Valacyclovir, 500 mg 50 pcs.

Antiviral agent.

Pharmacodynamics

Valacyclovir is an antiviral agent, it is L-valine ester of acyclovir. Acyclovir is an analog of the purine nucleoside (guanine). In humans, valacyclovir is rapidly and almost completely converted to acyclovir and L-valine, presumably by the enzyme valacyclovirhydrolase.

Acyclovir in vitro has specific inhibitory activity against herpes simplex virus (HPV) types 1, 2 (Herpes simplex 1, 2 types), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpes virus type 6. Acyclovir inhibits the synthesis of viral DNA immediately after phosphorylation and transformation into the active form acyclovirtriphosphate.

The first stage of phosphorylation occurs with the participation of virus-specific enzymes. For HPV, VZV and VEB viruses this enzyme is viral thymidine kinase, which is present only in virus-infected cells. Partial selectivity of phosphorylation is retained in cytomegalovirus and is mediated through the product of the phosphotransferase gene UL97. Activation of acyclovir by a specific viral enzyme largely explains its selectivity.

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

In immunocompromised patients, valacyclovir-unresponsive HPV and VZV are extremely rare, but can sometimes be found in patients with severe immune disorders, such as those with bone marrow transplants, those receiving chemotherapy for malignancies and those infected with HIV.

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

Indications

Adults and adolescents 12 to 18 years old

Adults

Active ingredient

Composition

1 film-coated tablet contains:

Composition of the tablet core:

The active ingredient:

Valacyclovir hydrochloride – 556.2 mg (in terms of valacyclovir 500.0 mg).

Auxiliary substances:

Microcrystalline cellulose – 84.3 mg,

Hypromellose – 42.0 mg,

crospovidone – 7.0 mg,

magnesium stearate – 7.0 mg,

colloidal silicon dioxide -3.5 mg.

Composition of the tablet shell:

Opadray II white (33G28435) – 25.0 mg (hypromellose – 40.0%, titanium dioxide – 25.0%, macrogol 3350 – 8.0%, lactose monohydrate – 21.0%, triacetin – 6.0%).

How to take, the dosage

Orally, regardless of meals, with water.

The treatment of infections of the skin and mucous membranes caused by HPV, including newly diagnosed and recurrent genital herpes (Herpes genitalis) as well as labial herpes (Herpes labialis)

Immunocompetent adults and adolescents aged 12 to 18 years

The treatment of infections of the skin and mucous membranes caused by HPV./p>

Immunocompetent adults and adolescents aged 12 to 18 years

The recommended dose is 500 mg twice daily.

In cases of relapses, treatment should continue for 3 or 5 days. In the case of primary herpes, which may be more severe, treatment should be started as soon as possible, and its duration should be increased from 5 to
10 days. For relapses of HPV, valacyclovir is most appropriately prescribed in the prodromal period or immediately after the onset of the first symptoms of the disease. Valacyclovir can prevent lesions if used at the first signs and symptoms of relapse caused by HPV.

As an alternative treatment for labial herpes, Valacyclovir is effective at a dose of 2,000 mg twice daily for 1 day. The second dose should be taken approximately 12 hours (but not earlier than 6 hours) after the first dose. When using this dosing regimen, the duration of treatment should not exceed 1 day, because exceeding this duration of treatment does not result in additional clinical benefit.

The therapy should be started when the earliest symptoms of labial herpes (i.e., tingling, itching, burning) appear.

Prevention (suppression) of recurrent infections of the skin and mucous membranes caused by HPV, including genital herpes, including in adults with immunodeficiency

Immunodeficiency/p>

Immunocompetent adults and adolescents aged 12 to 18 years

In immunocompetent patients, the recommended dose is 500 mg once daily.

The effectiveness of therapy should be evaluated after 6-12 months of treatment.

Adults with immunodeficiency

In adult patients with immunodeficiency, the recommended dose is 500 mg 2 times daily.

After 6-12 months of treatment, the effectiveness of therapy should be evaluated.

Prophylaxis of infections caused by CMV and disease after parenchymal organ transplantation

Adults and adolescents ages 12 to 18 years

The recommended dose is 2000 mg 4 times daily, administered as soon as possible after transplantation. The dose should be reduced depending on creatinine clearance.

The duration of treatment is usually 90 days, but in high-risk patients the course of treatment may be extended.

The treatment of herpes zoster and ophthalmic herpes zoster

Adults

The recommended dose is 1000 mg 3 times daily for 7 days.

Patients with impaired renal function

The dose of valacyclovir should be reduced in patients with significant impairment of renal function (see dosing regimen in Table 2). In these patients an adequate water-electrolyte balance should be maintained.

Valacyclovir should be used after hemodialysis in patients receiving intermittent hemodialysis.

Creatinine clearance should be determined frequently, especially during a period when renal function changes rapidly, such as immediately after transplantation or graft engraftment, and the dose of valacyclovir should be adjusted according to creatinine clearance rates.

There is no experience with valacyclovir in children with creatinine clearance values less than
50 mL/min/1.73 m2.

Patients with impaired liver function

According to the available data on the use of a single dose of valacyclovir 1000 mg in adult patients with mild to moderate liver cirrhosis (with preserved synthetic liver function) no dose adjustment of Valacyclovir is required. Pharmacokinetic data in adult patients with severe hepatic impairment (decompensated cirrhosis), with impaired hepatic synthetic function and the presence of portocaval anastomoses also do not indicate the need for dose adjustment of Valacyclovir, but clinical experience with these pathologies is limited.

Children under 12 years of age

There are no data on the use of Valacyclovir in children under 12 years of age.

