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Pharmacological properties

Pharmacodynamics

Mechanism of action. Famciclovir is a prodrug of penciclovir for oral use. Famciclovir is rapidly converted in vivo to penciclovir, which exhibits in vitro antiviral activity against herpes simplex viruses (type 1 and type 2), chickenpox virus, Epstein-Barr virus and cytomegalovirus.

The antiviral effect of orally taken famciclovir as a result of conversion to penciclovir in vivo was detected in different animal models. In cells infected with the virus, penciclovir is rapidly and efficiently converted to monophosphate (this process proceeds indirectly through virus-induced thymidine kinase), which, in turn, is converted to penciclovir triphosphate using cell kinases. This triphosphate is retained in infected cells for more than 12 hours and inhibits the elongation of the viral DNA chain by competitive inhibition with deoxyguanosine triphosphate for incorporation of viral nucleic acids that grow, thereby interrupting the replication of viral DNA. In uninfected cells under the action of penciclovir, the concentration of penciclovir triphosphate is barely noted. Consequently, the likelihood of its toxic effects on mammalian cells is too low and damage to therapeutic concentrations of penciclovir is unlikely for uninfected cells.

Resistance Like acyclovir, a common form of resistance among herpes simplex virus strains is a deficiency in the synthesis of the thymidine kinase (TC) enzyme. In such TK-deficient strains, cross resistance to penciclovir and acyclovir was noted. The results of 11 worldwide clinical trials of the use of penciclovir (topical or intravenous form) or famciclovir in immunocompetent or immunocompromised patients, including studies of treatment with famciclovir up to 12 months, revealed a slight overall frequency of penciclovir-resistant isolates: 0.2% (2 / 913) in immunocompetent patients and 2.1% (6/288) in immunocompromised patients. Resistant isolates are allocated mainly at the beginning of treatment or in the placebo group; Famciclovir or penciclovir-resistant isolates during or after treatment were isolated in only 2 immunocompromised patients.

Clinical efficacy. When conducting placebo-controlled and actively controlled studies among immunocompetent patients and immunocompromised patients with uncomplicated shingles, famciclovir was effective in localizing lesions. During an actively controlled clinical trial, famciclovir has been shown to be effective in treating ocular forms of shingles among immunocompetent patients.

The efficacy of famciclovir in immunocompetent patients with the first manifestation of genital herpes was established during three actively controlled trials. Two placebo-controlled studies among immunocompetent patients and one actively controlled study among HIV-infected patients with recurrent genital herpes showed the effectiveness of famciclovir.

In 2 placebo-controlled studies lasting 12 months, conducted among immunocompetent patients with recurrent genital herpes, it was found that patients treated with famciclovir significantly decreased the number of relapses compared with patients taking placebo. When conducting placebo-controlled and uncontrolled studies lasting up to 16 weeks, it was found that famciclovir is effective in the suppressive treatment of recurrent genital herpes in HIV-infected patients; a placebo-controlled study showed that famciclovir significantly reduced the ratio of the number of days of symptomatic and asymptomatic isolation of the herpes simplex virus.

Patients of childhood.The effects of the use of experimental famciclovir granules for oral administration were evaluated among 169 pediatric patients, whose age ranged from 1 month to 12 years. 100 of these patients aged 1–12 years old took famciclovir granules (doses ranged from 150 to 500 mg) either 2 times (47 patients with herpes simplex virus infections) or 3 times (53 patients with chickenpox) day for 7 days. Another 69 patients (18 patients aged 1–12 months, 51 patients aged 1–12 years) participated in studies on the pharmacokinetics and safety of a single dose using famciclovir granules for oral administration (doses ranged from 25 to 500 mg ) Dosages of famciclovir based on body weight were chosen to ensure a systemic exposure of penciclovir similar to that of penciclovir found in adults after taking 500 mg of famciclovir. None of these studies included a control group; therefore, it is impossible to conclude about the effectiveness of the studied treatment regimens. The safety profile is similar to that observed in adults. However, the systemic exposure of the active substance in infants aged 6 months was low, which thus excludes any assessment of the safety of famciclovir in this age group. Pharmacokinetics

Absorption. Famciclovir is a prodrug, an active anti-virus compound of penciclovir for oral use. When administered orally, famciclovir is rapidly and effectively absorbed and converted into penciclovir. The bioavailability of penciclovir after oral administration of famciclovir is 77%. The average peak plasma concentrations of penciclovir after oral administration of famciclovir in doses of 125 ;, 250; 500 and 750 mg were 0.8; 1.6; 3.3 and 5.1 μg / ml, respectively, and are achieved on average 45 minutes after taking the drug. The “plasma concentration / time” curves for penciclovir are identical for single and multiple (3 times a day and 2 times a day) dosing, which indicates the absence of cumulation of penciclovir with repeated dosing of famciclovir.

