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Famciclovir (Tablet, Film Coated)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/952

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Famciclovir (Tablet, Film Coated)
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Herpes Zoster: 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.<br/>Herpes Simplex Infections:<br/>Suppression of Recurrent Genital Herpes: The recommended dosage is 250 mg twice daily for up to 1 year. The safety and efficacy of famciclovir therapy beyond 1 year of treatment have not been established.<br/>HIV-Infected Patients: For recurrent orolabial or genital herpes simplex infection, the recommended dosage is 500 mg twice daily for 7 days.<br/>Patients with Reduced Renal Function: In patients with reduced renal function, dosage reduction is recommended (see PRECAUTIONS, General).<br/>Administration with Food: When famciclovir was administered with food, penciclovir Cdecreased approximately 50%. Because the systemic availability of penciclovir (AUC) was not altered, it appears that famciclovir tablets may be taken without regard to meals.
dailymed-instance:descripti...
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: CHNOM.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.<br/>Tablets for Oral Administration: 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.
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Pharmacokinetics:<br/>Absorption and Bioavailability: Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir. Following oral administration, little or no famciclovir is detected in plasma or urine. The absolute bioavailability of famciclovir is 77��8% as determined following the administration of a 500 mg famciclovir oral dose and a 400 mg penciclovir intravenous dose to 12 healthy male subjects. Penciclovir concentrations increased in proportion to dose over a famciclovir dose range of 125 mg to 1000 mg administered as a single dose. Single oral-dose administration of 125 mg, 250 mg, 500 mg, or 1000 mg famciclovir to healthy male volunteers across 17 studies gave the following pharmacokinetic parameters: Following oral single-dose administration of 500 mg famciclovir to seven patients with herpes zoster, the mean��SD AUC, C, and Twere 12.1��1.7 mcg hr/mL, 4.0��0.7 mcg/mL, and 0.7��0.2 hours, respectively. The AUC of penciclovir was approximately 35% greater in patients with herpes zoster as compared to healthy volunteers. Some of this difference may be due to differences in renal function between the two groups. There is no accumulation of penciclovir after the administration of 500 mg famciclovir t.i.d. for 7 days. Penciclovir Cdecreased approximately 50% and Twas delayed by 1.5 hours when a capsule formulation of famciclovir was administered with food (nutritional content was approximately 910 Kcal and 26% fat). There was no effect on the extent of availability (AUC) of penciclovir. There was an 18% decrease in Cand a delay in Tof about 1 hour when famciclovir was given 2 hours after a meal as compared to its administration 2 hours before a meal. Because there was no effect on the extent of systemic availability of penciclovir, it appears that famciclovir can be taken without regard to meals.<br/>Distribution: The volume of distribution (Vd) was 1.08��0.17 L/kg in 12 healthy male subjects following a single intravenous dose of penciclovir at 400 mg administered as a 1 hour intravenous infusion. Penciclovir is<20% bound to plasma proteins over the concentration range of 0.1 to 20 mcg/mL. The blood/plasma ratio of penciclovir is approximately 1.<br/>Metabolism: Following oral administration, famciclovir is deacetylated and oxidized to form penciclovir. Metabolites that are inactive include 6-deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated penciclovir (5%,<0.5% and<0.5% of the dose in the urine, respectively). Little or no famciclovir is detected in plasma or urine. An in vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in famciclovir metabolism. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase.<br/>Elimination: Approximately 94% of administered radioactivity was recovered in urine over 24 hours (83% of the dose was excreted in the first 6 hours) after the administration of 5 mg/kg radiolabeled penciclovir as a 1 hour infusion to three healthy male volunteers. Penciclovir accounted for 91% of the radioactivity excreted in the urine. Following the oral administration of a single 500 mg dose of radiolabeled famciclovir to three healthy male volunteers, 73% and 27% of administered radioactivity were recovered in urine and feces over 72 hours, respectively. Penciclovir accounted for 82% and 6-deoxy penciclovir accounted for 7% of the radioactivity excreted in the urine. Approximately60% of the administered radiolabeled dose was collected in urine in the first 6 hours. After intravenous administration of penciclovir in 48 healthy male volunteers, mean��S.D. total plasma clearance of penciclovir was 36.6��6.3 L/hr (0.48��0.09 L/hr/kg). Penciclovir renal clearance accounted for 74.5��8.8% of total plasma clearance. Renal clearance of penciclovir following the oral administration of a single 500 mg dose of famciclovir to 109 healthy male volunteers was 27.7��7.6 L/hr. The plasma elimination half-life of penciclovir was 2.0��0.3 hours after intravenous administration of penciclovir to 48 healthy male volunteers and 2.3��0.4 hours after oral administration of 500 mg famciclovir to 124 healthy male volunteers. The half-life in 17 patients with herpes zoster was 2.8��1.0 hours and 2.7��1.0 hours after single and repeated doses, respectively.<br/>HIV-Infected Patients: Following oral administration of a single dose of 500 mg famciclovir (the oral prodrug of penciclovir) to HIV-positive patients, the pharmacokinetic parameters of penciclovir were comparable to those observed in healthy subjects.<br/>Renal Insufficiency: Apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function. After the administration of a single 500 mg famciclovir oral dose (n = 27) to healthy volunteers and to volunteers with varying degrees of renal insufficiency (CLranged from 6.4 to 138.8 mL/min.), the following results were obtained (Table 3): In a multiple-dose study of famciclovir conducted in subjects with varying degrees of renal impairment (n = 18), the pharmacokinetics of penciclovir were comparable to those after single doses. A dosage adjustment is recommended for patients with renal insufficiency (see DOSAGE AND ADMINISTRATION).