Storage
active substance: famciclovir;

1 tablet of 125 mg contains 125 mg of famciclovir;

1 tablet of 250 mg contains 250 mg of famciclovir;

1 tablet of 500 mg contains 500 mg of famciclovir;

auxiliary substances: hydroxypropyl cellulose, anhydrous lactose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide (E 171), polyethylene glycol 4000, polyethylene glycol 6000 (500 mg tablets do not contain anhydrous lactose).

Medicinal form
Film-coated tablets.

Main physico-chemical properties: tablets 125 mg and 250 mg - white, round, biconvex tablets, covered with a film cover, with beveled edges, embossed with "FV" on one side and "125" or "250" on the other side;

tablets 500 mg - white, oval, biconvex, film-coated tablets, with beveled edges, embossed "FV 500" on one side and smooth on the other side.

Pharmacotherapeutic group
Antiviral means of direct action. Nucleosides and nucleotides. Famciclovir. ATX code J05A B09.

Pharmacological properties
Pharmacodynamics.

Famciclovir is rapidly converted in vivo to penciclovir, which demonstrates in vitro antiviral activity against herpes simplex viruses (types 1 and 2), varicella virus, Epstein-Barr virus, and cytomegalovirus.

The antiviral effect of orally administered famciclovir has been observed in various animal models. In virus-infected cells, penciclovir is rapidly and efficiently converted to triphosphate (this process takes place indirectly through virus-induced thymidine kinase). This triphosphate is present in infected cells for more than 12 hours and inhibits viral DNA replication. Penciclovir triphosphate has a half-life of 10 hours in HSV-1 cells, 20 hours in HSV-2 cells, and 7 hours in VZV-infected cells grown in culture.

In uninfected cells exposed to penciclovir, the concentration of penciclovir triphosphate is barely detectable. Therefore, the probability of its toxic effect on mammalian cells is too low, and damage to uninfected cells is unlikely at therapeutic concentrations of penciclovir.

As with acyclovir, resistance to penciclovir is associated primarily with mutations in the TK gene, leading to a deficiency or change in the substrate specificity of this enzyme, and to a much lesser extent with mutations in the DNA polymerase gene. Most clinical isolates of HSV and VZV that are resistant to acyclovir are also resistant to penciclovir, but cross-resistance is not universal.

The most common form of resistance to acyclovir among herpes simplex virus strains is a deficiency of thymidine kinase (TK) enzyme synthesis. Cross-resistance to both penciclovir and acyclovir is observed in such TC-deficient strains. However, the activity of penciclovir against newly isolated acyclovir-resistant strains of herpes simplex virus with damaged DNA polymerase was shown.

In studies of suppression of relapses of genital herpes, in which patients with a normally functioning immune system were given famciclovir for 4 months, no resistance to penciclovir was detected in the analysis of isolated cultures from 71 patients.

The results of studies of the use of penciclovir and famciclovir in patients, including treatment with famciclovir lasting up to 12 months, showed a low frequency of detection of penciclovir-resistant cultures: 0.2% of all 913 tested cultures from immunocompetent patients and 2.1% of 288 viral cultures isolated from patients with impaired immune system.

Resistant cultures were detected before treatment or in the placebo group, but only 2 cases of resistance in immunocompromised patients were observed during or after treatment with famciclovir or penciclovir.

A placebo-controlled study showed that famciclovir significantly reduced the duration of postherpetic neuralgia in patients over 50 years of age with shingles when administered as soon as possible after the onset of the rash (within 72 hours).

In placebo-controlled studies in immunocompromised patients with AIDS, famciclovir at a dose of 500 mg twice daily significantly reduced the ratio of days with symptoms of HSV-related lesions to days without symptoms.

In a large-scale clinical trial, famciclovir was shown to be effective and well tolerated in the treatment of ocular shingles.

Pharmacokinetics.

