Valtsikon tablets 500mg, No. 42

Adults

• treatment of herpes zoster (Herpes zoster) (the drug helps to relieve pain syndrome, reduces its duration and the percentage of patients with pain caused by herpes zoster, including acute and postherpetic neuralgia);

• treatment of infections of the skin and mucous membranes caused by the Herpes simplex virus types 1 and 2, including newly diagnosed and recurrent genital herpes (Herpes genitalis), as well as labial herpes (Herpes labialis);

• prevention (suppression) of recurrent infections of the skin and mucous membranes caused by the Herpes simplex virus types 1 and 2, including genital herpes;

• prevention of transmission of genital herpes virus to a healthy partner when using the drug as suppressive therapy in combination with safe sex.

Adults and children 12 years and older

• prevention of CMV infection, as well as the reaction of acute graft rejection (in patients with kidney transplants), opportunistic infections and other herpesvirus infections (HSV, VZV) after organ transplantation.

The reception mode is individual.

Film-coated tablets

1 tab.

active substance:

valacyclovir hydrochloride 556 mg (in terms of valacyclovir 500 mg)

excipients: MCC - 95 mg; hyprolose (hydroxypropyl cellulose) - 14 mg; crospovidone - 28 mg; magnesium stearate - 7 mg film shell: hypromellose - 10.5 mg; hyprolose (hydroxypropyl cellulose) - 4.07 mg; talc - 4.12 mg; titanium dioxide - 2.31 mg or dry mixture for a film coating white (hypromellose - 50%, hydroxypropyl cellulose - 19.4%, talc - 19.6%, titanium dioxide - 11%) - 21 mg

• Hypersensitivity to valacyclovir, acyclovir and / or any other component of the drug;

• HIV infection with a CD4 + lymphocyte count of less than 100 in 1 ?l;

• children's age (up to 12 years for the prevention of CMV infection after transplantation, up to 18 years - for other indications).

Precautions: hepatic / renal failure; elderly age; hypohydration; simultaneous intake of nephrotoxic drugs; pregnancy; lactation period; clinically expressed forms of HIV infection.

pharmachologic effect

Antiviral drug. Valacyclovir is a nucleoside inhibitor of herpes virus DNA polymerase. Blocks viral DNA synthesis and viral replication. In the human body, valacyclovir is completely converted to acyclovir and L-valine. Acyclovir in vitro has specific inhibitory activity against herpes simplex viruses 1, 2 types (Herpes simplex 1, 2 types), varicella-zoster virus and herpes zoster (Varicella zoster virus), cytomegalovirus, Epstein-Barr virus and human herpesvirus 6. Acyclovir inhibits the synthesis of viral DNA immediately after phosphorylation and conversion to the active form of acyclovir triphosphate. The first stage of phosphorylation occurs with the participation of virus-specific enzymes. For viruses Herpes simplex, Varicella zoster and Epstein-Barr, this enzyme is viral thymidine kinase,which is present in cells affected by the virus. Partial selectivity of phosphorylation is retained in cytomegalovirus and is mediated through the product of the UL 97 phosphotransferase gene. Activation of acyclovir by a specific viral enzyme largely explains its selectivity.

The process of phosphorylation of acyclovir (conversion from mono- to triphosphate) is completed by cellular kinases. Acyclovir triphosphate competitively inhibits viral DNA polymerase and, being an analogue of a nucleoside, is incorporated into viral DNA, which leads to an obligate chain break, termination of DNA synthesis and, consequently, blocking of viral replication.

In immunocompromised patients, Herpes simplex and Varicella zoster viruses with reduced sensitivity to valacyclovir are extremely rare (less than 0.1%), but sometimes they can be detected in patients with severely impaired immunity, for example, with a bone marrow transplant, in chemotherapy for malignant neoplasms and in HIV-infected.

Resistance is caused by a deficiency of the viral thymidine kinase, which leads to excessive spread of the virus in the host. Sometimes a decrease in sensitivity to acyclovir is due to the appearance of viral strains with a violation of the structure of viral thymidine kinase or DNA polymerase. The virulence of these varieties of the virus resembles that of its wild strain.

Pharmacokinetics

Suction

After oral administration, valacyclovir is well absorbed from the gastrointestinal tract, rapidly and almost completely converted into acyclovir and valine. This transformation is catalyzed by a liver enzyme called valacyclovir hydrolase.