Elderly patients

Possible impairment of renal function in elderly patients must be considered; the dose of Valacyclovir must be adjusted accordingly (see Table 2). Adequate water-electrolyte balance should be maintained.

Interaction

No clinically significant interactions have been established.

Acyclovir is excreted by the kidneys, mostly unchanged, through active renal secretion. Concomitant use of medicinal products with this excretion mechanism may lead to increased concentrations of acyclovir in blood plasma.

After administration of Valacyclovir at a dose of 1000 mg, cimetidine and probenecid, which are excreted by the same route as Valacyclovir, increase the AUC of acyclovir and thus decrease its renal clearance. However, due to the wide therapeutic index of acyclovir, no dose adjustment of Valacyclovir is required in this case.

Caution should be exercised in the case of concomitant use of Valacyclovir at higher doses (4000 mg per day or more) and drugs that compete with acyclovir for excretion pathway, because there is a potential threat of increased plasma concentrations of one or both drugs or their metabolites. An increase in the AUC of acyclovir and the inactive metabolite mycophenolate mofetil (an immunosuppressant used after organ transplantation) has been noted when these drugs are taken simultaneously.

The concomitant use of valacyclovir with nephrotoxic drugs, including aminoglycosides, organic platinum compounds, iodinated contrast agents, methotrexate, pentamidine, foscarnet, cyclosporine and tacrolimus, should be performed with caution, especially in patients with impaired renal function, and requires regular monitoring of renal function.

Special Instructions

Hydration

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

The use in patients with renal impairment and elderly patients

Because acyclovir is excreted by the kidneys, the dose of Valacyclovir should be reduced depending on the degree of renal impairment. Patients with renal impairment and elderly patients have an increased risk of developing neurological complications; these patients should be closely monitored. As a rule, these reactions are mostly reversible.

The use of high doses of Valacyclovir in patients with liver dysfunction and after liver transplantation

There are no data on the use of Valacyclovir at high doses (4000 mg daily or higher) in patients with liver disease, so high doses of Valacyclovir should be prescribed with caution in these patients. No special studies on the effect of Valacyclovir in liver transplantation have been conducted. However, prophylactic administration of acyclovir at high doses has been found to reduce the manifestation of CMV infection and disease.

Use in genital herpes

Patients should refrain from sexual intercourse in the presence of symptoms, even if antiviral treatment has been initiated. Valacyclovir suppressive therapy reduces the risk of genital herpes transmission, but it does not eliminate the risk of infection and does not lead to a complete cure. Valacyclovir therapy is recommended in combination with reliable barrier contraception.

The use in CMV infections

The use of Valacyclovir at high doses for prevention of CMV infection results in a higher incidence of side effects, including CNS disturbances, than when used at lower doses for other indications. Renal function parameters in these patients should be monitored closely, with adjustments made to the drug dose if necessary.

Impact on the ability to drive vehicles and mechanisms

There are 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 or operate moving mechanisms, it is necessary to take into account that adverse effects on the central nervous system may occur, so caution should be exercised.

Contraindications

With caution

Renal failure, elderly, patients at risk of dehydration, concurrent use of nephrotoxic drugs, pregnancy, lactation, clinically significant forms of HIV infection in patients.

Side effects

Frequency categories of side effects: very frequently (>1/10), frequently (>1/100 to < 1/10), infrequently (>1/1000 to < 1/100), rarely (>1/10000 to < 1/1000), very rarely (< 1/10000).

Gastrointestinal tract: frequently – nausea; rarely – abdominal discomfort, vomiting, diarrhea.

The blood and hemopoietic system: very rarely – leukopenia (mainly in patients with lowered immunity), thrombocytopenia.

Immune system disorders: rarely – anaphylaxis.

Nervous system and mental disorders: frequently – headache; rarely – dizziness, confusion, hallucinations, depression of consciousness; very rarely – tremor, agitation, ataxia, dysarthria, psychotic symptoms, seizures, encephalopathy, coma.

The symptoms listed above are mostly reversible and are usually seen in patients with renal failure or other predisposing conditions. Transplant patients who receive valacyclovir at high doses (8 g/day) for prevention of CMV infection develop neurologic reactions more often than when given at lower doses.

Respiratory system: infrequent – dyspnea.

Hepatic and biliary tract disorders: very rarely – reversible liver function tests, which are sometimes regarded as manifestation of hepatitis.

Skin and subcutaneous fat: infrequent – rashes, including manifestations of photosensitivity; rare – itching; very rare – urticaria, angioedema.

The urinary system: infrequent – hematuria (often associated with other renal disorders), rarely – renal dysfunction, very rare – acute renal failure, renal colic.

Aciclovir crystals deposition in the lumen of the renal tubules was also observed. During treatment, an adequate drinking regimen should be observed.

In patients with severe immune disorders, especially in adult patients with advanced stage of HIV infection receiving valacyclovir in high doses
(8 g/day daily) for a long time, cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination) were observed. Similar complications have been noted in patients with the same underlying and/or comorbidities but who did not receive valacyclovir.

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Overdose

Symptoms

In overdose of valacyclovir, acute renal failure may occur and neurological symptoms, including confusion, hallucinations, agitation, depression of consciousness and coma, nausea and vomiting have also been reported. The dosing regimen should be followed to prevent overdose. Many cases of overdose have been associated with the use of the drug to treat patients with impaired renal function and elderly patients due to non-compliance with dosing regimen (who received repeated doses of valacyclovir higher than recommended).

Treatment

Patients should be closely monitored for timely diagnosis of toxic manifestations. Hemodialysis significantly accelerates excretion of acyclovir from the blood plasma and may be considered the optimal treatment for overdose.

Pregnancy use

Similarities