When administered orally, famciclovir is rapidly and effectively absorbed and converted to the active antiviral compound penciclovir. Bioavailability of penciclovir after oral administration of famciclovir is 77%. The average concentrations of penciclovir in plasma after oral administration of famciclovir in doses of 125 mg, 250 mg and 500 mg were 0.8 μg/ml, 1.6 μg/ml and 3.3 μg/ml, respectively, and were observed on average 45 min after taking a dose. The plasma concentration/time (AUC) curves for penciclovir are 2.2 mcg/hr/mL, 4.3 mcg/hr/mL, 9.3 mcg/hr/mL, or 14.1 hr/mcg 

/ ml. In another study, the mean peak penciclovir plasma concentration after administration of famciclovir 250 mg, 500 mg, or 1000 mg was 1.5 μg/mL, 3.2 μg/mL, or 5.8 μg/mL, respectively, and the mean penciclovir AUC was 4.0 mcg/h/ml, 8.7 mcg/h/ml or 16.9 mcg/h/ml, these indicators were identical for single and repeated (3 times a day and 2 times a day) administration.

Eating reduces the Cmax and Tmax of penciclovir, but does not affect the bioavailability of penciclovir.

The final half-life of penciclovir after taking both single and repeated doses of famciclovir is about 2 hours. Accumulation of penciclovir after repeated doses of famciclovir is not noted. Penciclovir and its 6-dioxy precursor are weakly (< 20%) bound to plasma proteins.

The volume of distribution (Vd) of penciclovir is approximately 1 L/kg.

There are no significant differences in the distribution and elimination characteristics of penciclovir after oral or parenteral administration of famciclovir in immunocompetent patients or in patients with a compromised immune system.

Famciclovir is excreted mainly in the form of penciclovir and its 6-dioxy precursor, which are excreted in the urine, while unchanged famciclovir is not detected in the urine. Tubular secretion promotes renal elimination of the compound.

The terminal half-life of penciclovir is approximately 2 hours. Renal clearance is 80% of the total clearance of penciclovir.

Patients with shingles infection

Uncomplicated shingles infection does not significantly affect the pharmacokinetics of penciclovir altered after oral administration of famciclovir. The terminal half-life of penciclovir in patients with shingles infection was 2.8 hours and 2.7 hours, respectively, after single and repeated doses of famciclovir.

Patients with renal failure

Apparent plasma clearance, renal clearance, and elimination rate constant of penciclovir decreased linearly with decreasing renal function both after single and repeated doses. Dose adjustment is required for patients with renal insufficiency (see section "Method of administration and dosage").

Patients with liver failure

chronic liver disease in the compensation stage did not affect the degree of systemic bioavailability of penciclovir after oral administration of famciclovir. Patients with liver diseases in the stage of compensation do not need dosage correction (see the section "Method of administration and dosage" and "particulars of use"). The pharmacokinetics of penciclovir have not been studied in patients with severe decompensated liver disease.

Elderly patients

In a comparative cross-over study, the mean AUC of penciclovir was approximately 40% higher and the renal clearance of penciclovir was approximately 20% lower after oral administration of famciclovir in elderly volunteers (65-79 years) compared to younger volunteers. This difference may be due to differences in renal function between the two age groups. Dosage correction depending on age is not required if there are no renal function disorders (see section "Method of administration and dosage").

Sex

There were slight differences in the renal clearance of penciclovir between women and men, which was related to gender differences in renal function. Dosage correction depending on gender is not required.

Ethnicity

There were no differences in the pharmacokinetics of penciclovir between black and Caucasian volunteers.

Preclinical safety data.

Carcinogenicity

In 2-year studies, no changes were observed at a dosage of 200 mg/kg/day. At the maximum permissible dose of 600 mg/kg/day in female rats, an increased incidence rate of adenocarcinoma of the mammary gland, a typical tumor for this type of rat, was observed. There was no effect on the incidence rate of neoplasia in male rats at doses up to 240 mg/kg/day or in mice of either sex at doses up to 600 mg/kg/day.

