Virdel (Tablets) Instructions for Use

ATC Code

J05AB11 (Valaciclovir)

Active Substance

Valaciclovir (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Antiviral agent

Pharmacological Action

Antiviral drug. A specific nucleoside inhibitor of the DNA polymerase of herpes viruses. In the human body, it is rapidly converted into acyclovir and L-valine; as a result of phosphorylation, active acyclovir triphosphate is formed from acyclovir, which competitively suppresses viral DNA polymerase and, being an analogue of a purine nucleoside (guanine), is incorporated into the viral DNA, leading to complete chain termination, cessation of DNA synthesis, and blocking of virus replication.

The first stage of phosphorylation occurs under the influence of a virus-specific enzyme (for Herpes simplex viruses types 1 and 2, Varicella zoster – viral thymidine kinase, which is found only in virus-infected cells). For cytomegalovirus (CMV), the selectivity of the drug is due to the fact that phosphorylation is partially mediated by the product of the UL97 phosphotransferase gene.

The drug is active in vitro against Herpes simplex viruses (HSV) types 1 and 2, Varicella zoster virus, Epstein-Barr virus, CMV, and human herpes virus type 6.

In patients with preserved immunity, Herpes simplex and Varicella zoster viruses with reduced sensitivity to valaciclovir are extremely rare (less than 0.1%), but they can sometimes be detected in patients with severe immune disorders, for example, with bone marrow transplants, those receiving chemotherapy for malignant neoplasms, and in HIV-infected individuals.

Pharmacokinetics

Absorption

After oral administration, it is well absorbed from the gastrointestinal tract. With the participation of the liver enzyme valaciclovir hydrolase, it is rapidly and almost completely converted into acyclovir and L-valine.

The bioavailability (in terms of acyclovir) when taken at a dose of 1000 mg is 54% and does not depend on food intake. After administration of valaciclovir at a dose of 1 g 4 times/day, the AUC is approximately equal to the AUC with intravenous administration of acyclovir at a dose of 5 mg every 8 hours.

C_max in plasma after a single dose of 1 g is 15-25 µmol/ml, the time to reach C_max is 1.6-2.1 hours; after 3 hours, unmetabolized Valaciclovir is not detected in the plasma.

Distribution

Plasma protein binding of valaciclovir is 13-18%, acyclovir is 9-33%.

Acyclovir is widely distributed in body tissues and fluids, including the brain, liver, uterus, vaginal mucosa and secretion, semen, cerebrospinal fluid (50% of the plasma concentration), and herpes blister fluid. It penetrates the placenta and into breast milk.

Metabolism

The metabolism of valaciclovir/acyclovir is not associated with cytochrome P450 enzymes.

After repeated administration of valaciclovir in patients with normal renal function, acyclovir does not accumulate.

Excretion

T_1/2 of valaciclovir in patients with normal renal function is less than 30 minutes; of acyclovir – 2.5-3.3 hours.

It is excreted by the kidneys (45.6%), mainly in the form of acyclovir (more than 80% of the dose) and its metabolite 9-carboxymethoxymethylguanine, less than 1% is excreted unchanged; and through the intestines (47.12%) within 96 hours.

Pharmacokinetics in special clinical cases

T_1/2 of valaciclovir in end-stage chronic renal failure is 14 hours, in elderly patients (65-83 years old) – 3.3-3.7 hours.

In patients on hemodialysis, T_1/2 is about 4 hours; during a 4-hour procedure, about 30% of the drug is removed. With peritoneal dialysis, the drug is removed to a lesser extent.

Indications

Adults

• Treatment of herpes zoster (shingles);
• Treatment of skin and mucous membrane infections caused by HSV types 1 and 2 (including newly diagnosed genital herpes, recurrent genital herpes (Herpes genitalis) and labial herpes (Herpes labialis);
• Prevention (suppression) of recurrences of skin and mucous membrane infections caused by HSV types 1 and 2 (including genital herpes);
• Reduction of the risk of transmission of genital herpes to a healthy partner.

Adults and adolescents 12 years and older

• Prevention of cytomegalovirus infection occurring during organ transplantation.

ICD codes

Dosage Regimen

Tablets

Orally, regardless of meals.

Treatment of herpes zoster (treatment is recommended to be started when the first symptoms appear).

Adults – 1000 mg 3 times/day for 7 days.

Treatment of infections caused by HSV (treatment is recommended to be started in the prodromal period or when the first symptoms appear).

Adults – 500 mg 2 times/day. For recurrent herpes, the course of treatment is 3-5 days; if necessary, the course of treatment can be extended to 10 days.

