbed following oral administration and metabolized to penciclovir. Little or no prodrug is present in plasma or urine.

Absolute bioavailability of penciclovir is 77% following oral administration of famciclovir; peak penciclovir plasma concentrations attained within 0.5-0.9 hours.

Pharmacokinetics in HIV-infected patients similar to healthy individuals.

Food

Administration of famciclovir with food decreases peak penciclovir plasma concentrations and delays time to peak concentrations but does not affect penciclovir AUC.

Distribution

Extent

Not known whether penciclovir crosses the placenta or is distributed into human milk.

Plasma Protein Binding

Penciclovir <20% bound to plasma proteins.

Elimination

Metabolism

Famciclovir is deacetylated and oxidized to penciclovir. Penciclovir is phosphorylated to penciclovir triphosphate (the active metabolite) in cells infected with HSV-1, HSV-2, or VZV. The inactive metabolite 6-deoxy penciclovir is converted to penciclovir by aldehyde oxidase.

Famciclovir not metabolized by CYP enzymes.

Elimination Route

Famciclovir eliminated principally by the kidneys as penciclovir and other metabolites. 73% of an oral famciclovir dose eliminated in urine and 27% eliminated in feces within 72 hours.

Half-life

Elimination half-life of penciclovir after oral administration of famciclovir 1.6-3 hours.

Intracellular half-life of penciclovir triphosphate in cells infected with HSV-1 or HSV-2 is 10 and 20 hours, respectively; intracellular half-life in VZV-infected cells is 7-14 hours.

Special Populations

AUC of penciclovir not affected when oral famciclovir used in patients with well-compensated chronic liver disease (chronic hepatitis, chronic ethanol abuse, primary biliary cirrhosis). Pharmacokinetics not evaluated in severe uncompensated hepatic impairment.

Renal clearance decreased and terminal elimination half-life increased in patients with renal impairment; half-life 6.2 hours if Clcr 20-39 mL/minute and 13.4 hours if Clcr <20 mL/minute.

AUC may be greater and renal clearance decreased in geriatric patients >=65 years of age, presumably because of decreased renal function.

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