Virostat®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIOSTAT® (VIROSTAT)

Composition:

Active substance: famciclovir;

1 tablet contains 250 mg or 500 mg of famciclovir;

Excipients: sodium starch glycolate (type A), hydroxypropyl cellulose, magnesium stearate; coating: Opadry White film-coating mixture: hypromellose (hydroxypropyl methylcellulose), titanium dioxide, polyethylene glycol (macrogol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: white or almost white, round, biconvex, film-coated tablets;

500 mg tablets: white or almost white, elongated, biconvex, film-coated tablets.

Pharmacotherapeutic group. Direct-acting antiviral agents. Nucleosides and nucleotides. Famciclovir. ATC 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-zoster 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 into its triphosphate form (this process is mediated indirectly via virus-induced thymidine kinase). This triphosphate remains present in infected cells for over 12 hours and inhibits viral DNA replication. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1 (Herpes Simplex virus)-infected cells, 20 hours in HSV-2-infected cells, and 7 hours in Varicella Zoster virus (VZV)-infected cells cultured in vitro.

In uninfected cells exposed to penciclovir, concentrations of penciclovir triphosphate are barely detectable. Therefore, the likelihood of its toxic effects on mammalian cells is very low, and damage to non-infected cells is unlikely at therapeutic concentrations of penciclovir.

As with acyclovir, resistance to penciclovir is primarily associated with mutations in the thymidine kinase (TK) gene, leading to deficiency or altered substrate specificity of this enzyme, and to a lesser extent, with mutations in the DNA polymerase gene. Most clinical isolates of HSV and VZV resistant to acyclovir are also resistant to penciclovir; however, cross-resistance is not universal.

The most common form of acyclovir resistance among herpes simplex virus strains is deficiency in thymidine kinase (TK) enzyme synthesis. In such TK-deficient strains, cross-resistance to both penciclovir and acyclovir is observed. However, activity of penciclovir has been demonstrated against recently isolated acyclovir-resistant herpes simplex virus strains with impaired DNA polymerase.

In studies on suppression of genital herpes recurrences, where patients with normal immune function received famciclovir for 4 months, no resistance to penciclovir was detected upon analysis of isolated cultures from 71 patients.

Results from studies using penciclovir and famciclovir, including treatment with famciclovir lasting up to 12 months, showed a low frequency of penciclovir-resistant isolates: 0.2% of 913 total tested cultures from immunocompetent patients and 2.1% of 288 viral cultures isolated from immunocompromised patients.

Resistant isolates were identified either before treatment initiation or in the placebo group; only 2 cases of resistance in immunocompromised patients occurred during or after treatment with famciclovir or penciclovir.

Studies have shown that famciclovir significantly reduced the duration of postherpetic neuralgia in patients over 50 years of age with herpes zoster, provided treatment was initiated as early as possible after rash onset (within 72 hours).

In studies involving immunodeficient 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 asymptomatic days.

The efficacy and good tolerability of famciclovir in the treatment of ophthalmic zoster have been demonstrated.

Pharmacokinetics

After oral administration, famciclovir is rapidly and efficiently absorbed and converted into the active antiviral compound penciclovir. The bioavailability of penciclovir following oral administration of famciclovir is 77%. Mean plasma concentrations of penciclovir after oral administration of famciclovir at doses of 125 mg, 250 mg, and 500 mg were 0.8 mcg/mL, 1.6 mcg/mL, and 3.3 mcg/mL, respectively, reached on average 45 minutes after dosing. The area under the plasma concentration-time curve (AUC) for penciclovir was 2.2 mcg·h/mL, 4.3 mcg·h/mL, 9.3 mcg·h/mL, or 14.1 h·mcg/mL. In another study, mean peak plasma concentrations of penciclovir after administration of famciclovir at doses of 250 mg, 500 mg, or 1000 mg were 1.5 mcg/mL, 3.2 mcg/mL, or 5.8 mcg/mL, respectively, and mean AUC values for penciclovir were 4.0 mcg·h/mL, 8.7 mcg·h/mL, or 16.9 mcg·h/mL. These parameters were consistent after both single and repeated doses (three times daily or twice daily).

