Description
Valacyclovir Kanon Pharmacodynamics
Mechanism of action
Valacyclovir is an antiviral agent and is an L-valine ester of acyclovir. Acyclovir is an analog of the purine nucleotide (guanine).
In humans, valacyclovir is rapidly and almost completely converted to acyclovir valine, presumably by the enzyme valacyclovirhydrolase. Acyclovir is a specific herpes virus inhibitor with in vitro activity against herpes simplex virus (HPV) types 1 and 2, Varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpes virus type 6. Acyclovir inhibits the synthesis of viral deoxyribonucleic acid (DNA) immediately after phosphorylation and conversion to the active form, acyclovirtriphosphate. The first stage of phosphorylation requires the activity of virus-specific enzymes. For HPV, VZV, and VEB, this enzyme is viral thymidine kinase, which is present only in virus-affected cells. In CMV, part of the phosphorylation selectivity is maintained indirectly through the product of the phosphotransferase gene UL97. This need for 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 chain breaking, termination of DNA synthesis and, consequently, to blocking of virus replication.
Resistance to acyclovir is usually due to thymidine kinase deficiency, which leads to excessive spread of the virus in the host. In rare cases, decreased sensitivity to acyclovir is due to the emergence of virus strains with disrupted viral thymidine kinase or DNA polymerase structure. The virulence of these strains is similar to that of the wild strain.
An extensive study of HPV and EHV strains sampled from patients treated with acyclovir or used as prophylaxis found that viruses with hypersensitivity to valacyclovir are extremely rare but may be found in rare cases in patients with severe immune disorders, such as bone marrow or organ transplant recipients, patients receiving chemotherapy for malignancies, and HIV-infected patients.
Valacyclovir helps relieve pain: it reduces its duration and reduces the percentage of patients with pain caused by herpes zoster, including acute post-herpetic neuralgia.
Indications
Adults and adolescents 12 to 18 years of age
Treatment of skin and mucous membrane infections caused by HPV, including newly diagnosed and recurrent genital herpes (Herpes genitalis) and labial herpes (Herpes labialis);
prevention (suppression) of recurrent infections of the skin and mucous membranes caused by HPV, including genital herpes, including in adults with immunodeficiency;
prevention of infections caused by cytomegalovirus (CMV) and diseases after transplantation of parenchymal organs.
Adults
Treatment of herpes zoster and ophthalmic herpes zoster.
Contraindications
– Hypersensitivity to valacyclovir, acyclovir or any other component of the drug;
– Childhood under 12 years of age;
– Children under 18 years of age for treatment of herpes zoster and ophthalmic herpes zoster.
Pregnancy and lactation:
Fertility .
In animal studies, valacyclovir had no effect on fertility. However, the use of high doses of acyclovir when administered parenterally has caused testicular effects in rats and dogs. Studies on the effect of valacyclovir on fertility in humans have not been conducted. However, no changes in sperm count, motility, or morphology were reported in 20 patients after 6 months of daily valacyclovir doses ranging from 400 mg to 1,000 mg.
Pregnancy
There are limited data on the use of valacyclovir in pregnancy.
The drug should be used in pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.
Pregnancy outcomes in women taking valacyclovir or other drugs containing acyclovir (acyclovir is the active metabolite of valacyclovir) have been documented in pregnancy registries, 111 and 1246 observations, respectively (of which 29 and 756 took the drugs in the first trimester of pregnancy), representing pregnancy outcomes reported prospectively. Analysis of the data presented in the registry of pregnant women exposed to acyclovir showed no increase in birth defects in their children compared to the general population, and no specificity or pattern indicating a common cause was found for any of the malformations. Because the pregnancy registry included a small number of women who took valacyclovir during pregnancy, no reliable and definitive conclusions about the safety of valacyclovir in pregnancy can be drawn.
Breastfeeding period
Acyclovir, the main metabolite of valacyclovir, passes into breast milk. After oral administration of valacyclovir at a dose of 500 mg, cmax in breast milk was 0.5-2.3 times (1.4 times on average) higher than corresponding concentrations of acyclovir in maternal blood plasma. The ratio of AUC values of acyclovir in breast milk to AUC values in maternal blood serum ranged from 1.4 to 2.6 (mean 2.2). The mean concentration of acyclovir in breast milk was 2.24 μg/mL (9.95 μmol/L). When the mother takes valacyclovir at a dose of 500 mg twice daily, breastfed infants are exposed to the same acyclovir as when it is taken orally at a dose of about 0.61 mg/kg/day. The half-life of acyclovir from breast milk is the same as that of blood plasma. Valacyclovir in unchanged form was not detected in maternal plasma, breast milk or urine.
