KAPD/DPKA 4

INSTRUCTIONS for medical use of the medicinal product Virolex (Virolex)

Composition

The active substance is acyclovir; 1 tablet contains 200 mg of acyclovir; excipients: lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (type A), povidone, magnesium stearate.

Pharmaceutical form

Tablets.

Main physical and chemical properties

White, round, biconvex tablets.

Pharmacotherapeutic group

Antiviral drugs for systemic use.

ATC code J05A B01.

Pharmacological properties

Pharmacodynamics

Acyclovir is an antiviral agent with systemic action. It has a virostatic effect and is effective against Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) and Varicella-zoster virus (VZV).

In its active form, which has antiviral activity, acyclovir is transformed only after penetration into the cell infected with the herpes simplex virus (HSV). After that, under the influence of thymidine kinase, which is produced by the virus, acyclovir is phosphorylated in cells to form acyclovir monophosphate, which, under the action of cellular enzymes, is converted to acyclovir diphosphate and then to the active form of acyclovir triphosphate, which has antiviral activity and blocks the replication of viral DNA. The affinity of acyclovir triphosphate for viral DNA polymerase is 10-30 times higher than for cellular DNA polymerase, which allows it to selectively inhibit the activity of the viral enzyme. In addition, viral DNA polymerase incorporates acyclovir into the composition of viral DNA, resulting in chain termination during DNA synthesis. Due to these mechanisms of action, acyclovir effectively inhibits the process of virus replication, but does not affect normal processes in the cell.

Pharmacokinetics

After oral administration, acyclovir is slowly and not completely absorbed from the gastrointestinal tract. The maximum concentration in plasma is reached within 1.5-2 hours. The bioavailability of acyclovir is from 13% to 21%, and it decreases with increasing dose.

Acyclovir easily penetrates into all tissues, organs, and fluid environments of the body: brain, kidneys, lungs, liver, muscles, spleen, uterus, vaginal mucosa, vaginal secretions, cerebrospinal fluid, and hermetically sealed vesicular fluid. 15.4% is bound to plasma proteins. The half-life after oral administration in adults with normal kidney function is 3 hours. In healthy individuals, acyclovir is excreted mainly by the kidneys with urine (80%). 8.5-14% of acyclovir is excreted as a metabolite of carboxymethoxymethylguanine. Acyclovir is also found in feces in an amount of less than 2% and in a small amount in exhaled CO2.

The pharmacokinetics of acyclovir in children aged 2 years is similar to its pharmacokinetics in adults.

Clinical characteristics

Indications

• Treatment of viral infections of the skin and mucous membranes caused by the herpes simplex virus, including primary and recurrent genital herpes.
• Suppression (prevention of relapses) of infections caused by the herpes simplex virus in patients with normal immunity.
• Prevention of infections caused by the herpes simplex virus in patients with immunodeficiency.
• Treatment of infections caused by the Varicella zoster virus (chickenpox and shingles).

Contraindications

Hypersensitivity to acyclovir, valacyclovir, or any other component of the preparation.

Interaction with other medicinal products and other types of interactions

Clinically significant interactions between acyclovir and other medications have not been found.

Acyclovir is excreted mainly in an unchanged state by the kidneys through tubular secretion, so any medications that have a similar mechanism of excretion may increase the concentration of acyclovir in plasma. Probenecid and cimetidine increase the AUC (area under the concentration-time curve) of acyclovir and decrease its clearance. When used concurrently with immunosuppressants in patients after organ transplantation, the levels of acyclovir and the inactive metabolite of mycophenolate in plasma also increase, but due to the wide therapeutic index of acyclovir, dose adjustment is not required.

Caution should be exercised when using acyclovir concurrently with nephrotoxic or neurotoxic preparations.

An experimental study of five men indicates that concomitant therapy with acyclovir increases the AUC of fully administered theophylline by approximately 50%. It is recommended to measure the concentration in plasma during concomitant therapy with acyclovir.

Special instructions

Patients with impaired renal function and elderly patients.

Acyclovir is excreted from the body mainly through renal clearance, so patients with renal insufficiency should have their dose reduced. Elderly patients also have a high likelihood of impaired renal function, so this group of patients may also require dose adjustment. Patients with renal insufficiency and elderly patients are at risk of developing neurological side effects and should be under close supervision to detect these side effects. According to available data, such reactions are generally reversible in case of discontinuation of the preparation (see "Side effects" section). Prolonged or repeated courses of acyclovir treatment in individuals with severely weakened immunity may lead to the selection of viral strains with reduced sensitivity, which may not respond to prolonged treatment with acyclovir.