<br/>Hepatic Insufficiency: Well-compensated chronic liver disease (chronic hepatitis [n = 6], chronic ethanol abuse [n = 8], or primary biliary cirrhosis [n = 1]) had no effect on the extent of availability (AUC) of penciclovir following a single dose of 500 mg famciclovir. However, there was a 44% decrease in penciclovir mean maximum plasma concentration and the time to maximum plasma concentration was increased by 0.75 hours in patients with hepatic insufficiency compared to normal volunteers. No dosage adjustment is recommended for patients with well-compensatedhepatic impairment. The pharmacokinetics of penciclovir have not been evaluated in patients with severe uncompensated hepatic impairment.<br/>Elderly Subjects: Based on cross-study comparisons, mean penciclovir AUC was 40% larger and penciclovir renal clearance was 22% lower after the oral administration of famciclovir in elderly volunteers (n = 18, age 65 to 79 years) compared to younger volunteers. Some of this difference may be due to differences in renal function between the two groups.<br/>Gender: The pharmacokinetics of penciclovir were evaluated in 18 healthy male and 18 healthy female volunteers after single-dose oral administration of 500 mg famciclovir. AUC of penciclovir was 9.3��1.9 mcg hr/mL and 11.1��2.1 mcg hr/mL in males and females, respectively. Penciclovir renal clearance was 28.5��8.9 L/hr and 21.8��4.3 L/hr, respectively. These differences were attributed to differences in renal function between the two groups. No famciclovir dosage adjustment based on gender is recommended.<br/>Pediatric Patients: The pharmacokinetics of famciclovir or penciclovir have not been evaluated in patients<18 years of age.<br/>Race: The pharmacokinetics of famciclovir or penciclovir with respect to race have not been evaluated.<br/>Drug Interactions:<br/>Effects on Penciclovir: No clinically significant alterations in penciclovir pharmacokinetics were observed following single-dose administration of 500 mg famciclovir after pre-treatment with multiple doses of allopurinol, cimetidine, theophylline, or zidovudine. 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.<br/>Effects of Famciclovir on Coadministered Drugs: The steady-state pharmacokinetics of digoxin were not altered by concomitant administration of multiple doses of famciclovir (500 mg t.i.d.). No clinically significant effect on the pharmacokinetics of zidovudine or zidovudine glucuronide was observed following a single oral dose of 500 mg famciclovir.
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Famciclovir tablets are contraindicated in patients with known hypersensitivity to the product, its components, and penciclovir cream.
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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
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General: 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.<br/>Information for Patients: 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/orsymptoms 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.<br/>Drug Interactions: 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.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Famciclovir was administered orally unless otherwise stated.<br/>Carcinogenesis: Two-year dietary carcinogenicity studies with famciclovir were conducted in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in animals of this strain) was seen in female rats receiving the high dose of 600 mg/kg/day (1.1 to 4.5x the human systemic exposure at the recommended total daily oral dose ranging between 2000 mg and 500 mg, based on area under the plasma concentration curve comparisons [24 hr AUC] for penciclovir). No increases in tumor incidence were reported in male rats treated at doses up to 240 mg/kg/day (0.7 to 2.7x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.3 to 1.2x the human AUC).<br/>Mutagenesis: Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential in a battery of in vitro and in vivo assays. Famciclovir and penciclovir were negative in in vitro tests for gene mutations in bacteria (S. typhimurium and E. coli) and unscheduled DNA synthesis in mammalian HeLa 83 cells (at doses up to10,000 and 5,000 mcg/plate, respectively). Famciclovir was also negative in the L5178Y mouse lymphoma assay (5000 mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat dominant lethal study (5000 mg/kg). Famciclovir induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage (1200 mcg/mL). Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation (1000 mcg/mL). In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation (250 mcg/mL). Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow (500 mg/kg), but not when administered orally.<br/>Impairment of Fertility: Testicular toxicity was observed in rats, mice, and dogs following repeated administration of famciclovir or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm count, and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity to male reproduction was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of dosing at 500 mg/kg/day (1.4 to 5.7x the human AUC). The no observable effect level for sperm and testicular toxicity in rats following chronic administration (26 weeks) was 50 mg/kg/day (0.15 to 0.6x the human systemic exposure based on AUC comparisons). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26weeks) at doses of 600 mg/kg/day (0.3 to 1.2x the human AUC) and 150 mg/kg/day (1.3 to 5.1x the human AUC), respectively. Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg/day (2.7 to 10.8x the human AUC). Two placebo-controlled studies in a total of 130 otherwise healthy men with a normal sperm profile over an 8 week baseline period and recurrent genital herpes receiving oral famciclovir (250 mg b.i.d.) (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.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: 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.<br/>Pediatric Use: Safety and efficacy in children under the age of 18 years have not been established.<br/>Geriatric Use: 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.
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Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by hemodialysis (see PRECAUTIONS, General).
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Famciclovir
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Famciclovir (Tablet, Film Coated)
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Immunocompetent Patients: 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 lists 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 lists selected laboratory abnormalities in genital herpes suppression trials.<br/>HIV-Infected Patients: 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%).<br/>Postmarketing Experience: 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.
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Herpes Zoster: Famciclovir tablets are indicated for the treatment of acute herpes zoster (shingles).<br/>Herpes Simplex Infections: Famciclovir tablets are indicated for:
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Famciclovir