Valacyclovir Canon should be administered with caution to women during breastfeeding.
However, intravenous acyclovir is used to treat HPV in infants at a dose of 30 mg/kg/day.
Dosage and administration
- Valacyclovir Canon can be taken regardless of meals, the tablets should be washed down with water.
- Treatment of infections of the skin and mucous membranes caused by HPV, including newly diagnosed and recurrent genital herpes (Herpes genitalis) and labial herpes (Herpes labialis)
- Immunocompetent adults and adolescents 12 to 18 years of age
- 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 early as possible and its duration should be increased from 5 to 10 days. In case of recurrent HPV, it is most correct to prescribe Valacyclovir Canon in the prodromal period or immediately after the appearance of the first symptoms of the disease.
- Valacyclovir can prevent lesions from developing if used at the first signs and symptoms of recurrence caused by HPV.
- As an alternative treatment for labial herpes, it is effective to prescribe Valacyclovir Canon in 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, since exceeding this duration of treatment leads to no additional clinical benefit.
- Therapy should be initiated 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 immunodeficient adults
- Immunocompetent adults and adolescents 12 to 18 years of age
- In immunocompetent patients, the recommended dose is 500 mg once daily.
- After 6 to 12 months of treatment, the efficacy of therapy should be evaluated.
- Adults with immunodeficiency
- In immunocompromised adults, the recommended dose is 500 mg 2 times daily.
- In 6-12 months of treatment it is necessary to evaluate the effectiveness of therapy.
- Prevention of infections caused by CMV and disease after parenchymal organ transplantation
- Adults and adolescents between 12 and 18 years of age.
- 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 prolonged.
- Treatment of herpes zoster and ophthalmic herpes zoster
- Adults
- The recommended dose is 1000 mg 3 times a day for 7 days.
- Special patient groups
- Children
- The efficacy of treatment with Valacyclovir Canon in children has not been studied.
- Elderly patients
- Possible impairment of renal function in elderly patients should be taken into account, the dose of Valacyclovir Canon should be adjusted accordingly.
- Adequate water-electrolyte balance should be maintained.
- Patients with impaired renal function
- The dose of Valacyclovir Canon should be reduced in patients with severe renal dysfunction (see dosing regimen in Table 2). In such patients an adequate water-electrolyte balance should be maintained.
- Table 2. Dosage adjustment of Valacyclovir Canon for use in adults and adolescents aged 12 to 18 years with impaired renal function
- Indications
Creatinine clearance, ml/min - Dose of Valacyclovir Canon
- Herpes zoster and ophthalmic herpes zoster in immunocompetent adults (treatment)
at least 50
1000 mg 3 times daily
30 to 49
1000 mg 2 times daily
10 to 29
1000 mg 1 time per day
less than 10
500 mg once daily
HPV (treatment) - Immunocompetent adults and adolescents 12 to 18 years of age
at least 30
500 mg 2 times daily
less than 30
500 mg once daily - Labial herpes in immunocompetent adults and adolescents 12 to 18 years of age (treatment)
at least 50
2000 mg 2 times daily
30 to 49
1000 mg 2 times a day
10 to 29
500 mg two times a day
less than 10
500 mg 1 time per day
HPV (prophylaxis (suppression)) - Immunocompetent adults and adolescents 12 to 18 years of age
not less than 30
500 mg 1 time per day
less than 30
500 mg 1 time per day less than 30 - Adults with immunodeficiency
at least 30
500 mg twice daily
less than 30
500 mg 1 time daily - Prevention of infections caused by TDMV in adults and adolescents aged 12 to 18 years
at least 75
2000 mg 4 times daily
50 to 75
1500 mg 4 times a day
25 to 50
1500 mg 3 times daily
10 to 25
1500 mg 2 times daily - Less than 10 or in patients on hemodialysis
1500 mg once daily