Special attention should be paid to maintaining adequate hydration in patients receiving high doses of acyclovir.

The risk of kidney damage increases with concomitant use of other nephrotoxic preparations.

Available data from clinical studies are not sufficient to conclude that treatment with acyclovir reduces the frequency of complications associated with chickenpox in immunocompetent patients.

Special precautions regarding non-active components of the preparation

The preparation contains lactose, so patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not use the preparation.

Use during pregnancy or breastfeeding

Information on the effect of acyclovir on female fertility is not available.

In a study of 20 male patients with a normal number of spermatozoa, oral administration of up to 1 g per day for 6 months did not reveal a clinically significant effect on the number of spermatozoa, motility, or morphology.

In the post-registration registry of surveillance of pregnant women, the results of the use of various pharmaceutical forms of acyclovir during pregnancy have been documented.

No increase in the number of congenital malformations in children whose mothers used acyclovir tablets during pregnancy was found compared to the general population. However, acyclovir tablets should be used only when the potential benefit of the preparation for the mother outweighs the potential risk to the fetus.

When taking 200 mg of acyclovir orally 5 times a day, acyclovir penetrates into breast milk in concentrations that are 0.6-4.1% of the corresponding level of acyclovir in plasma. A child who is breastfed may absorb acyclovir in a dose of up to 0.3 mg/kg body weight per day. Therefore, acyclovir should be prescribed to breastfeeding women with caution, taking into account the risk-benefit ratio.

Ability to affect the speed of reaction when driving vehicles or operating other mechanisms

When deciding on the possibility of driving a car or operating other mechanisms, the clinical status of the patient and the profile of side effects of the preparation should be taken into account. Clinical studies on the effect of acyclovir on the speed of reaction when driving a car or working with other mechanisms have not been conducted. In addition, the pharmacology of acyclovir does not provide grounds for expecting any negative impact.

Method of administration and dosage

The tablet should be taken whole, with water. When using high doses of acyclovir, it is necessary to maintain adequate hydration of the body.

Adults

Treatment of infections caused by the herpes simplex virus

For the treatment of infections caused by the herpes simplex virus, Virolex tablets should be taken in a dose of 200 mg 5 times a day with an approximate 4-hour interval, except for the night period.

Treatment should last for 5 days, but in the case of severe primary infection, it may be extended.

For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or patients with reduced absorption in the intestine, the dose can be doubled to 400 mg or the preparation for intravenous administration can be used.

Treatment should be started as soon as possible after the onset of the infection. In the case of recurrent herpes, it is best to start treatment during the prodromal period or after the appearance of the first signs of skin lesions.

Prevention of relapses (suppressive therapy) of infections caused by the herpes simplex virus

For patients with normal immunity, to prevent relapses of infections caused by the herpes simplex virus, Virolex tablets should be taken in a dose of 200 mg 4 times a day with a 6-hour interval.

For convenience, most patients can take 400 mg of Virolex 2 times a day with a 12-hour interval.

Treatment will be effective even after reducing the dose of Virolex to 200 mg, which should be taken 3 times a day with an 8-hour interval or even 2 times a day with a 12-hour interval.

In some patients, radical improvement is observed after taking a daily dose of 800 mg of Virolex.

For observation of possible changes in the natural course of the disease, therapy with Virolex should be periodically interrupted for 6-12 months.

Prevention of infections caused by the herpes simplex virus

For the prevention of infections caused by the herpes simplex virus, patients with immunodeficiency should take Virolex tablets in a dose of 200 mg 4 times a day with a 6-hour interval. For patients with significant immunodeficiency (e.g., after bone marrow transplantation) or patients with reduced absorption in the intestine, the dose can be doubled to 400 mg or the preparation for intravenous administration can be used.

The duration of prevention depends on the duration of the risk period.

Treatment of chickenpox and shingles

For the treatment of infections caused by the chickenpox and shingles viruses, Virolex tablets should be taken in a dose of 800 mg 5 times a day with a 4-hour interval, except for the night period. Treatment should last for 7 days.

Patients with severe immunodeficiency (e.g., after bone marrow transplantation) or patients with reduced absorption in the intestine are better off using intravenous administration.