For labial herpes, it is also possible to take valaciclovir at a dose of 2 g 2 times/day (the second dose should be taken approximately 12 hours later, but not earlier than 6 hours after the first dose); the course of treatment is 1 day. Treatment is recommended to be started at the very first symptoms of labial herpes, such as tingling, itching, burning.

Prevention (suppression) of recurrences of infections caused by HSV

Adults

Patients with normal immune status – 500 mg once/day, patients with immunodeficiency – 500 mg 2 times/day.

Reduction of the risk of transmission of genital herpes to a healthy partner

To reduce the risk of transmission of genital herpes to a healthy partner in heterosexual adult patients with preserved immunity and with the number of exacerbations up to 9 per year: 500 mg once/day for a year or more every day during regular sexual contacts. There are no data on the prevention of infection in other patient populations.

Prevention of cytomegalovirus infection after transplantation

Adults and adolescents aged 12 years and older – 2 g 4 times/day. Treatment is recommended to be started as early as possible after transplantation. The dose should be reduced depending on CC. The course of treatment is 90 days (in patients at high risk of developing infections, it may be extended).

In elderly patients, dose adjustment is not required, except in cases of significant renal impairment.

In chronic renal failure, the dosage regimen is established depending on CC and indications .

Treatment of herpes zosterCC 15-30 ml/min – 1 g 2 times/day; CC less than 15 ml/min– 1 g once/day.

Treatment of infections caused by HSVCC less than 15 ml/min – 500 mg once/day.

Treatment of labial herpesCC 31-49 ml/min – 1 g 2 times/day for 1 day; CC 15-30 ml/min – 500 mg 2 times/day for 1 day; CC less than 15 ml/min – 500 mg as a single dose.

Prevention (suppression) of recurrences of infections caused by HSV

Adult patients with normal immune status:CC less than 15 ml/min – 250 mg once/day, adult patients with immunodeficiency : CC less than 15 ml/min – 500 mg once/day.

Reduction of the risk of transmission of genital herpes to a healthy partnerCC less than 15 ml/min – 250 mg once/day.

Prevention of cytomegalovirus infection after transplantation

Adults and adolescents aged 12 years and older: CC 75 ml/min and more – 2 g 4 times/day; CC from 50 to less than 75 ml/min– 1.5 g 4 times/day; CC from 25 to less than 50 ml/min – 1.5 g 3 times/day; CC from 10 to less than 25 ml/min – 1.5 g 2 times/day; CC less than 10 ml/min or in patients on hemodialysis – 1.5 g once/day.

For patients on hemodialysis, the drug is recommended to be taken immediately after the hemodialysis procedure in the same dose as for patients with CC less than 15 ml/min.

Patients with impaired liver function

In patients with mild or moderate liver cirrhosis (liver synthetic function preserved), dose adjustment is not required. In a pharmacokinetic study in patients with severe liver cirrhosis (with impaired liver synthetic function and the presence of shunts between the portal system and the general vascular bed), no data were obtained indicating the need to adjust the dosage regimen; however, clinical experience with the use of valaciclovir in this category of patients is limited.

Adverse Reactions

By frequency of occurrence, side effects are divided into the following categories: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%).

From the central nervous system common – headache; rare – dizziness, confusion, hallucinations, impaired mental abilities; very rare – agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma.

The listed symptoms are reversible and are usually observed in patients with impaired renal function or against the background of other predisposing conditions.

From the respiratory system uncommon – shortness of breath.

From the digestive system common – nausea; rare – abdominal discomfort, vomiting, diarrhea; very rare – reversible impairment of liver function tests, which are sometimes regarded as manifestations of hepatitis.

From the skin and subcutaneous tissues uncommon – skin rash, photosensitivity; rare – itching.

Allergic reactions very rare – urticaria, angioedema, anaphylactic reactions.

From the urinary system rare – impaired renal function; very rare – acute renal failure, renal colic. Renal colic may be associated with impaired renal function.

From the hematopoietic organs very rare – leukopenia, thrombocytopenia.

Other: in patients with severe immune disorders, especially in adult patients with late-stage AIDS receiving Valaciclovir in high doses (8 g/day daily) for a long time, cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination) have been observed. Similar complications have been noted in patients with the same diseases but not receiving Valaciclovir.

Contraindications

• HIV infection with CD4+ lymphocyte count less than 100/µl;
• Childhood (up to 12 years – for the prevention of cytomegalovirus infection during organ transplantation, up to 18 years – for other indications);
• Hypersensitivity to valaciclovir, acyclovir, as well as to other components of the drug.