Food intake reduces Cmax and Tmax of penciclovir but does not affect its bioavailability.

The terminal half-life of penciclovir after both single and repeated doses of famciclovir is approximately 2 hours. No accumulation of penciclovir occurs with repeated dosing. Penciclovir and its 6-deoxy precursor bind weakly (< 20%) 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 immunocompromised patients.

Famciclovir is excreted primarily as penciclovir and its 6-deoxy precursor, which are eliminated in urine; unchanged famciclovir is not detected in urine. Tubular secretion contributes to renal elimination of the compound.

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

Patients with Herpes Zoster Infection

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

Patients with Renal Impairment

Visible plasma clearance, renal clearance, and elimination rate constant of penciclovir decreased linearly with decreasing renal function after both single and repeated doses. Dose adjustment is required for patients with renal impairment (see section "Dosage and Administration").

Patients with Hepatic Impairment

Compensated chronic liver disease did not affect the extent of systemic bioavailability of penciclovir after oral administration of famciclovir. Dose adjustment is not required for patients with compensated liver disease (see sections "Dosage and Administration" and "Special Warnings"). Pharmacokinetics of penciclovir have not been studied in patients with severe decompensated liver disease.

Elderly Patients

Study data indicate that mean AUC of penciclovir was approximately 40% higher, and renal clearance of penciclovir approximately 20% lower, after oral administration of famciclovir in elderly volunteers (65–79 years) compared to younger volunteers. This difference may be attributed to differences in renal function between the two age groups. Dose adjustment based on age is not necessary if renal function is normal (see section "Dosage and Administration").

Gender

Minor differences in renal clearance of penciclovir between women and men were observed, related to gender differences in renal function. Dose adjustment based on gender is not required.

Ethnicity

No differences in penciclovir pharmacokinetics were observed between individuals of African and Caucasian descent.

Preclinical Safety Data

Carcinogenicity

No adverse effects were observed at doses of 200 mg/kg/day. At the maximum tolerated dose of 600 mg/kg/day, an increased incidence of adenocarcinoma of the mammary gland, a tumor type typical for this strain of rat, was observed in female rats. No effect on neoplasia incidence was observed 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 showed no genotoxicity in in vivo and in vitro tests designed to detect gene mutations, chromosomal damage, and DNA damage. Penciclovir, like other drugs in this class, may cause chromosomal damage but did not induce gene mutations in bacterial or mammalian cell systems, and no increase in DNA repair was observed in vitro.

Reproductive Toxicity

Famciclovir was well tolerated by laboratory animals. As with other drugs in this class, degenerative changes in testicular epithelium were observed.

Famciclovir did not show a significant effect on sperm count, morphology, or motility in men. Impaired fertility was observed in male rats at a dose of 500 mg/kg/day. No effect on fertility was observed in female rats receiving famciclovir at doses up to 1000 mg/kg/day.

Clinical characteristics.

Indications.

Infections caused by Varicella Zoster virus (VZV) — herpes zoster:

• herpes zoster, including herpes zoster with ophthalmic involvement in immunocompetent adults;
• herpes zoster in adult patients with compromised immunity.

Infections caused by Herpes Simplex virus (HSV) — genital herpes:

• treatment of initial episodes and recurrences of genital herpes in immunocompetent adults;
• treatment of recurrences of genital herpes in adult patients with compromised immunity;
• suppression of recurrent genital herpes in immunocompetent adults and in adults with compromised immunity.

Contraindications.

Hypersensitivity to famciclovir or any of the excipients of the medicinal product, as well as hypersensitivity to penciclovir.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on famciclovir

Probenecid and other drugs affecting renal physiology may alter plasma levels of penciclovir (the active metabolite of famciclovir).

Therefore, patients receiving famciclovir 500 mg three times daily concomitantly with probenecid should be monitored, particularly for toxicity. Dose adjustment of the drug may be required for such patients.