After a single dose of 250-2000 mg of valacyclovir, the Cmax of acyclovir in blood plasma in healthy volunteers with normal renal function averages 10-37 ?mol / l (2.2-8.3 ?g / ml), and the average time to reach Cmax is 1-2 hours. valacyclovir in a dose of 1000 mg acyclovir bioavailability is 54% and does not depend on food intake. Cmax of valacyclovir in blood plasma is only 4% of the concentration of acyclovir and is achieved on average 30-100 minutes after taking the drug; after 3 hours, the Cmax level remains the same or decreases. Valacyclovir and acyclovir have similar pharmacokinetic parameters after oral administration.

Distribution

Communication with proteins of valacyclovir - 13-18%, acyclovir - 9-33%. Acyclovir is well distributed in tissues and body fluids, including the brain, kidneys, lungs, liver, aqueous humor, lacrimal fluid, intestines, muscles, spleen, uterus, mucous membrane and vaginal secretions, semen, amniotic fluid, cerebrospinal fluid (50% of concentration in plasma), liquid herpetic vesicles. The highest concentrations are found in the kidneys, liver and intestines. Penetrates through the placenta and into breast milk.

Withdrawal

Valacyclovir is excreted in the urine, mainly in the form of acyclovir (more than 80% of the dose) and its metabolite 9-carboxymethoxymethylguanine, less than 1% of the drug is excreted unchanged. T1 / 2 of valacyclovir is less than 30 minutes, acyclovir - 2.5-3.3 hours.

Pharmacokinetics in special clinical situations

In elderly patients (65-83 years), the T1 / 2 of acyclovir is 3.3-3.7 hours, and in patients with end-stage renal failure, it is approximately 14 hours.

The pharmacokinetics of valacyclovir and acyclovir are not significantly impaired in patients infected with Herpes simplex and Varicella zoster viruses.

In HIV-infected patients, the pharmacokinetic parameters of acyclovir after oral administration of valacyclovir at a dose of 1000 mg and 2000 mg are comparable to those observed in healthy volunteers.

In organ transplant recipients receiving valacyclovir at a dose of 2000 mg 4 times / day, the Cmax of acyclovir is equal or higher than that in healthy volunteers who received the same dose of the drug, and the daily AUC values ??were significantly higher.

In late pregnancy, the stable daily area under the pharmacokinetic curve after taking 1000 mg of valacyclovir was approximately 2 times more than that when taking acyclovir at a dose of 1200 mg / day.

Side effect

From the side of the central nervous system: headache, dizziness, psychotic symptoms, agitation, decreased mental abilities, ataxia, coma, confusion or depression of consciousness, dysarthria, encephalopathy, mania, hallucinations, convulsions, tremors. These reactions are reversible and are usually observed in patients with impaired renal function or other predisposing conditions. In patients with a transplanted organ, receiving high doses of valacyclovir (8 g / day) for the prevention of cytomegalovirus infection, neurological reactions develop more often than when taken at lower doses.

From the respiratory system: dyspnea.

From the digestive system: nausea, abdominal discomfort, vomiting, diarrhea, reversible violations of liver function tests (increased activity of ALT, AST, ALP), which are sometimes regarded as manifestations of hepatitis.

From the hematopoietic system: leukopenia (mainly observed in patients with reduced immunity), thrombocytopenia, anemia, thrombotic thrombocytopenic purpura.

On the part of the skin: erythema multiforme, rashes, photosensitivity, alopecia.

Allergic reactions: itching, urticaria, angioedema, anaphylaxis.

From the urinary system: pain in the projection of the kidneys, impaired renal function, incl. acute renal failure, renal colic. Renal colic may be associated with impaired renal function.

From the senses: visual impairment.

On the part of laboratory parameters: decreased hemoglobin content, hypercreatininemia.

Others: dysmenorrhea, nasopharyngitis, respiratory tract infections, increased blood pressure, tachycardia, fatigue.

In patients with severely impaired immunity, especially in adult patients with advanced stage of HIV infection, receiving high doses of valacyclovir (8 g / day daily) for a long time, cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination ). Similar adverse reactions have been reported in patients with the same conditions but not receiving valacyclovir.

Application during pregnancy and lactation

There are limited data on the use of valacyclovir during pregnancy. Valacyclovir is used only in cases where the potential benefit to the mother outweighs the potential risk to the fetus.

The reported data on the outcome of pregnancy in women taking valacyclovir or acyclovir (the active metabolite of valacyclovir) did not show an increase in the number of birth defects in their children compared to the general population. Since the register includes a small number of women who took valacyclovir during pregnancy, it is impossible to make reliable and definite conclusions about the safety of using valacyclovir during pregnancy.

Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After taking valaciclovir orally at a dose of 500 mg, the Cmax of acyclovir in breast milk was 0.5-2.3 times (on average 1.4 times) higher than the corresponding concentration of acyclovir in the mother's blood plasma. The average concentration of acyclovir in breast milk was 2.24 ?g / ml (9.95 ?mol / L). When a mother takes valacyclovir by mouth at a dose of 500 mg 2 times / day, the child will be exposed to the same effects of acyclovir as when taking acyclovir by mouth at a dose of about 0.61 mg / kg / day.

Application for violations of liver function

The drug should be used with caution in liver failure.

Application for impaired renal function

The drug should be used with caution in case of renal failure.

Application in children

There is no data on the use of ValciconЃ in children under 12 years of age.

For children and adolescents over the age of 12, the drug is prescribed for the prevention of cytomegalovirus infection after transplantation.

Use in elderly patients

In elderly patients, dose adjustment is not required, with the exception of significant renal dysfunction. It is necessary to maintain an adequate water and electrolyte balance.

special instructions

In patients at risk of dehydration, especially in elderly patients, adequate fluid replacement should be ensured during treatment.

Since acyclovir is excreted by the kidneys, the dose of ValciconЃ should be adjusted depending on the degree of impairment of renal function. Patients with renal impairment have an increased risk of neurological complications and should be closely monitored. As a rule, these reactions are reversible and disappear after discontinuation of the drug.

In patients with chronic renal failure, it is recommended to frequently determine CC, especially during the period when renal function is rapidly changing (in particular, immediately after transplantation or graft engraftment), while the dose of valacyclovir is adjusted in accordance with CC indicators. There is no data on the use of valacyclovir in high doses (? 4 g / day) in patients with liver disease, therefore, high doses of ValciconЃ should be prescribed to them with caution.

Suppressive therapy with valacyclovir reduces the risk of transmission of genital herpes, but does not eliminate the risk of infection and does not lead to a complete cure. Therapy with ValciconЃ is recommended in combination with safe sex.

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

If side effects from the central nervous system occur (including agitations, hallucinations, confusion, delirium, seizures and encephalopathy), the drug is canceled.

Impact on the management of vehicles and mechanisms

There is no data on the effect of valacyclovir, used in therapeutic doses, on the ability to drive vehicles and mechanisms. However, when assessing the patient's ability to drive a car or moving machinery, it must be borne in mind that side effects from the central nervous system may occur, so caution should be exercised.

Overdose

Symptoms: in case of an overdose of valacyclovir, acute renal failure and the development of neurological symptoms, including confusion, hallucinations, agitation, depression of consciousness and coma, are also noted, nausea and vomiting are also noted. To prevent overdose, care should be taken when using the drug. Many cases of overdose were associated with the use of the drug for the treatment of patients with impaired renal function and elderly patients, due to non-adherence to the dosage regimen (who repeatedly received doses of valacyclovir exceeding the recommended ones).

Treatment. Patients are subject to careful observation for the timely diagnosis of toxic manifestations. Hemodialysis significantly accelerates the elimination of acyclovir from blood plasma and can be considered the optimal treatment for symptomatic overdose.

Drug interactions

Cimetidine and tubular secretion blockers reduce the effect (reduce the rate, but not the completeness of the conversion to acyclovir). Correction of the dosage regimen in individuals with normal CC is not required.

Nephrotoxic drugs increase the risk of kidney dysfunction. Care must be taken (observe changes in renal function) when combining ValciconЃ in higher doses (4 g / day or more) with drugs that affect other renal functions (for example, cyclosporine, tacrolimus).

Acyclovir is excreted by the kidneys, mainly unchanged, through active renal secretion. The combined use of drugs with this elimination mechanism can lead to an increase in the concentration of acyclovir in the blood plasma. After prescribing ValciconЃ at a dose of 1000 mg, cimetidine and probenecid, which are excreted in the same way as valacyclovir, increase the AUC of acyclovir and thus reduce its renal clearance. Due to the wide therapeutic range of acyclovir, dose adjustment of ValciconЃ is not required in this case.

Care must be taken in the case of the simultaneous use of valacyclovir in higher doses (4 g / day and above) and drugs that compete with acyclovir for the elimination pathway, because there is a potential threat of an increase in blood plasma levels of one or both drugs or their metabolites. 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 valacyclovir does not change when taken simultaneously with digoxin, aluminum / magnesium-containing antacids, thiazide diuretics.