With caution hepatic/renal failure, clinically pronounced forms of HIV infection; pregnancy, lactation period; elderly age; hypohydration, simultaneous use of nephrotoxic drugs.

Use in Pregnancy and Lactation

There are limited data on the use of valaciclovir during pregnancy. Valaciclovir is used only in cases where the potential benefit to the mother outweighs the possible risk to the fetus. Registered data on the outcome of pregnancy in women taking Valaciclovir or acyclovir did not show an increase in the number of congenital defects in their children compared to the general population. Since the registry includes a small number of women who took Valaciclovir during pregnancy, reliable and definite conclusions about the safety of using valaciclovir during pregnancy cannot be made.

Acyclovir, the main metabolite of valaciclovir, is excreted in breast milk. When the mother takes valaciclovir orally at a dose of 500 mg 2 times/day, the infant will be exposed to the same amount of acyclovir as when taking it orally at a dose of about 0.61 mg/kg/day. The half-life of acyclovir from breast milk is the same as from blood plasma. Valaciclovir in unchanged form was not detected in maternal plasma, breast milk, or infant urine. Valaciclovir should be prescribed with caution to nursing women. However, intravenous administration of acyclovir at a dose of 30 mg/kg/day is used in newborns to treat diseases caused by the herpes simplex virus.

Use in Hepatic Impairment

With caution : hepatic insufficiency.

Use in Renal Impairment

With caution : renal insufficiency.

Pediatric Use

Contraindicated in childhood (up to 12 years – for the prevention of cytomegalovirus infection during organ transplantation, up to 18 years – for other indications).

Geriatric Use

With caution : elderly age.

Special Precautions

In patients at risk of dehydration, especially elderly patients, it is necessary to maintain an adequate water-electrolyte balance.

Close monitoring of patients with impaired renal function and elderly patients is recommended due to the higher risk of adverse events from the central nervous system, acute renal failure, and the risk of overdose in this category of patients.

In patients with chronic renal failure, it is recommended to frequently determine creatinine clearance, especially during periods when renal function is rapidly changing (in particular, immediately after transplantation or engraftment of the transplant), and the dose of valaciclovir is adjusted according to creatinine clearance. In the absence of severe renal impairment, no adjustment of the dosage regimen is required.

Valaciclovir should be used with caution (especially in doses exceeding 4 mg/day) simultaneously with drugs that compete with acyclovir for the elimination pathway, as well as with drugs that impair renal function.

There are no data on the use of valaciclovir in high doses (4 g/day and more) in patients with liver diseases, so the drug should be prescribed with caution in high doses to this category of patients.

Valaciclovir reduces the risk of transmission of genital herpes in heterosexual adult patients with preserved immunity. There are no data on the prevention of infection in other patient populations.

Valaciclovir reduces the risk of transmission of genital herpes but does not eliminate it completely and does not lead to a complete cure. During therapy with valaciclovir, the patient should take measures to ensure the safety of the partner during sexual contacts.

Taking the drug in high doses for a long time in conditions accompanied by severe immunodeficiency (bone marrow transplantation, clinically pronounced forms of HIV infection, kidney transplantation) led to the development of thrombocytopenic purpura and hemolytic-uremic syndrome, up to a fatal outcome.

If adverse effects from the central nervous system occur (including agitation, hallucinations, confusion, delirium, convulsions, and encephalopathy), the drug should be discontinued.

Effect on ability to drive vehicles and operate machinery

When assessing the patient’s ability to drive a car and other mechanisms, the patient’s clinical condition and the profile of side effects of valaciclovir should be taken into account.

Overdose

Symptoms: acute renal failure and disorders from the central nervous system (confusion, hallucinations, agitation, convulsions, coma); nausea and vomiting are possible.

Treatment: hemodialysis (in case of acute renal failure and anuria).

Drug Interactions

Cimetidine and probenecid (tubular secretion blockers) increase the AUC of acyclovir and reduce its renal clearance. In patients with normal CC, no adjustment of the dosage regimen is required, because acyclovir has a wide therapeutic range.

Nephrotoxic drugs (including cyclosporine, tacrolimus) increase the risk of impaired renal function.

Acyclovir is excreted from the body in the urine mainly unchanged by active tubular secretion. With the simultaneous use of valaciclovir and drugs that compete for this elimination mechanism, an increase in the level of acyclovir or both drugs (or their metabolites) is possible. An increase in the AUC of acyclovir and the inactive metabolite of mycophenolate mofetil was noted with the simultaneous use of these drugs.

The pharmacokinetics of valaciclovir does not change with simultaneous use with digoxin, aluminum/magnesium-containing antacids, thiazide diuretics.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.