Famvir (Famciclovir)

FAMVIR™

SmithKline Beecham

Famciclovir

Antiviral Agent

Action And Clinical Pharmacology: Famciclovir is the orally administered pro-drug of the antiviral agent penciclovir. Famciclovir itself has no antiviral activity until it is biotransformed to penciclovir. Following oral administration little or no famciclovir is detected in plasma or urine since famciclovir is rapidly converted via deacetylation and oxidation to penciclovir. Studies in volunteers have shown that famciclovir is well absorbed and produces plasma penciclovir concentrations superior to those obtained following oral administration of penciclovir alone.

The mean bioavailability of penciclovir after administration of oral famciclovir is 77%. The mean peak plasma concentration of penciclovir, following a 500 mg oral dose of famciclovir was 3.3 µg/mL and occurred at a mean time of 0.89 hours postdose. Plasma concentration time curves of penciclovir are similar following single and repeat dosing. The terminal plasma elimination half-life of penciclovir after both single and repeat oral dosing with famciclovir is 2.3 hours. The elimination of famciclovir is by metabolism, principally to penciclovir and its 6-deoxy precursor, which are subsequently excreted in urine.

Penciclovir is a substituted guanine analogue with potent and selective antiviral activity against varicella zoster virus and other human herpes viruses. Penciclovir is in the same class of antiviral drugs as acyclovir, and both are phosphorylated by viral thymidine kinase and then by cellular enzymes to the active triphosphate form in virus-infected cells. Penciclovir triphosphate inhibits viral DNA polymerase competitively with deoxyguanosine triphosphate and is incorporated into the extending DNA chain, preventing significant chain elongation. Consequently, viral DNA synthesis and, therefore, viral replication are inhibited. Inhibition of the virus reduces the period of viral shedding, limits the degree of spread and level of pathology, and thereby facilitates healing.

Penciclovir is not readily phosphorylated in uninfected cells and does not inhibit cellular DNA synthesis even at concentrations ³20 times those achieved in clinical usage.

Clinical Trials: Herpes Zoster and Postherpetic Neuralgia: In patients with uncomplicated herpes zoster, famciclovir has been shown to significantly reduce the duration of virus shedding and to relieve the signs and symptoms of the disease.

A 7-day, double-blind, placebo-controlled trial was conducted in 419 patients with uncomplicated herpes zoster treated within 72 hours of initial lesion appearance. According to the randomization scheme, 138 patients were given famciclovir 500 mg t.i.d., 135 patients famciclovir 750 mg t.i.d. and 146 patients given placebo. No additional efficacy was demonstrated with the higher dose of famciclovir (750 mg t.i.d.), when compared to famciclovir 500 mg t.i.d. In the total population, 65.2% of patients had a positive viral culture at some time during their acute infection. Patients treated with famciclovir 500 mg had a shorter median duration of viral shedding (time to last positive viral culture) than did placebo-treated patients (1 day and 2 days, respectively; p=0.0001).

The times to loss of vesicles (p=0.01), loss of ulcers (p=0.01), and loss of crusts (p=0.05), were shorter for famciclovir 500 mg-treated patients than for placebo-treated patients in the overall study population.

The follow-up phase of this trial was designed to monitor the progression of postherpetic neuralgia (PHN) after treatment with either famciclovir or placebo for 7 days during acute infection. There was no difference in the incidence of postherpetic neuralgia between the treatment groups at the time of rash resolution. In the 186 patients (44.4% of total study population) who did develop postherpetic neuralgia, the median duration of postherpetic neuralgia was shorter in patients treated with famciclovir 500 mg than in those treated with placebo (63 days and 119 days, respectively; p=0.02).

A second 7-day, double-blind, controlled trial involved 545 patients with uncomplicated herpes zoster treated within 72 hours of initial lesion appearance. According to the randomization scheme, 134 patients received 250 mg t.i.d. of famciclovir, 134 patients received 500 mg t.i.d. of famciclovir, 138 patients received 750 mg t.i.d. of famciclovir and 139 patients received 800 mg of acyclovir given 5 times a day. Famciclovir was found to be as effective as acyclovir at all dose levels for cutaneous lesion healing parameters, time to loss of pain and viral shedding.

