Virkaxa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VERAХA

Composition:

Active substance: famciclovir;

1 tablet contains 125 mg or 250 mg or 500 mg of famciclovir;

Excipients: pregelatinized starch, sodium lauryl sulfate, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, stearic acid, Opadry White OY-S-28924 (hypromellose (5 cP), titanium dioxide (E 171), hypromellose (15 cP), polyethylene glycol 4000, polyethylene glycol 6000).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

125 mg tablets: white, film-coated, round, biconvex, with beveled edges;

250 mg tablets: white, film-coated, round, biconvex, with a score line on one side, with beveled edges;

500 mg tablets: white, film-coated, oval, biconvex, with a score line on both sides.

Pharmacotherapeutic group.

Direct-acting antiviral agents. Nucleosides and nucleotides, excluding reverse transcriptase inhibitors. Famciclovir. ATC code J05A B09.

Pharmacological Properties

Pharmacodynamics

After oral administration, famciclovir is rapidly converted into penciclovir, which is active against Herpes simplex types I and II, Varicella zoster virus, as well as Epstein-Barr virus and cytomegalovirus.

Penciclovir enters virus-infected cells, where under the action of viral thymidine kinase it is rapidly converted into a monophosphate, which, in turn, with the participation of cellular enzymes is transformed into the triphosphate form. Penciclovir triphosphate remains in virus-infected cells for over 12 hours, inhibiting viral DNA (deoxyribonucleic acid) synthesis and viral replication. The half-life of penciclovir triphosphate in cells infected with Varicella zoster, Herpes simplex type I, and Herpes simplex type II is 9, 10, and 20 hours, respectively. The concentration of penciclovir triphosphate in uninfected cells does not exceed the minimum detectable level; therefore, at therapeutic concentrations, penciclovir does not affect uninfected cells. The likelihood of its toxic effects is very low, and damage to uninfected cells by therapeutic concentrations of penciclovir is unlikely.

Penciclovir is active against recently identified acyclovir-resistant strains of Herpes simplex virus with altered DNA polymerase.

The incidence of resistance to famciclovir (penciclovir) does not exceed 0.3% in immunocompetent patients and 0.19% in immunocompromised patients. Resistance was observed only at the beginning of treatment and did not develop during or after completion of therapy.

In patients with herpes zoster, the severity and duration of postherpetic neuralgia are significantly reduced.

In immunocompromised patients due to human immunodeficiency virus (HIV) infection, famciclovir at a dose of 500 mg twice daily reduces the number of days of Herpes simplex virus shedding (both with and without clinical manifestations).

Pharmacokinetics

After oral administration, famciclovir is rapidly and efficiently absorbed and converted into the active antiviral compound penciclovir.

The bioavailability of penciclovir is 77%. The increase in penciclovir plasma concentration occurs in parallel with increasing single doses of famciclovir in the range of 125–1000 mg. The maximum concentration (Cmax) of penciclovir after oral administration of 125 mg, 250 mg, or 500 mg of famciclovir is reached on average within 45 minutes and amounts to 0.8 µg/mL, 1.6 µg/mL, and 3.3 µg/mL, respectively. In other studies, Cmax of penciclovir after oral administration of 250 mg, 500 mg, or 1000 mg of famciclovir was 1.5 µg/mL, 3.2 µg/mL, and 5.8 µg/mL, respectively.

Systemic bioavailability [area under the concentration-time curve (AUC)] of penciclovir is independent of food intake. The AUC of penciclovir after a single dose of famciclovir and after dividing the daily dose of famciclovir into 2 or 3 doses are similar, indicating the absence of penciclovir accumulation with repeated administration of famciclovir.

Protein binding of penciclovir and its 6-deoxy precursor to plasma proteins is less than 20%.

Famciclovir is excreted mainly in the form of penciclovir and its 6-deoxy precursor, which are excreted unchanged in urine. Famciclovir is not detected in urine. The elimination half-life of penciclovir in plasma during the terminal phase after single and multiple doses of famciclovir is approximately 2 hours.

