Famvir

No clinically significant alterations in penciclovir (active metabolite of famciclovir) pharmacokinetics were observed following single dose administration of 500 mg famciclovir after pretreatment with multiple doses of cimetidine, allopurinol, theophylline, zidovudine, or promethazine or when given shortly after an antacid (magnesium and aluminium hydroxide), or concomitantly with emtricitabine. 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.

Probenecid and other drugs that affect renal physiology could affect plasma levels of penciclovir.

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.

The pharmacokinetics of digoxin were not altered by concomitant administration of single or multiple (t.i.d) 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 coadministered with zidovudine or emtricitabine.

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.

Following each dialysis treatment, the recommended dose of famciclovir is 250 mg (herpes zoster) or 125 mg (genital herpes) in immunocompetent patients and 250 mg (recurrent episodes of mucocutaneous herpes simplex) in HIV-infected patients.

If a dose of FAMVIR is missed, it should be taken as soon as the patient remembers. The next dose should be taken at the normal time.

The patient should carry on as normal until they have finished all the tablets.

Do not double-dose.

The recommended dosage is 125 mg twice a day for 5 days. Initiation of treatment is recommended during the prodromal period or as soon as possible after onset of lesions.

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

No dosage adjustment is required in patients with well-compensated hepatic impairment. No data are available for patients with severe uncompensated hepatic impairment (see Action and Clinical Pharmacology).

The recommended dose is 500 mg 3 times per day for 7 days. Therapy should be initiated within 72 hours of the onset of the rash.

For recurrent episodes of mucocutaneous herpes simplex infection, the recommended dosage is 500 mg twice a day for 7 days.

FAMVIR (famciclovir) tablets should be swallowed whole and may be taken with or without food.

Because they are reported spontaneously from a population of unknown size, estimates of frequency of post-marketing adverse events cannot be made. The following events have been chosen for inclusion due to their seriousness, frequency of reporting, potential causal connection to FAMVIR, or a combination of these factors: headache, nausea and confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly), rash, urticaria, pruritus, serious skin reactions (e.g. erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis), vomiting, dizziness, somnolence (predominantly in the elderly), hallucinations and jaundice and abnormal liver function tests.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In post-market experience, thrombocytopenia has been reported.

Each white, oval, biconvex, film-coated tablet, with bevelled edges, 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 glycols, sodium starch glycolate and titanium dioxide. Bottles of 30 and 60. Blister packages of 21.

Each white, round, biconvex, film-coated tablet, with bevelled edges, debossed with FV on one side and 125 on the other, contains: famciclovir 125 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycols, sodium starch glycolate and titanium dioxide. Blister packages of 10.

Each white, round, biconvex, film-coated tablet, with bevelled edges, debossed with FV on one side and 250 on the other, contains: famciclovir 250 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycols, sodium starch glycolate and titanium dioxide. Bottles of 30 and 60. Blister packages of 30.

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 safety between younger and older patients (see Adverse Reactions).

The efficacy of FAMVIR (famciclovir) has not been established for first episode genital herpes infections, disseminated zoster, or in immunocompromised patients with herpes zoster (see Action and Clinical Pharmacology). Dosage adjustment is required when administering famciclovir to patients with moderate or severe renal dysfunction (see Dosage and Administration). No special precautions are required for patients with well-compensated hepatic impairment. Famciclovir has not been studied in patients with severe uncompensated hepatic impairment (see Action and Clinical Pharmacology).

Genital herpes is a sexually transmitted disease with an increased risk of transmission during acute episodes. There are no data evaluating whether FAMVIR 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 anti-viral has been initiated) in order to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding.

FAMVIR 125 mg, 250 mg and 500 mg tablets contain lactose (26.9 mg, 53.7 mg and 107.4 mg, respectively). Patients with rare heredity problems of galactose intolerance, a severe case of lactase deficiency or glucose-galactose malabsorption should not take FAMVIR 125 mg, 250 mg and 500 mg tablets.

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 a 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.

FAMVIR can cause dizziness, drowsiness or confusion in very rare cases. Patients who experience any of these symptoms while taking FAMVIR should take special care when driving or using machines (see Adverse Reactions, Post-Market Adverse Drug Reactions).

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.

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

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.

Plasma protein binding of penciclovir and its 6-deoxy precursor is low (<20%) and penciclovir distributes freely between plasma and blood cells.

Following oral administration, famciclovir is rapidly, extensively and consistently absorbed and converted to the antivirally active compound, penciclovir. The mean (range) bioavailability of penciclovir after oral famciclovir is 77% (69.5-84.5%). The extent of systemic availability (AUC) of penciclovir from oral famciclovir is unaffected by food.

In a healthy male volunteer study using a single oral dose of famciclovir, the pharmacokinetics of penciclovir were linear over the famciclovir dose range 125 to 750 mg. The mean (range) peak plasma concentration of penciclovir, calculated from dose normalised estimates across all single dose healthy male volunteer studies, following a single 500 mg dose of famciclovir was 3.3 µg/mL (range 1.3-6.3 µg/mL) and occurred at a mean time of 0.89 hours post-dose (range 0.5-5.0 hours). The mean terminal half-life of penciclovir was 2.3 hours (range 0.99-5.26 hours).

Pharmacokinetic parameter estimates of penciclovir following oral administration of a single dose of famciclovir to patients with uncomplicated herpes zoster were essentially identical to values reported in healthy volunteers matched for age. Repeated oral dosing of famciclovir every 8 hours for up to 7 days in patients with herpes zoster infections had no significant effect on the pharmacokinetics of penciclovir compared to that described after single doses 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.

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 >20 times those achieved in clinical usage.

Little or no famciclovir is detected in plasma or urine since famciclovir undergoes extensive first-pass metabolism to penciclovir. The major metabolites identified in plasma and urine are penciclovir (67±4% of radioactivity in plasma at 1.5 h following a 500 mg oral dose of [¹⁴C] famciclovir and 82±2.2% of radioactivity in 0-24 h urine) and, to a lesser extent, its 6-deoxy precursor, which has no antiviral activity (11±4% in plasma and 7±0.5% in urine at the corresponding time points). Other minor, virally inactive metabolites identified in human urine are monoacetylated penciclovir and 6-deoxy monoacetylated penciclovir (each <0.5% of the dose).

Renal clearance values for penciclovir exceed creatinine clearance indicating that net active tubular secretion and glomerular filtration contribute to renal elimination.

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.

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 volunteers (65-79 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 and Administration).

Following oral administration little or no famciclovir is detected in plasma or urine since famciclovir is rapidly converted via deacetylation and oxidation to penciclovir. An in vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in famcyclovir metabolism. The conversion of B-deoxy penciclovir is catalyzed by aldehyde oxidase.

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 insufficiency (see Dosage and Administration).

Following single oral administration of famciclovir to patients with well-compensated hepatic impairment, there was no change in the extent of availability of penciclovir compared with healthy volunteers. There was, however, a decrease in the rate of availability of penciclovir in the hepatically impaired subjects. Mean maximum plasma concentrations of penciclovir were decreased by 43% and the time to maximum plasma concentrations increased by 0.75 hours. However, no dosage adjustment for patients with well-compensated hepatic impairment is recommended. The pharmacokinetics of penciclovir following oral famciclovir in patients with severe uncompensated hepatic impairment has not been studied.

Following oral administration of a single dose of 500 mg famciclovir to HIV positive patients, the pharmacokinetic parameters of penciclovir were comparable to those observed in healthy subjects.