Each film-coated tablet contains 250 mg famciclovir.
Certain dosage strengths may not be available in all countries.
Excipients/Inactive Ingredients: Tablet core: anhydrous lactose, sodium starch glycollate, hydroxypropyl cellulose, magnesium stearate.
Tablet coating: hypromellose/hydroxypropylmethyl/cellulose, titanium dioxide (Cl 77891, E171), polyethylene glycol 4000/Macrogol 4000, polyethylene glycol 6000/Macrogol 6000.
Pharmaceutical formulations may vary between countries.
Pharmacology: Pharmacodynamics: Famciclovir is the oral prodrug of penciclovir. Famciclovir is rapidly converted in vivo into penciclovir, which has in vivo and in vitro activity against human herpes viruses including Varicella zoster virus (VZV) and Herpes simplex types 1 and 2 viruses.
The antiviral effect of orally administered famciclovir has been demonstrated in several animal models; this effect is due to in vivo conversion to penciclovir. In virus-infected cells the viral thymidine kinase (TK) phosphorylates penciclovir to a monophosphate form that, in turn, is converted to penciclovir triphosphate by cellular kinases. This tiphosphate inhibits replication of viral DNA and has a half-life of 9, 10, and 20 hours in cells infected with Varicella zoster virus, Herpes simplex virus Types 1 and Herpes simplex virus Type 2 respectively. In uninfected cells treated with penciclovir, concentrations of penciclovir triphosphate are only barely detectable. Accordingly, uninfected cells are unlikely to be affected by therapeutic concentrations of penciclovir.
Like with aciclovir, penciclovir resistance is associated with mutations principally in the TK gene resulting in deficiency or altered substrate specificity to this enzyme, and to a much lesser extent in the DNA polymerase gene. Most aciclovir-resistant HSV and VZV clinical isolates are also resistant to penciclovir, but cross-resistance is not universal. A placebo controlled study in patients with immunodeficiency due to HIV has shown that famciclovir 500 mg b.i.d significantly decreased the proportion of days of both symptomatic and asymptomatic HSV shedding.
Results from 11 worldwide clinical studies involving penciclovir (topical or intravenous formulations) or famciclovir in immunocompetent patients, including studies of up to 12 months treatment with famciclovir, have shown a small overall frequency of penciclovir resistant isolates: 0.2% (2/913) in immunocompetent patients and 2.1% (6/288) in immunocompromised patients. The resistant isolates were mostly found at the start of treatment or in a placebo group, with resistance occurring on or after treatment with famciclovir or penciclovir only in two immunocompromised patients.
Pharmacokinetics: General characteristics: Absorption: Famciclovir is the oral prodrug of the antivirally active compound penciclovir. Following oral administration, famciclovir is rapidly and extensively absorbed and rapidly converted to penciclovir. Bioavailability of penciclovir after oral famciclovir is high and constant at 77%. Penciclovir plasma concentrations increased in proportion to dose over a famciclovir dose range of 125 mg to 1000 mg administered as a single dose. In one study mean peak plasma concentration of penciclovir, following a 125 mg and 250 mg, 500 mg and 750 mg oral dose of famciclovir, was 0.8 micrograms/mL and 1.6 micrograms/mL, 3.3 micrograms/mL and 5.1 micrograms/mL respectively and occurred at a median time of 45 minutes post-dose. In another study mean peak concentration of penciclovir, following a 250 mg, 500 mg and 1000 mg oral dose of famciclovir, was 1.5 µg/mL, 3.2 µg/mL and 5.8 µg/mL. The extent of systemic availability (AUC) of penciclovir from oral famciclovir is unaffected by food. Plasma concentration-time curves of penciclovir are similar following single and repeat (three times daily and twice daily) dosing, indicating that there is no accumulation of penciclovir on repeated dosing with famciclovir.
Distribution: Penciclovir and its 6-deoxy precursor are poorly (<20%) bound to plasma proteins.
Metabolism and elimination: Famciclovir is eliminated principally as penciclovir and its 6-deoxy precursor which are excreted in urine unchanged. Famvir has not been detected in urine. Tubular secretion contributes to the renal elimination of the compound. The terminal plasma half-life of penciclovir after both single and repeat dosing with famciclovir was approximately 2 hours.
Characteristics in special populations: Patients with herpes zoster: Uncomplicated herpes zoster does not significantly alter the pharmacokinetics of penciclovir measured after the oral administration of famciclovir. The terminal plasma half-life of penciclovir in patients with herpes zoster was 2.8 h and 2.7 h, respectively, after single and repeated doses of famciclovir.
Patients with renal impairment: The apparent plasma clearance, renal clearance, and plasma elimination rate constant of penciclovir decreased linearly with reductions in renal function, both after single and repeated dosing. Dose adjustment is necessary in patients with renal impairment (see DOSAGE & ADMINISTRATION).