Genital Herpes Infections: Treatment of Recurrent Episodes: Famciclovir was studied in two placebo-controlled trials of 626 otherwise healthy patients with a recurrence of genital herpes who were treated with famciclovir 125 mg b.i.d. (n=160), famciclovir 250 mg b.i.d. (n=169), famciclovir 500 mg b.i.d. (n=154) or placebo (n=143) for 5 days. In the two studies combined, the median time to healing in famciclovir 125 mg-treated patients was 4 days compared to 5 days in placebo treated patients (p= 0.0001) and the median time to cessation of viral shedding was 1.8 vs 3.4 days in famciclovir 125 mg and placebo recipients, respectively (p= 0.0001). The median time to loss of all symptoms was 3.2 days in famciclovir 125 mg-treated patients vs 3.8 days in placebo treated patients (p= 0.0001). Pretreatment, self-obtained viral cultures were positive in 31%, 25%, 30% and 24% for the famciclovir 125 mg, 250 mg, 500 mg and placebo recipients respectively in the patient-initiated study. Of those patients whose pretreatment culture was negative, significantly fewer patients self-initiating famciclovir treatment went on to become viral culture positive compared to placebo. Patients initiating treatment early (during the prodrome) were half as likely to commence viral shedding compared to placebo patients. Additionally, in the clinic-initiated study, famciclovir reduced the number of patients who developed new lesions.

Famciclovir was also studied in three acyclovir-controlled, double-blind trials in 951 otherwise healthy patients with first episode genital herpes.

Famciclovir for 5 or 10 days provided comparable efficacy to acyclovir although the studies were not powered to show statistical equivalence.

Suppression of Recurrent Episodes: A total of 934 otherwise healthy adults with frequently recurring genital herpes, were enrolled in two 12-month, placebo-controlled studies. Patients either had at least six recurrences 12 months prior to study entry or a history of at least 6 recurrences per year while not receiving other suppressive therapies. Sixty-two percent of patients had experienced at least 12 genital herpes recurrences in the previous 24 months. Treatment arms consisted of famciclovir 125 mg t.i.d. (n=233), 250 mg b.i.d. (n=236), 250 mg t.i.d. (n=232) and placebo (n=233). Compared to placebo, famciclovir 250 mg b.i.d. significantly delayed the time to developing the first clinically confirmed recurrence by 10 months in one study (medians: >365 days for famciclovir vs. 67 days for placebo; p=0.0001) and 9.5 months in another study (medians: 336 days for famciclovir vs. 47 days for placebo; p=0.0001).

Indications And Clinical Uses: For the treatment of acute herpes zoster (shingles). Early treatment of acute herpes zoster (shingles) in immune-competent individuals with oral famciclovir resulted in decreased time to loss of vesicles; decreased time to loss of crusts; and decreased viral shedding.

The results of clinical studies indicate that early treatment of acute herpes zoster with oral famciclovir resulted in decreased duration of postherpetic neuralgia. Those most likely to benefit are patients who initiate treatment within 48 hours of onset of rash or are greater than 50 years of age or those patients with severe pain at the time of treatment initiation.

Famciclovir is indicated to treat or suppress recurrent episodes of genital herpes in immunocompetent adults.

In clinical studies of immunocompetent patients with recurrent genital herpes (typically ³6 episodes in a 12 month period) famciclovir suppressed lesional episodes, slowed the rate to first recurrence and patients were more likely to remain free from recurrences for a 12-month period. Suppressive therapy in patients with fewer than 6 episodes of genital herpes in a 12 month period was not evaluated in these clinical studies.

Initiation of famciclovir treatment of recurrent genital herpes during the prodrome or as soon as possible after the onset of lesions resulted in decreased duration of viral shedding, decreased time to lesion healing and decreased time to resolution of symptoms (including pain, tenderness, itching and burning).

Contra-Indications: Patients with known hypersensitivity to the product.

Precautions: General: The efficacy of famciclovir has not been established for first episode genital herpes infections, ophthalmic zoster, disseminated zoster or in immunocompromised patients (see Pharmacology). Dosage adjustment may be required when administering famciclovir to patients with moderate or severe renal dysfunction (see Dosage).

Genital herpes is a sexually transmitted disease with an increased risk of transmission during acute episodes. There are no data evaluating whether famciclovir will prevent transmission of infection to others. Patients should be advised to avoid intercourse when lesions and/or symptoms are present (even if treatment with an antiviral has been initiated) in order to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding.

Pregnancy: Although animal studies have not shown any embryotoxic or teratogenic effects with famciclovir or penciclovir, the safety of famciclovir in human pregnancy has not been established. Because animal reproductive studies are not always predictive of human response, famciclovir should, therefore, not be used in pregnancy unless the potential benefits are considered to outweigh the potential risks associated with treatment.