Genotoxicity

Famciclovir did not show genotoxicity in in vivo and in vitro tests designed to detect gene mutation, chromosomal damage and DNA damage. Penciclovir, like other drugs of this class, can cause chromosomal damage, but did not cause gene mutations in bacterial or mammalian cell systems, and there was no evidence of increased DNA repair in vitro.

Reproductive toxicity

Famciclovir is well tolerated by laboratory animals. as with the use of other drugs of this class, degenerative changes in the testicular epithelium were observed.

Famciclovir was found to have no significant effect on sperm count, morphology or motility in men. Fertility impairment was observed in male rats at 500 mg/kg/day. No effect on fertility was observed in female rats administered famciclovir at doses up to 1000 mg/kg/day.

Indication
Infections caused by Varicella Zoster Viruses (VZV) – Shingles

girdle 

ringworm, including shingles with ocular localization in immunocompetent adult patients;
shingles in adult patients with weakened immunity.
Infections caused by Herpes Simplex viruses (HSV) are genital herpes

treatment of the first manifestations and recurrences of infectious genital herpes in immunocompetent adult patients;
treatment of relapses of genital herpes in adult patients with weakened immunity;
suppression of recurrent genital herpes in immunocompetent and immunocompromised adult patients.
Contraindication
Known hypersensitivity to famciclovir or other components of the drug, as well as hypersensitivity to penciclovir.

Interaction with other medicinal products and other forms of interaction
The effect of other drugs on famciclovir

Probenecid and other drugs that affect the physiology of the kidneys can change the level of penciclovir (active metabolite of famciclovir) in plasma.

Therefore, patients receiving Famvir® 500 mg three times daily with probenecid on consecutive days should be monitored, particularly for toxicity, and a reduction in the Famvir® dose may be considered for such patients.

No clinically significant changes in the pharmacokinetics of penciclovir have been observed following administration of a single dose of 500 mg of famciclovir after prior treatment with multiple doses of allopurinol, cimetidine, theophylline, zidovudine, or promethazine, or when administered shortly after antacids (magnesium hydroxide and aluminum hydroxide), or when administered concurrently with emtricitabine. No clinically significant effect on the pharmacokinetics of penciclovir was observed after repeated (three times a day) administration of famciclovir (500 mg) with multiple doses of digoxin.

Transformation of the inactive metabolite 6-deoxypenciclovir to penciclovir (by deacetylation of famciclovir) is catalyzed by aldehyde oxidase. There is a potential interaction with other drugs that are metabolized by this enzyme and/or inhibited by this enzyme. Clinical studies of the interaction of famciclovir with cimetidine and promethazine, inhibitors of aldehyde oxidase, in vitro did not show a significant effect on the formation of penciclovir. However, raloxifene, a more potent aldehyde oxidase inhibitor studied in vitro, may interfere with the formation of penciclovir and thus the efficacy of famciclovir.

The effect of famciclovir on other drugs

The pharmacokinetics of digoxin did not change with the simultaneous use of single or multiple (three times a day) doses of famciclovir (500 mg). No clinically significant effect on the pharmacokinetics of zidovudine, its metabolites zidovudine glucuronide, or emtricitabine was observed after a single oral dose of 500 mg of famciclovir when co-administered with zidovudine or emtricitabine.

Although famciclovir is only a weak inhibitor of aldehyde oxidase in vitro, interactions with drugs metabolized by aldehyde oxidase are potentially possible. In the course of preclinical studies, the possibility of induction of cytochrome P450 and suppression of CYP3A4 was not revealed.

Features of use
Application to patients with renal failure

Special attention should be paid to patients with impaired kidney function, who need dosage correction (see sections "Method of use and dosage" and "Overdose").

Acute renal failure has been observed in patients with renal failure after using doses that are high in relation to the degree of renal impairment.

Use in patients with liver failure

Patients with mild and moderate hepatic impairment do not require dose adjustment. This also applies to elderly patients who do not have kidney failure. In patients with severe liver failure, the effect of famciclovir has not been studied. The conversion of famciclovir to its active metabolite penciclovir in such patients may be impaired, which may lead to a decrease in the concentration of penciclovir in plasma and, as a result, to a decrease in the effectiveness of famciclovir.

Application in the treatment of shingles

Clinical response should be carefully monitored, especially in immunocompromised patients. Intravenous antiviral therapy should be considered if the response to oral therapy is considered insufficient.

Patients with complicated shingles, such as visceral involvement, disseminated shingles, motor neuropathy, encephalitis, and cerebrovascular complications, should receive intravenous antiviral therapy.

Moreover, immunocompromised patients with ocular shingles or patients at high risk of disease spread and internal organ involvement should receive intravenous antiviral therapy.

Transmission of genital herpes

Genital herpes is a sexually transmitted disease. The risk of transmission increases in the acute phase of the disease. Patients need reco

recommend avoiding sexual contact if symptoms are present, even if antiviral therapy has already been started. In the process of suppressive therapy with antiviral agents, the frequency of virus release is significantly reduced. However, the risk of transmission remains theoretically possible, so patients should use appropriate contraceptives.

Other

Tablets Famvir® 125 mg and 250 mg contain lactose (26.9 mg and 53.7 mg, respectively). Patients with rare hereditary galactose intolerance, namely: acute lactase deficiency or glucose-galactose malabsorption, should not take Famvir® 125 mg and 250 mg.

Use during pregnancy or breastfeeding
Pregnancy

Although animal studies have not shown any embryotoxic or teratogenic effects of Famvir® or penciclovir, the safety of famciclovir in pregnant women has not been established.

Lactation

Studies in rats have shown that penciclovir is excreted in the breast milk of lactating females administered oral Famvir®. It is not known whether penciclovir is excreted in human breast milk. Therefore, famciclovir can be used during pregnancy or during breastfeeding only if the expected benefit of treatment for the woman exceeds the possible risk for the child.

Fertility

Based on the review of clinical data, the effect of famciclovir on male fertility after long-term oral administration of the drug at a dose of 250 mg twice a day was not detected.

The ability to influence the speed of reaction when driving a motor vehicle or working with other mechanisms
There are no data on impaired ability of patients to drive vehicles and work with other mechanisms under the influence of Famvir®. However, patients who experience dizziness, drowsiness, confusion, or other central nervous system disorders while using Famvir should refrain from driving or operating machinery.

Method of application and dosage
Since the systemic bioavailability of penciclovir did not change when famciclovir was taken with food, famciclovir can be used regardless of food intake.

Shingles in immunocompetent patients

For the treatment of shingles - 500 mg 3 times a day for 7 days. For the treatment of shingles with eye complications - 500 mg 3 times a day for 7 days. Treatment gives better results if it is started immediately after the rash appears.

Shingles in immunocompromised patients

500 mg 3 times a day for 10 days. It is recommended to start treatment immediately after the appearance of rashes.

Genital herpes in immunocompetent patients

· the first manifestation of genital herpes

250 mg 3 times a day for 5 days. It is recommended to start treatment immediately after the first manifestation of genital herpes.

Recurrence of genital herpes

125 mg 2 times a day for 5 days. It is recommended to start treatment in the prodromal period (tingling, itching, heartburn, pain) or immediately after the first manifestation of genital herpes.

Recurrence of genital herpes in immunocompromised patients

500 mg 2 times a day for 7 days. It is recommended to start treatment in the prodromal period (tingling, itching, heartburn, pain) or immediately after the appearance of rashes.

Suppression of recurrent genital herpes in immunocompetent patients

250 mg 2 times a day. The duration of treatment depends on the severity of the course of the disease, but treatment should be stopped after 12 months of continuous therapy, in order to reassess the severity of relapses and their frequency. The minimum reassessment period should cover two relapses. A dose of 500 mg 2 times a day was effective for patients with weakened immunity.

Suppression of recurrent genital herpes in immunocompromised patients

500 mg 2 times a day.