Pharmacokinetics in Special Cases

In patients with infection caused by Varicella zoster virus, no significant changes in pharmacokinetic parameters of penciclovir are observed. The elimination half-life of penciclovir in the terminal phase after single and multiple doses of famciclovir is 2.8 and 2.7 hours, respectively.

Patients with Renal Impairment

In patients with renal impairment, a linear relationship is observed between reduced plasma clearance, renal clearance, rate of penciclovir elimination from plasma, and the degree of severity of renal impairment after single and multiple doses of famciclovir. The pharmacokinetics of famciclovir in patients with severe (decompensated) renal dysfunction have not been studied.

Patients with Hepatic Impairment

In patients with mild to moderate hepatic impairment, AUC is unchanged. The pharmacokinetics of penciclovir in patients with severe hepatic impairment have not been studied. A possible impairment in the conversion of famciclovir into the active metabolite penciclovir in these patients cannot be excluded, which may lead to reduced plasma concentrations of penciclovir and, consequently, reduced efficacy of famciclovir.

Elderly Patients (aged 65 years and older)

In patients aged 65–70 years, an approximately 40% increase in mean AUC of penciclovir and an approximately 20% reduction in renal clearance of penciclovir were observed compared to patients under 65 years of age. This may be partially attributed to age-related changes in renal function in patients aged 65 years and older.

Patient gender does not influence the pharmacokinetic parameters of famciclovir (minor differences in penciclovir clearance between males and females).

When famciclovir (single or multiple doses of 500 mg once, twice, or three times daily) was administered to healthy volunteers and patients of non-Negroid race with impaired renal or hepatic function, no differences in pharmacokinetic parameters were observed compared to administration in similar patient groups of Caucasian (Europid) race.

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 impaired 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 impaired immunity;

‒ suppression of recurrent genital herpes in immunocompetent adults and in adult patients with impaired immunity.

Contraindications.

Known hypersensitivity to famciclovir or to 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 medicinal products affecting renal physiology may alter plasma levels of penciclovir (the active metabolite of famciclovir).

Therefore, patients receiving Virox (famciclovir) at a dose of 500 mg three times daily together with probenecid on consecutive days should be monitored, particularly for toxicity, and dose reduction of Virox may be considered for such patients.

No clinically significant changes in the pharmacokinetics of penciclovir were observed after administration of a single 500 mg dose of famciclovir following prior treatment with multiple doses of allopurinol, cimetidine, theophylline, zidovudine, or promethazine, or after intake 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 is catalyzed by aldehyde oxidase. A potential interaction with other medicinal products metabolized and/or inhibited by this enzyme may therefore occur. Clinical interaction studies of famciclovir with cimetidine and promethazine, inhibitors of aldehyde oxidase, in vitro, did not show a significant effect on penciclovir formation. However, raloxifene, a more potent inhibitor of aldehyde oxidase, may affect penciclovir formation.

Effect of famciclovir on other medicinal products

The pharmacokinetics of digoxin were 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 or its metabolites (zidovudine glucuronide or emtricitabine) was observed after administration of 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, interaction with medicinal products metabolized by aldehyde oxidase is potentially possible. Studies have shown no potential for induction of cytochrome P450 or inhibition of CYP3A4.

Special precautions for use.

Patients with renal impairment

Particular attention should be paid to patients with impaired renal 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 impairment.

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. The conversion of famciclovir into its active metabolite penciclovir may be impaired in such patients, which could lead to reduced plasma concentrations of penciclovir and, consequently, potentially 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, e.g. involving internal organs, disseminated herpes zoster, motor neuropathy, encephalitis, and cerebrovascular complications, should be treated with intravenous antiviral therapy.

In addition, intravenous antiviral therapy should be administered to immunocompromised patients with ocular forms of herpes zoster or to patients at high risk of disease dissemination and 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 intercourse 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, so patients should use appropriate contraceptive measures.