Lactation: Following oral administration of famciclovir to lactating rats, penciclovir is excreted in milk. It is not known whether it (penciclovir) is excreted in human milk, thus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Children: Safety and efficacy in children under the age of 18 years has not been established.

Geriatrics: Of 816 patients with herpes zoster in clinical studies who were treated with famciclovir, 248 (30.4%) were ³65 years of age and 103 (13%) were ³75 years of age. No overall differences were observed in safety between younger and older patients (see Adverse Effects).

Drug Interactions: No clinically significant alterations in penciclovir pharmacokinetics were observed following single dose administration of 500 mg famciclovir after pretreatment with multiple doses of cimetidine, allopurinol, theophylline or zidovundine. Furthermore, no clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose (t.i.d.) administration of famciclovir (500 mg) with multiple doses of digoxin. After single dose administration of 0.375 mg digoxin and 500 mg famciclovir in 12 healthy male volunteers, the Cmax of digoxin increased 19±18% as compared to digoxin administered alone. There was no change in digoxin AUC 0-t where t ranged from 10 to 72 hours. The pharmacokinetics of penciclovir or digoxin were not altered by concomitant administration of multiple doses of famciclovir (500 mg t.i.d.) and digoxin to 22 healthy volunteers for 14 days. Probenecid and other drugs that affect renal physiology could affect plasma levels of penciclovir. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. No clinically relevant drug interactions mediated via this enzyme are reported in the literature. Interactions with other drugs metabolized by aldehyde oxidase could potentially occur.

Impairment of Fertility: As with other drugs of this class, testicular toxicity has been observed in animals receiving both famciclovir and penciclovir. Two placebo-controlled studies in a total of 130 otherwise healthy men with normal sperm profile over an 8 week baseline period and recurrent genital herpes receiving oral famciclovir (250 mg bid) (n=66) or placebo (n=64) therapy for 18 weeks showed no evidence of significant effects on sperm count, motility or morphology during treatment or during an 8 week follow-up. Preliminary results of another placebo-controlled trial in a total of 117 otherwise healthy men with recurrent genital herpes and a normal sperm profile over an 8 week baseline period receiving famciclovir (250 mg bid, n=59) and placebo (n=58) therapy for 52 weeks showed no evidence of significant effects in sperm concentration, total sperm count, percent motility, percent abnormal morphology and percent dead sperm during treatment or during a 12 week follow-up.

Adverse Reactions: The most frequent adverse reactions reported during herpes zoster clinical trials with oral famciclovir 3 times daily.

Market Experience: During clinical practice, confusion (including delirium, disorientation, confusional state) has been reported. While infrequent, most of these spontaneous reports have occurred in the elderly.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No acute overdosage has been reported. Appropriate symptomatic and supportive therapy should be given. Penciclovir is dialyzable; plasma concentrations are reduced by approximately 75% following 4 hours hemodialysis.

Dosage And Administration: Herpes Zoster Infections: The recommended dose is 500 mg 3 times/day for 7 days. Therapy should be initiated within 72 hours of the onset of rash.

Genital Herpes Infections: Recurrent Episodes: The recommended dosage is 125 mg tablet twice a day for 5 days. Initiation of treatment is recommended during the prodromal period or as soon as possible after onset of lesions.

Suppression of Recurrent Episodes: The recommended dosage is 250 mg twice daily for up to 1 year. The safety and efficacy of Famvir therapy beyond 1 year of treatment has not been established.

Tablets should be swallowed whole and may be taken with or without food.

Hemodialysis Patients: The recommended dose of famciclovir is 250 mg (herpes zoster) or 125 mg (genital herpes) administered following each dialysis treatment.

Availability And Storage: 125 mg: Each white, round, film-coated tablet, with a raised hexagonal shaped area on both faces, debossed with FAMVIR on one side and 125 on the other, contains: famciclovir 125 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, sodium starch glycolate and titanium dioxide. Blister packages of 10.

250 mg: Each white, round, film-coated tablet, with a raised hexagonal shaped area on both faces, debossed with FAMVIR on one side and 250 on the other, contains: famciclovir 250 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, sodium starch glycolate and titanium dioxide. Bottles of 30 and 60.

500 mg: Each white, oval, film-coated tablet, debossed with FAMVIR on one side and 500 on the other, contains: famciclovir 500 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, sodium starch glycolate and titanium dioxide. Bottles of 21.

Store at controlled room temperature (15 to 30°C).

FAMVIR™ SmithKline Beecham Famciclovir Antiviral Agent

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