Patients with hepatic impairment: Mild and moderate hepatic impairment had no effect on the extent of systemic availability of penciclovir following oral famciclovir. No dose adjustment is recommended for patients with mild and moderate hepatic impairment (see DOSAGE & ADMINISTRATION). The pharmacokinetics of penciclovir have not been evaluated in patients with severe hepatic impairment. Conversion of famciclovir to the active metabolite penciclovir may be impaired in these patients resulting in lower penciclovir plasma concentrations, and thus possibly a decrease of efficacy of famciclovir (see PRECAUTIONS).
Elderly subjects: Based on cross-study comparisons, the mean penciclovir AUC was about 40% higher and penciclovir renal clearance about 20% lower after oral administration of famciclovir in elderly (65 to 79 years) compared to younger volunteers.
Some of this difference may be due to differences in renal function between the two age groups. No dose adjustment based on age is recommended unless renal function is impaired (see DOSAGE & ADMINISTRATION).
Gender: Small differences in renal clearance of penciclovir between females and males have been reported and were attributed to gender differences in renal function. No dose adjustment based on gender is recommended.
Race: A retrospective evaluation was performed to compare the pharmacokinetic parameters obtained in Black and Caucasian subjects after single and repeat once-daily, twice-daily, or three times-daily administration of famciclovir 500 mg. Data from a study in healthy volunteers (single dose), a study in subjects with varying degrees of renal impairment (single and repeat dose) and a study in subjects with hepatic impairment (single dose) did not indicate any relevant differences in the pharmacokinetics of penciclovir between Black and Caucasian subjects.
Toxicology: Nonclinical Safety Data: Famciclovir is well tolerated in laboratory animals. In common with other drugs of this class, degenerative changes of the testicular epithelium were noted.
Famciclovir has no significant effects on spermatogenesis or sperm morphology and motility in man. At doses greatly in excess of those used therapeutically, impaired fertility was observed in male rats - no such effects being observed in female rats.
At a dose level approximately 50 times the normal therapeutic dose in female rats there was an increased incidence of mammary adenocarcinoma, a common tumour in this strain of rats used in the studies. No such effect was seen in male rats or in mice of either sex.
Additionally, famciclovir was not found to be genotoxic in a comprehensive battery of in vivo and in vitro tests designed to detect gene mutation, chromosomal damage and repairable damage to DNA. Penciclovir (the active metabolite of famciclovir), in common with other drugs of this class, has been shown to cause chromosomal damage, but did not induce gene mutation in bacterial or mammalian cell systems, nor was there evidence of increased DNA repair in vitro. These findings are not considered to have any clinical significance.
Herpes zoster: Famvir is indicated for the treatment of herpes zoster in immunocompetent adults.
Genital herpes: Famvir is indicated for the treatment of first and recurrent episodes of genital herpes in immunocompetent adults.
Dosage regimen: General target population: Herpes zoster: Adults: 250 mg three times daily for seven days. Treatment should be initiated as soon as possible after a diagnosis of herpes zoster.
First episode genital herpes: Adults: 250 mg three times daily for five days. Treatment should be initiated as soon as possible after a diagnosis of first episode of genital herpes.
Episodic treatment of recurrent genital herpes: Adults: 125 mg twice daily for five days. Treatment should be initiated at the first sign or symptom of a recurrent episode (e.g. tingling, itching, burning, pain, or lesion).
Special populations: Patients with renal impairment: Because reduced clearance of penciclovir is related to impaired renal function, as measured by creatinine clearance, special attention should be given to dose adjustments in patients with impaired renal function. Dose recommendations for adult patients with renal impairment are provided in Table 1: Patients with renal impairment on hemodialysis: Since four hours of hemodialysis resulted in up to 75% reduction in plasma penciclovir concentrations, Famvir should be administered immediately following dialysis. The recommended dose regimens for hemodialysis are included in Table 1. (See Table 1.)
Click on icon to see table/diagram/image
Patients with hepatic impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available for patients with severe hepatic impairment (see PHARMACOLOGY under Actions).
Pediatric patients: There are currently insufficient data on the safety and efficacy of Famvir in children and therefore its use in children is not recommended.
Geriatric patients (65 years of age or older): Dosage modification is not required unless renal function is impaired.
Black patients: A placebo-controlled study in immunocompetent Black patients with recurrent genital herpes showed no difference in efficacy between patients receiving famciclovir 1000 mg twice daily for one day and placebo. There were no unexpected or new safety findings in this trial in Black patients.
The relevance of these study results to the five-day episodic treatment regimen for recurrent genital herpes or other indications in Black patients is unknown (see PHARMACOLOGY under Actions).