No clinically significant changes in the pharmacokinetics of penciclovir were observed when a single 500 mg dose of famciclovir was administered after prior treatment with multiple doses of allopurinol, cimetidine, theophylline, zidovudine, or promethazine, or shortly after administration of antacids (magnesium hydroxide and aluminium hydroxide), or when co-administered with emtricitabine. No clinically significant effect on the pharmacokinetics of penciclovir was observed after multiple (three times daily) administration of famciclovir (500 mg) with multiple doses of digoxin.

The conversion of the inactive metabolite 6-deoxypenciclovir to penciclovir (via deacetylation of famciclovir) is catalyzed by aldehyde oxidase. Potential interactions with other drugs metabolized by this enzyme and/or inhibitors of this enzyme are possible. Studies of the interaction of famciclovir with cimetidine and promethazine, inhibitors of aldehyde oxidase, in vitro, showed no significant effect on the formation of penciclovir. However, raloxifene, a more potent inhibitor of aldehyde oxidase studied in vitro, may affect the formation of penciclovir and thus the efficacy of famciclovir.

Effect of famciclovir on other medicinal products

The pharmacokinetics of digoxin was not altered when a single or multiple (three times daily) doses of famciclovir (500 mg) were co-administered. 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 famciclovir 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. Studies have shown no potential for induction of cytochrome P450 or inhibition of CYP3A4.

Special precautions for use

Use in patients with renal impairment

Particular attention should be paid to patients with impaired kidney function, who require dose adjustment (see sections "Dosage and administration" and "Overdose").

Acute renal failure has been observed in patients with renal impairment after administration of doses that are high relative to the degree of renal function deterioration.

Use in patients with hepatic impairment

Patients with mild to moderate hepatic impairment do not require dose adjustment. This also applies to elderly patients without renal impairment. The effect of famciclovir has not been studied in patients with severe hepatic impairment. Conversion of famciclovir to its active metabolite penciclovir may be impaired in such patients, which could lead to reduced plasma concentrations of penciclovir and, consequently, to decreased efficacy of famciclovir.

Use in the treatment of herpes zoster

Close monitoring of clinical response is required, especially in immunocompromised patients. Consideration should be given to the use of intravenous antiviral therapy if the response to oral treatment is considered inadequate.

Patients with complicated herpes zoster, such as those with visceral involvement, disseminated herpes zoster, motor neuropathy, encephalitis, or cerebrovascular complications, should receive intravenous antiviral therapy.

In addition, intravenous antiviral therapy should be administered to immunocompromised patients with ocular forms of herpes zoster and to patients at high risk of disease dissemination or visceral involvement.

Transmission of genital herpes

Genital herpes is a sexually transmitted disease. The risk of transmission increases during the acute phase of the disease. Patients should be advised to avoid sexual contact during symptomatic periods, even if antiviral therapy has already been initiated. During suppressive antiviral therapy, the frequency of viral shedding is significantly reduced. However, the risk of transmission remains theoretically possible; therefore, patients should use appropriate contraceptive measures.

Use during pregnancy or breastfeeding

Pregnancy. Although animal studies have not shown any embryotoxic or teratogenic effects of famciclovir or penciclovir, the safety of famciclovir use during pregnancy has not been established.

Lactation. Studies in rats have shown that penciclovir is excreted in the milk of females administered famciclovir orally. It is unknown whether penciclovir is excreted in human breast milk. Therefore, famciclovir should be used during pregnancy or breastfeeding only if the expected benefit to the woman outweighs the potential risk to the infant.

Fertility

According to clinical data, no effect of famciclovir on male fertility has been observed after long-term oral administration of the drug at a dose of 250 mg twice daily.

Ability to affect reaction speed when driving or operating machinery

There are no data indicating that famciclovir impairs the ability of patients to drive or operate machinery. However, patients who experience dizziness, somnolence, confusion, or other central nervous system disorders during treatment should refrain from driving or operating machinery.