Treatment should be started as soon as possible after the onset of the disease; the result will be better if treatment is started immediately after the appearance of rashes.

Children

For the treatment and prevention of infections caused by the herpes simplex virus, children with immunodeficiency aged 2 years and older can be given doses similar to those for adults.

For the treatment of chickenpox in children aged 6 years and older, 800 mg of Virolex should be prescribed 4 times a day; children aged 2-6 years can receive 400 mg of Virolex 4 times a day. The duration of treatment is 5 days.

The dose of the preparation can be calculated more accurately based on the child's body weight - 20 mg/kg body weight per day (not exceeding 800 mg) of Virolex, divided into 4 doses.

There are no special data on the use of Virolex for the prevention (prevention of relapses) of infections caused by the herpes simplex virus or for the treatment of infections caused by the shingles virus in children with normal immunity.

This pharmaceutical form of the preparation should not be used in children under 2 years of age.

Elderly patients

It should be taken into account that elderly patients may have impaired renal function, in which case the dose of the preparation should be adjusted accordingly (see "Renal insufficiency"). It is necessary to maintain adequate hydration of the body.

Renal insufficiency

Virolex should be prescribed with caution to patients with renal insufficiency. It is necessary to maintain adequate hydration of the body.

When preventing and treating infections caused by the herpes simplex virus in patients with renal insufficiency, the recommended oral doses do not lead to the accumulation of acyclovir, the level of which exceeds the safe level established for intravenous administration. However, for patients with severe renal insufficiency (creatinine clearance less than 10 mL/min), a dose of 200 mg 2 times a day with an interval of approximately 12 hours is recommended.

When treating infections caused by the Varicella zoster virus (chickenpox and shingles), for patients with significantly reduced immunity, in the case of severe renal insufficiency (creatinine clearance less than 10 mL/min), a dose of 800 mg 2 times a day with an approximate 12-hour interval is recommended, and for patients with moderate renal insufficiency (creatinine clearance between 10-25 mL/min) - 800 mg 3 times a day with an interval of approximately 8 hours.

Overdose

Symptoms. Acyclovir is only partially absorbed in the gastrointestinal tract. In patients with accidental overdose of acyclovir in a dose of up to 20 g, no toxic effect was found. With accidental repeated overdose of oral acyclovir over several days, gastrointestinal (nausea and vomiting) and neurological symptoms (headache and confusion) occur.

With an overdose of intravenous acyclovir, the level of creatinine in the serum, urea in the blood, and, accordingly, renal insufficiency increases. Neurological manifestations of overdose can be confusion, hallucinations, agitation, seizures, and coma.

Treatment. The patient should be carefully examined for signs of intoxication. Since the level of acyclovir in the blood is well eliminated by hemodialysis, the latter should be used in case of overdose.

Side effects

From the blood and lymphatic system:

• Anemia
• Leukopenia
• Thrombocytopenia

From the immune system:

• Anaphylaxis

Mental disorders and disorders from the nervous system:

• Headache
• Dizziness
• Agitation
• Confusion
• Tremor
• Ataxia
• Dysarthria
• Hallucinations
• Psychotic symptoms
• Seizures
• Somnolence
• Encephalopathy
• Coma

These phenomena are usually reversible. They often occur in patients with impaired renal function or other predisposing factors.

From the respiratory system and thoracic cavity:

• Dyspnea

From the gastrointestinal tract:

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain

From the liver and bile ducts:

• Reversible increase in bilirubin levels and corresponding liver enzymes
• Hepatitis
• Jaundice

From the skin and subcutaneous tissue:

• Itching
• Rash (including photosensitivity)
• Urticaria
• Observed accelerated diffuse hair loss, which was associated with a wide range of disease processes and medications; the connection with acyclovir therapy has not been established
• Angioedema

From the kidneys and urinary tract:

• Increased urea and creatinine in the blood
• Acute renal insufficiency
• Pain in the kidneys

Pain in the kidneys may be associated with renal insufficiency and crystalluria.

General disorders:

• Increased fatigue
• Fever

Shelf life

5 years.

Storage conditions

Store at a temperature not exceeding 25°C.

Store in a place inaccessible to children.

Packaging

10 tablets in a blister pack; 2 blister packs in a cardboard box.

Release category

By prescription.

Manufacturer

KRKA, d.d., Novo mesto, Slovenia.

Location of the manufacturer and address of the place of business

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.