Method of administration:
Since the systemic availability (AUC) of penciclovir, the active metabolite of famciclovir, was not altered when famciclovir was administered with food, it appears that Famvir can be taken without regard to meals (see PHARMACOLOGY under Actions).
Overdose experience with famciclovir is limited. In the event of an overdose supportive and symptomatic therapy should be given as appropriate. Acute renal failure has been reported rarely in patients with underlying renal disease where the famciclovir dosage has not been appropriately reduced for the level of renal function. Penciclovir, the active metabolite of famciclovir, is dialysable and plasma concentrations are reduced by approximately 75% following four hours of hemodialysis.
Famvir is contraindicated in patients with known hypersensitivity to famciclovir or other constituents of Famvir.
It is also contraindicated in those patients who have shown hypersensitivity to penciclovir, the active metabolite of famciclovir.
Patients with renal or hepatic impairment: Special attention should be paid to patients with impaired renal function as dosage adjustment is necessary (see DOSAGE & ADMINISTRATION and OVERDOSAGE). No special precautions are required for elderly patients with normal renal function and patients with mild or moderate hepatic impairment. Famciclovir has not been studied in patients with severe hepatic impairment. Conversion of famciclovir to the active metabolite penciclovir may be impaired in these patients resulting in lower penciclovir plasma conentrations, and thus possibly a decrease of efficacy of famciclovir (see PHARMACOLOGY under Actions.)
Transmission of genital herpes: Genital herpes is a sexually transmitted disease. The risk of transmission is increased during acute episodes. Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated.
Women of child-bearing potential: There are no data supporting any special recommendations in women of child-bearing potential.
Pregnancy: Although animal studies have not shown any embryotoxic or teratogenic effects with famciclovir or penciclovir (the active metabolite of famciclovir), there are insufficient data on the use of Famvir in pregnant women. Famvir should, therefore, not be used during pregnancy unless the potential benefits are considered to outweigh the potential risks associated with treatment.
Breast-feeding: Following oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk. There is no information on excretion in human milk. Famvir should not be used in nursing mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment.
Fertility: Famciclovir has been shown to have no significant effects on sperm count, morphology or motility in man. Clinical data do not indicate an impact of famciclovir on male fertility following long-term treatment at an oral dose of 250 mg twice daily.
Headache and nausea were reported clinical trials. These were generally mild or moderate in nature and occurred at a similar incidence in patients receiving placebo treatment. All other adverse reactions were added from post-marketing experience.
The pooled global placebo or active controlled clinical trials (n=2326 for Famvir arm) were retrospectively reviewed to obtain a frequency category for all adverse reactions mentioned as follows. Adverse drug reactions (Table 2) are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse drug reaction: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). (See Table 2.)
Click on icon to see table/diagram/image
Effects of other medicinal products on famciclovir: Concurrent use of probenecid may result in increased plasma concentrations of penciclovir the active metabolite of famciclovir (see PHARMACOLOGY under Actions).
The conversion of the inactive metabolite 6-deoxy penciclovir (formed by deacetylation of famciclovir) to penciclovir is catalysed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme and/or inhibiting this enzyme could potentially occur. Clinical interaction studies of famciclovir with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir. However, raloxifene, the most potent aldehyde oxidase inhibitor observed in vitro, could affect the formation of penciclovir and thus the efficacy of famciclovir. When raloxifene is co-administered with famciclovir the clinical efficacy of the antiviral therapy should be monitored.
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, zidovudine, or promethazine or when given shortly after an antacid (magnesium and aluminium hydroxide), or concomitantly with emtricitabine. No clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose (three times daily) administration of famciclovir (500 mg) with multiple doses of digoxin.
Effects of famciclovir on other medicinal products: Although famciclovir is only a weak inhibitor of aldehyde oxidase in vitro, interactions with drugs metabolized by aldehyde oxidase could potentially occur. Evidence from preclinical studies has shown no potential for induction of cytochrome P450 enzymes and inhibition of CYP3A4.
The pharmacokinetics of digoxin were not altered by concomitant administration of single or multiple (three times daily) doses of famciclovir (500 mg). No clinically significant effects on the pharmacokinetics of zidovudine, its metabolite zidovudine glucuronide or emtricitabine were observed following a single oral dose of 500 mg famciclovir co-administered with zidovudine or emtricitabine.
Incompatibilities: No specific incompatibilities.
J05AB09 - famciclovir ; Belongs to the class of nucleosides and nucleotides excluding reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
FC tab 250 mg (white, round, biconvex with or without bevelled edges, debossed with "FAMVIR" or "FV" on one side and 250 on the reverse side) x 3 x 7's.