Food does not affect AUC of penciclovir.

Distribution. Penciclovir and its 6-dioxi precursor weakly (20%) bind to plasma proteins.

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

Final T½ penciclovir after taking both single and repeated doses of famciclovir is about 2 hours.

Preclinical studies demonstrated a lack of induction of cytochrome P450 and inhibition of SUR ZA4.

Special populations

Patients with shingles infection. Uncomplicated herpes zoster infection does not significantly affect the pharmacokinetics of penciclovir determined after oral administration of famciclovir. Final t½ penciclovir in patients with shingles infection was 2.8 and 2.7 hours, respectively, after taking single and repeated doses of famciclovir.

Patients with renal failure. Visible plasma clearance, renal clearance, and the elimination rate constant of penciclovir decreased linearly with a decrease in renal function both after a single dose and after repeated doses. Dose adjustment is necessary for patients with renal failure (see APPLICATION).

Patients with liver failure. Mild to moderate impaired liver function did not affect the degree of systemic bioavailability of penciclovir after oral administration of famciclovir. For patients with mild to moderate impaired liver function, dose adjustment is not required (see APPLICATION, SPECIAL INSTRUCTIONS). The pharmacokinetics of penciclovir have not been studied in patients with severe hepatic impairment.The conversion of famciclovir to the active metabolite penciclovir may be impaired in such patients and lead to lower plasma concentrations of penciclovir and, as a result, a decrease in the effectiveness of famciclovir.

Children. When taking repeated doses of famciclovir orally (250 or 500 mg 3 times a day) by pediatric patients (6–11 years old) infected with hepatitis B, there was no significant effect on the pharmacokinetics of penciclovir as compared to single dose data. Cumulation of penciclovir was not observed. In children (1–12 years old) with herpes simplex virus or chickenpox infection who took oral doses of famciclovir, the apparent clearance of penciclovir increased non-linearly according to body weight. T½ penciclovir from blood plasma tends to decrease with decreasing age, from an average of 1.6 hours in patients aged 6-12 years to 1.2 hours in patients whose age is 1-2 years.

Elderly patients (≥65 years old). According to a comparative cross-sectional study, the average AUC of penciclovir was approximately 430% higher, and the renal clearance of penciclovir was approximately 20% lower after oral administration of famciclovir in elderly volunteers (65–79 years) compared with those in young volunteers. This difference may be partially due to differences in renal function between the two age groups. Dose adjustment depending on age is not required if there are no impaired renal function (see APPLICATION).

Floor. Minor deviations in the renal clearance of penciclovir between women and men were recorded, which was associated with gender differences in renal function. Dose adjustment based on gender is not required.

Preclinical safety data. General toxicity. In studies of the pharmacology of safety and toxicity of repeated doses, no particular danger to humans has been identified.

Genotoxicity. Famciclovir did not show genotoxicity in in vivo and in vitro tests designed for the manifestation of gene mutations, chromosomal damage, and reversible 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, nor have data been obtained regarding an increase in DNA repair in vitro.

Carcinogenicity. At high doses in female rats, an increased development rate of adenocarcinoma with localization in the mammary gland, a typical tumor for this type of rat, used for carcinogenicity studies, was noted. There was no effect on the incidence rate of neoplasia in male rats or mice of either sex.

Reproductive toxicity. Fertility impairment (including histopathological changes in the testes, impaired sperm morphology, decreased sperm concentration and motility, and decreased fertility) was observed in male rats at a dose of 500 mg / kg / day. In addition, degenerative changes in the testicular epithelium were revealed in studies of general toxicity. These changes were reversible and were also observed with the use of other drugs of this class. No effect on fertility was found in female rats in which famciclovir was used.

Indications

Infections caused by varicella zoster virus:

- Shingles, including shingles with ocular localization in immunocompetent adult patients;

- Shingles in adult immunocompromised patients.

Herpes simplex virus infections:

- treatment of the first manifestations and relapses of 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 adult patients and in adult patients with weakened immunity.