Dosage and Administration

Since the systemic bioavailability of penciclovir was not altered when famciclovir was administered with food, famciclovir may be administered regardless of meals.

Herpes zoster in immunocompetent patients

For the treatment of herpes zoster — 500 mg three times daily for 7 days. For the treatment of herpes zoster with ocular complications — 500 mg three times daily for 7 days. Treatment is most effective when initiated immediately upon the appearance of the rash.

Herpes zoster in immunocompromised patients:

500 mg three times daily for 10 days. Treatment should be initiated promptly upon the appearance of the rash.

Genital herpes in immunocompetent patients:

• First episode of genital herpes:

250 mg three times daily for 5 days. Treatment should be initiated immediately upon the first signs of genital herpes;

• Recurrent genital herpes:

125 mg twice daily for 5 days*. Treatment should be initiated during the prodromal phase (tingling, itching, burning, pain) or immediately upon the first appearance of lesions.

* It is recommended to use famciclovir formulations at appropriate dosages.

Recurrent genital herpes in immunocompromised patients:

500 mg twice daily for 7 days. Treatment should be initiated during the prodromal phase (tingling, itching, burning, pain) or immediately upon the appearance of lesions.

Suppression of recurrent genital herpes in immunocompetent patients:

250 mg twice daily. The duration of treatment depends on the severity of the disease, but therapy should be discontinued after 12 months of continuous treatment to reassess the severity and frequency of recurrences. The minimum re-evaluation period should cover two recurrences. The dosage of 500 mg twice daily has been shown to be effective in immunocompromised patients.

Suppression of recurrent genital herpes in immunocompromised patients:

500 mg twice daily.

Dosage in patients with renal impairment

Since the clearance of penciclovir is reduced in patients with impaired renal function, dosage adjustment should be based on creatinine clearance.

The following dosage regimen is recommended:

Table 1

Herpes zoster in patients with normally functioning immune system and patients with impaired immune system

Creatinine clearance (mL/min/1.73 m2)	Dosage
≥ 60	500 mg 3 times daily for 7 or 10 days**
40 to 59	500 mg 2 times daily for 7 or 10 days**
20 to 39	500 mg once daily for 7 or 10 days**
< 20	250 mg once daily for 7 or 10 days**
Patients undergoing dialysis	250 mg after each dialysis for 7 or 10 days**

**7 days — for patients with normal immunity, 10 days — for patients with impaired immune system.

Table 2

First episode of genital herpes**

Creatinine clearance (mL/min/1.73 m2)	Dosage
≥ 40	250 mg three times daily for 5 days
From 20 to 39	250 mg twice daily for 5 days
< 20	250 mg once daily for 5 days
Patients undergoing dialysis	250 mg after each dialysis session for 5 days

Table 3

Recurrence of genital herpes in patients with normally functioning immune system

Creatinine clearance (mL/min/1.73 m2)	Dosage
≥ 20	125 mg twice daily for 5 days*
< 20	125 mg once daily for 5 days*
Patients undergoing dialysis	125 mg after each dialysis for 5 days*

* Famciclovir is recommended to be used in the appropriate dosage.

Table 4

Recurrent genital herpes in patients with impaired immune system

Creatinine clearance (ml/min/1.73 m2)	Dosage
≥ 40	500 mg twice daily for 7 days
From 20 to 39	500 mg once daily for 7 days
< 20	250 mg once daily for 7 days
Patients undergoing dialysis	250 mg after each dialysis for 7 days

Table 5

Suppression of recurrent genital herpes in patients with normal immune function

Creatinine clearance (ml/min/1.73 m2)	Dosage
≥ 40	250 mg twice daily
From 20 to 39	125 mg twice daily*
< 20	125 mg once daily*
Patients on dialysis	125 mg after each dialysis session*

* Famciclovir is recommended to be used in appropriate dosage.