Use during pregnancy or breastfeeding

Pregnancy

Experimental studies have not revealed embryotoxic or teratogenic effects of famciclovir and penciclovir.

Penetration of penciclovir into breast milk has been observed during studies of systemic administration of famciclovir. It is unknown whether penciclovir penetrates into breast milk. The safety of famciclovir use in pregnant women and women who are breastfeeding has not been established. The use of the drug during pregnancy or breastfeeding is possible only if the benefit to the mother outweighs the potential risk to the fetus or infant.

Period of breastfeeding

It is unknown whether famciclovir penetrates into breast milk. Animal studies have shown that penciclovir passes into breast milk. If the woman's condition requires the use of famciclovir, the question of discontinuing breastfeeding should be considered.

Fertility

No effect of famciclovir on male fertility was 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 on impairment of patients' ability to drive or operate machinery under the influence of Virexas. However, patients who experience dizziness, somnolence, confusion, or other central nervous system disorders during treatment with Virexas should refrain from driving or operating machinery.

Dosage and Administration

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

Herpes zoster in immunocompetent patients

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 as soon as possible after the rash appears.

Herpes zoster in immunocompromised patients

500 mg three times daily for 10 days. Treatment should be initiated as soon as possible after the onset of rash.

Genital herpes in immunocompetent patients

First episode of genital herpes

250 mg three times daily for 5 days. Treatment should be initiated as soon as possible after symptom onset.

Recurrent genital herpes

125 mg twice daily for 5 days. Treatment should be initiated in the prodromal phase (tingling, itching, burning, pain) or immediately upon lesion appearance.

Recurrent genital herpes in immunocompromised patients

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

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 frequency and severity of recurrences. The re-evaluation period should cover at least two recurrences. The dose 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 penciclovir clearance is reduced in association with impaired renal function, dosage adjustment is required according to creatinine clearance.

The following dosage regimen is recommended:

Herpes zoster in patients with normal immune function

and patients with impaired immune function

Table 1

∗7 days – for patients with normal immunity, 10 days – for patients with impaired immune function.

First episode of genital herpes

Table 2

Recurrent genital herpes in patients with normally functioning immune system

Table 3

Recurrent genital herpes in patients with impaired immune system

Table 4

Suppression of recurrent genital herpes in patients

with normally functioning immune systems

Table 5

Suppression of recurrent genital herpes in patients with compromised immune systems

Table 6

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 included in the tables above, according to each specific indication.

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

Patients with hepatic impairment

Dosage adjustment is not required in patients with hepatic impairment. Data in patients with severe hepatic insufficiency are lacking.

Elderly patients (≥ 65 years of age)

Dosage adjustment is not necessary provided renal function is normal.

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 observed in clinical studies where patients with genital herpes received 250 mg three times daily.

A similar response 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 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, the drug should not be used in patients of this age group.

Overdose

Data regarding famciclovir overdose are limited. Reports of accidental acute overdose (10.5 g) are limited. Long-term administration of famciclovir (10 g daily 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 of Virex. Drug concentrations 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 intensity and occurred in patients receiving placebo as well.

The adverse effects observed during clinical studies and the post-marketing period, classified by frequency, are listed below: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000), 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: angioneurotic edema, 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), necrotizing vasculitis*).

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

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

Overall, the adverse events reported during clinical trials in immunocompromised patients were similar to those reported in patients with intact immune systems. 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 published literature on the use of the medicinal product, which were not recorded during clinical trials. Reports of such adverse reactions were received voluntarily from a population of uncertain size.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging.

For 125 mg strength: 10 tablets in a blister; 1 blister in a cardboard pack.

For 250 mg strength: 7 tablets in a blister; 3 blisters in a cardboard pack.

For 500 mg strength: 7 tablets in a blister; 2 or 3 blisters in a cardboard pack.

Prescription category.

Prescription only.

Manufacturer.

PharmaPass S.A.

Manufacturer's address and place of business.

28 Oktovriou 1, Agia Varvara, 123 51, Greece