Application

Shingles in immunocompetent adult patients. 500 mg 3 times a day for 7 days.

Treatment should be started as soon as possible after the diagnosis of shingles.

Shingles in adult immunocompromised patients. 500 mg 3 times a day for 10 days.

Treatment should be started as soon as possible after the diagnosis of shingles.

Genital herpes in immunocompetent adult patients

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

Relapse of genital herpes. 125 mg 2 times a day for 5 days. It is recommended to start treatment as soon as possible in the prodromal period (discomfort, itching, burning, pain) or immediately after the manifestation of disorders.

Relapse of genital herpes in adult immunocompromised patients. 500 mg 2 times a day for 7 days. It is recommended to start treatment as soon as possible in the prodromal period (discomfort, itching, burning, pain) or immediately after the appearance of violations.

Suppression of recurrent genital herpes in immunocompetent adult patients. 250 mg 2 times a day. Treatment should be discontinued after 12 months of continuous antiviral therapy in order to re-evaluate the severity of relapses and their frequency. The minimum reappraisal period should cover 2 relapses. Patients who have a significant severity of the disease can resume suppressive therapy.

Suppression of recurrent genital herpes in adult immunocompromised patients. 500 mg 2 times a day.

Dosage for patients with impaired renal function. Since a decrease in clearance of penciclovir is associated with impaired renal function in accordance with a change in creatinine clearance, special attention should be paid to dosing for patients with impaired renal function.

Recommended dosage regimens for adult patients with impaired renal function are presented in table. 1-6.

Table 1. Shingles in immunocompetent adult patients and immunocompromised patients
Creatinine clearance, ml / min Dosage adjustment
≥60 500 mg 3 times a day for 7 or 10 days *
40–59 500 mg 2 times a day for 7 or 10 days *
20–39 500 mg 1 time per day for 7 or 10 days *
20 250 mg once a day for 7 or 10 days *
Dialysis patients 250 mg after each dialysis for 7 or 10 days *

* 7 days - for patients with normal immunity, 10 days - for patients with weakened immunity.

Table 2. The first manifestation of genital herpes in immunocompetent adult patients
Creatinine clearance, ml / min Dosage adjustment
≥40 250 mg 3 times a day for 5 days
20–39 250 mg 2 times a day for 5 days
20 250 mg 1 time per day for 5 days
Dialysis patients 250 mg after each dialysis for 5 days
Table 3. Relapse of genital herpes in immunocompetent adult patients
Creatinine clearance, ml / min Dosage adjustment
≥20 125 mg 2 times a day for 5 days
20 125 mg 1 time per day for 5 days
Dialysis patients 125 mg after each dialysis for 5 days
Table 4. Relapse of genital herpes in adult immunocompromised patients
Creatinine clearance, ml / min Dosage adjustment
≥40 500 mg 2 times a day for 7 days
20–39 500 mg once a day for 7 days
20 250 mg 1 time per day for 7 days
Dialysis patients 250 mg after each dialysis for 7 days
Table 5. Suppression of recurrent genital herpes in immunocompetent adult patients
Creatinine clearance, ml / min Dosage adjustment
≥40 250 mg 2 times a day
20–39 125 mg 2 times a day
20 125 mg once daily
Dialysis patients 125 mg after each dialysis
Table 6. Suppression of recurrent genital herpes in adult immunocompromised patients
Creatinine clearance, ml / min Dosage adjustment
≥40 500 mg 2 times a day
20–39 500 mg 2 times a day
20 250 mg once daily
Dialysis patients 250 mg after each dialysis

Patients with impaired renal function on hemodialysis. 4-hour hemodialysis leads to a decrease in the concentration of penciclovir in blood plasma by approximately 75%, a dose of famciclovir should be used immediately after dialysis. The dosage regimen for patients on dialysis is shown in table. 1-6.

Patients with impaired liver function. For patients with mild to moderate liver disease, a dose change is not required. Data on patients with severe liver failure are not available.

Elderly patients (≥65 years old). Dose adjustment is not required if there is no impaired renal function.

Famvir can be taken without regard to meals.

Normal sensitivity was observed in patients with herpes zoster, who took a dose of 750 mg 3 times a day for 7 days. A similar sensitivity was found in patients with genital herpes who took up to 750 mg 3 times a day for 5 days and up to 500 mg 3 times a day for 10