Table 6

Suppression of recurrent genital herpes in patients with impaired immune system

Creatinine clearance (ml/min/1.73 m2)	Dosage
≥ 40	500 mg twice daily
From 20 to 39	500 mg twice daily
< 20	250 mg once daily
Patients undergoing dialysis	250 mg after each dialysis

Patients with impaired renal function undergoing hemodialysis

A 4-hour hemodialysis reduces plasma concentrations of penciclovir by approximately 75% — the dose of famciclovir should be administered immediately after dialysis. The dosing regimen for patients undergoing dialysis is provided in the tables above, according to each specific indication.

Since reduced penciclovir clearance is associated with impaired renal function, as determined by creatinine clearance, special caution is required in patients with renal impairment.

Patients with hepatic impairment

Dosage adjustment is not required in patients with mild to moderate hepatic impairment. Data in patients with severe hepatic impairment are lacking.

Elderly patients (≥ 65 years of age)

Dosage adjustment is not required unless renal function is impaired.

Maximum tolerated daily dose and duration of treatment

Normal tolerability was observed in patients with herpes zoster who received 750 mg three times daily for 7 days. Similar tolerability was observed in patients with genital herpes who received up to 750 mg three times daily for 5 days and up to 500 mg three times daily for 10 days. Normal tolerability was demonstrated in studies where patients with genital herpes received 250 mg three times daily.

Similar tolerability was observed in immunocompromised patients with herpes zoster who received up to 500 mg three times daily for 10 days, and in immunocompromised patients with recurrent herpes simplex who received up to 500 mg twice daily for 7 days and 500 mg twice daily for 8 weeks.

Children

The efficacy and safety of famciclovir in children and adolescents (under 18 years of age) have not been established. Therefore, famciclovir is not recommended for patients in this age group.

Overdose

Data on famciclovir overdose are limited. There have been few reports of accidental acute overdose (10.5 g). Long-term administration of famciclovir (10 g per day for 2 years) did not result in complications. In case of overdose, supportive therapy should be administered. Isolated cases of acute renal failure have been reported in patients with a history of renal disease who did not receive appropriate dose reduction. Plasma concentrations of the drug are reduced by approximately 75% during a 4-hour hemodialysis session.

Adverse Reactions

Headache, nausea, diarrhea, and somnolence have been reported during clinical trials. These were generally mild or moderate in severity and occurred in patients receiving placebo as well.

The adverse effects observed during clinical trials and in the post-marketing period are listed below. The adverse effects are classified by frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including isolated cases.

Blood and lymphatic system disorders:
Rare – thrombocytopenia.

Psychiatric disorders:
Uncommon – confusion (predominantly in elderly patients);
Rare – hallucinations.

Central nervous system (CNS) disorders:
Very common – headache;
Common – dizziness;
Uncommon – somnolence (predominantly in elderly patients);
Rare – seizures*.

Cardiac disorders:
Rare – palpitations.

Gastrointestinal disorders:
Common – nausea, vomiting, abdominal pain, diarrhea;
Isolated cases – pancreatitis*.

Hepatobiliary disorders:
Common – altered liver function tests;
Rare – cholestatic jaundice.

Immune system disorders:
Rare – anaphylactic shock*, anaphylactic reactions*.

Skin and subcutaneous tissue disorders:
Common – rash, pruritus;
Uncommon – angioedema, facial edema, eyelid edema, periorbital edema, laryngeal edema, urticaria;
Rare – severe skin reactions* (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), necrotic vasculitis*).

Renal and urinary disorders:
Acute renal failure has been observed rarely in patients with renal disease when the dose was not appropriately adjusted.

Famciclovir is generally well tolerated in patients with impaired immune systems.

Overall, the adverse events observed during clinical trials in immunocompromised patients were similar to those in patients without immune disorders. However, nausea, vomiting, and changes in liver function tests were reported more frequently, particularly with higher doses.

* Adverse reactions identified from spontaneous post-marketing reports and publications on the use of famciclovir, which were not recorded during clinical trials. Reports of such adverse reactions were submitted voluntarily from a population of undefined size.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product's approval is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report all suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

7 tablets per blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of business operations.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua