FAMCICLOVIR TABLETS
8117
8118
8119
Rx only

Famciclovir tablets contain famciclovir, an orally administered prodrug of the antiviral agent penciclovir. Chemically, famciclovir is known as 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate. It is a synthetic acyclic guanine derivative and has the following structure:

C₁₄H₁₉N₅O₄ M.W. 321.3

Famciclovir is a white to pale yellow solid. It is freely soluble in acetone and methanol, and sparingly soluble in ethanol and isopropanol. At 25°C famciclovir is freely soluble (> 25% w/v) in water initially, but rapidly precipitates as the sparingly soluble (2% to 3% w/v) monohydrate. Famciclovir is not hygroscopic below 85% relative humidity. Partition coefficients are: octanol/water (pH 4.8) P = 1.09 and octanol/phosphate buffer (pH 7.4) P = 2.08.

Each white, film-coated tablet contains famciclovir. The 125 mg and 250 mg tablets are round; the 500 mg tablets are capsule-shaped. Inactive ingredients consist of croscarmellose sodium, hydroxypropyl cellulose, hypromellose, polydextrose, polyethylene glycol, silicified microcrystalline cellulose, sodium starch glycolate, sodium stearyl fumarate, titanium dioxide, and triacetin.

Famciclovir undergoes rapid biotransformation to the active antiviral compound penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2, or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted to penciclovir triphosphate by cellular kinases. In vitro studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited.

Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2-, and 7 hours in VZV-infected cells grown in culture; however, the clinical significance is unknown.

In cell culture studies, penciclovir is inhibitory to the following herpes viruses (uled in decreasing order of potency): HSV-1, HSV-2, and VZV. Sensitivity test results, expressed as the concentration of the drug required to inhibit the growth of the virus by 50% (EC₅₀) or 99% (EC₉₉) in cell culture, vary greatly depending upon a number of factors, including the assay protocols, and in particular the cell type used. See Table 1.

Penciclovir-resistant mutants of HSV and VZV can result from mutations in the viral thymidine kinase (TK) and DNA polymerase genes. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). The most commonly encountered acyclovir-resistant mutants that are TK negative are also resistant to penciclovir. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.

Famciclovir was studied in a placebo-controlled, double-blind trial of 419 immunocompetent adults with uncomplicated herpes zoster. Comparisons included famciclovir 500 mg t.i.d., famciclovir 750 mg t.i.d., or placebo. Treatment was begun within 72 hours of initial lesion appearance and therapy was continued for 7 days.

The median time to full crusting in famciclovir-treated patients was 5 day compared to 7 days in placebo-treated patients. The times to full crusting, loss of vesicles, loss of ulcers, and loss of crusts were shorter for famciclovir 500 mg-treated patients than for placebo-treated patients in the overall study population. The effects of famciclovir were greater when therapy was initiated within 48 hours of rash onset; it was also more pronounced in patients 50 years of age or older. Among the 65.2% of patients with at least one positive viral culture, famciclovir-treated patients had a shorter median duration of viral shedding than placebo-treated patients (1 day and 2 days, respectively).

There were no overall differences in the duration of pain before rash healing between famciclovir- and placebo-treated groups. In addition, there was no difference in the incidence of pain after rash healing (postherpetic neuralgia) between the treatment groups. 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). No additional efficacy was demonstrated with higher doses of famciclovir.

A double-blind controlled trial in 545 immunocompetent adults with uncomplicated herpes zoster treated within 72 hours of initial lesion appearance compared three doses of famciclovir to acyclovir 800 mg 5 times per day. Times to full lesion crusting and times to loss of acute pain were comparable for all groups and there were no statistically significant differences in the time to loss of postherpetic neuralgia between famciclovir- and acyclovir-treated groups.

A randomized, double-blind, multicenter study compared famciclovir 500 mg twice daily for 7 days (n = 150) with oral acyclovir 400 mg 5 times daily for 7 days (n = 143) in HIV-infected patients with recurrent mucocutaneous HSV infection treated within 48 hours of lesion onset. Approximately 40% of patients had a CD₄ count below 200 cells/mm³, 54% of patients had anogenital lesions and 35% had orolabial lesions. Famciclovir therapy was comparable to oral acyclovir in reducing new lesion formation and in time to complete healing.

Famciclovir tablets are indicated for the treatment of acute herpes zoster (shingles).

Famciclovir tablets are indicated for:

• suppression of recurrent genital herpes in immunocompetent patients
• treatment of recurrent mucocutaneous herpes simplex infections in HIV-infected patients.

Famciclovir tablets are contraindicated in patients with known hypersensitivity to the product, its components, and penciclovir cream.

The efficacy of famciclovir has not been established for initial episode genital herpes infection, ophthalmic zoster, disseminated zoster or in immunocompromised patients with herpes zoster.

Dosage adjustment is recommended when administering famciclovir to patients with creatinine clearance values < 60 mL/min. (see DOSAGE AND ADMINISTRATION). In patients with underlying renal disease who have received inappropriately high doses of famciclovir for their level of renal function, acute renal failure has been reported.

Patients should be informed that famciclovir is not a cure for genital herpes. There are no data evaluating whether famciclovir will prevent transmission of infection to others. As genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical management of recurrent episodes is indicated, patients should be advised to initiate therapy at the first sign or symptom.

There is no evidence that famciclovir will affect the ability of a patient to drive or to use machines. However, patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking famciclovir should refrain from driving or operating machinery.

Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir.

The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme could potentially occur.

Famciclovir was administered orally unless otherwise stated.

Following oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. It is not known whether it is excreted in human milk. There are no data on the safety of famciclovir in infants.

Safety and efficacy in children under the age of 18 years have not been established.

Of 816 patients with herpes zoster in clinical studies who were treated with famciclovir, 248 (30.4%) were ≥ 65 years of age and 103 (13%) were ≥ 75 years of age. No overall differences were observed in the incidence or types of adverse events between younger and older patients.

Of 610 patients with recurrent herpes simplex (type 1 or type 2) in clinical studies who were treated with famciclovir, 26 (4.3%) were ≥ 65 years of age and 7 (1.1%) were ≥ 75 years of age. Clinical studies of famciclovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In general, appropriate caution should be exercised in the administration and monitoring of famciclovir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The safety of famciclovir has been evaluated in clinical studies involving 816 famciclovir-treated patients with herpes zoster (famciclovir, 250 mg t.i.d. to 750 mg t.i.d.) and 1,197 patients with recurrent genital herpes treated with famciclovir as suppressive therapy (125 mg q.d. to 250 mg t.i.d.) of which 570 patients received famciclovir (open-labeled and/or double-blind) for at least 10 months. Table 5 uls selected adverse events.

The following adverse events have been reported during post-approval use of famciclovir: urticaria, hallucinations and confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly). Because these adverse events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Table 6 uls selected laboratory abnormalities in genital herpes suppression trials.

In HIV-infected patients, the most frequently reported adverse events for famciclovir (500 mg twice daily; n = 150) and acyclovir (400 mg, 5x/day; n = 143), respectively, were headache (16.7% vs. 15.4%), nausea (10.7% vs. 12.6%), diarrhea (6.7% vs. 10.5%), vomiting (4.7% vs. 3.5%), fatigue (4.0% vs. 2.1%), and abdominal pain (3.3% vs. 5.6%).

The following adverse events have been reported during post-approval use of famciclovir: urticaria, serious skin reactions (e.g., erythema multiforme), jaundice, thrombocytopenia, hallucinations, dizziness, somnolence and confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly). Because these adverse events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by hemodialysis (see PRECAUTIONS, General).

The recommended dosage is 500 mg every 8 hours for 7 days. Therapy should be initiated promptly as soon as herpes zoster is diagnosed. No data are available on efficacy of treatment started greater than 72 hours after rash onset.

For recurrent orolabial or genital herpes simplex infection, the recommended dosage is 500 mg twice daily for 7 days.

In patients with reduced renal function, dosage reduction is recommended (see PRECAUTIONS, General).

When famciclovir was administered with food, penciclovir C_max decreased approximately 50%. Because the systemic availability of penciclovir (AUC) was not altered, it appears that famciclovir tablets may be taken without regard to meals.

Famciclovir tablets are supplied as follows:

125 mg – White, round, film-coated tablets, debossed with “8117” on one side and “93” on the other side; available in bottles of 10 and 100.

250 mg – White, round, film-coated tablets, debossed with “8118” on one side and “93” on the other side; available in bottles of 10 and 100.

500 mg – White, capsule-shaped, film-coated tablets, debossed with “8119” on one side and “93” on the other side; available in bottles of 10 and 100.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Manufactured In Canada By:

NOVOPHARM LIMITED

Toronto, Canada M1B 2K9

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Iss. 4/2007