Valacyclovir Canon, 500 mg 10 pcs

Pharmacotherapeutic group:

antiviral agent.

ATX code:

J05AB11

Pharmacological properties

Pharmacodynamics

Mechanism of action

Valacyclovir is an antiviral agent and is an L-valine complex ester of acyclovir. Acyclovir is an analog of the purine nucleotide (guanine).

In the human body, valacyclovir is rapidly and almost completely converted to acyclovir and valine, presumably by the enzyme valacyclovirhydrolase.

Aciclovir 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 transformation into the active form – acyclovir triphosphate. 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.

Part of the phosphorylation selectivity is maintained in CMV indirectly through the product of the UL97 phosphotransferase gene. 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 breaking of the chain, cessation 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 of the virus is similar to that of its wild strain.

. In an extensive study of HBV and EHV strains sampled from patients treated with acyclovir or used as prophylaxis, it was found that viruses with hypersensitivity to Valacyclovir are extremely rare and may be found in rare cases in patients with severe immune impairments, such as bone marrow or organ transplant recipients, patients receiving chemotherapy for malignancies, and HIV-infected patients.

Valacyclovir helps manage pain: decreasing its duration and decreasing the percentage of patients with pain caused by herpes zoster, including acute post-herpetic neuralgia.

Pharmacokinetics

After oral administration, valacyclovir is well absorbed from the gastrointestinal (GI) tract and is rapidly and almost completely converted to acyclovir and valine. This conversion is probably carried out by the liver enzyme valacyclovir hydrolase.

The bioavailability of acyclovir is 54% when taking valacyclovir at a dose of 1000 mg or more and is not reduced by food intake.

The pharmacokinetics of valacyclovir are not dose-dependent. The rate and extent of absorption decrease with increasing dose, resulting in a less proportional increase in maximum plasma concentration (Cmax) compared to the therapeutic dose range and decreased bioavailability at doses above 500 mg.

Table 1. Results of acyclovir pharmacokinetics assessment of single doses of valacyclovir from 250 mg to 2,000 mg in healthy volunteers with normal hepatic function

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Cmax – maximum concentration in plasma;
Tmax – time to reach maximum concentration in blood plasma;
AUC – area under the pharmacokinetic curve “concentration-time”.

The values of Cmax and AUC reflect the mean standard deviation. The values for Tmax reflect the median value and range of values.

The maximum plasma concentration of valacyclovir is only 4% of that of acyclovir; the median time to reach it is from 30 to 100 min after drug administration.

In 3 hours after taking the drug, the concentration of valacyclovir reaches the level of quantification or lower. Valacyclovir and acyclovir have similar pharmacokinetic parameters after single and multiple dosing. VZV and HPV do not significantly change the pharmacokinetics of valacyclovir and acyclovir after oral valacyclovir administration.

Distribution

The degree of binding of valacyclovir to plasma proteins is very low (15%). The degree of penetration into the cerebrospinal fluid (CSF) is determined as the ratio of AUC in CSF to AUC in plasma and is about 25% for acyclovir and metabolite 8-hydroxyaciclovir (8-OH-ACV); about 2.5% for metabolite 9-(carboxymethoxy)methylguanine (CMMG).

Metabolism

After oral administration, valacyclovir is converted to acyclovir and L-valine via presystemic metabolism in the intestine and/or hepatic metabolism.

Aciclovir is converted to minor metabolites: CMMG by ethyl alcohol and aldehyde dehydrogenase; 8-OH-ACV by aldehydoxidase. Approximately 88% of the total cumulative plasma exposure is to acyclovir, 11% to CMMG, and 1% to 8-OH-ACV. Valacyclovir and acyclovir are not metabolized by cytochrome P450 isoenzymes.

In patients with normal renal function the elimination half-life of acyclovir from the blood plasma after single or multiple doses of valacyclovir is about 3 hours. Less than 1% of the dose of valacyclovir taken is excreted unchanged by the kidneys.

Valacyclovir is excreted from the body by the kidneys primarily as acyclovir (more than 80% of the dose taken) and acyclovir metabolite – CMMG.

Special patient groups

Patients with impaired renal function

Aciclovir excretion correlates with renal function, exposure to acyclovir increases with the severity of renal failure. In patients with end-stage renal failure, the average half-life of acyclovir after valacyclovir administration is about 14 hours, compared to about 3 hours with normal renal function.

. Exposure of acyclovir and its metabolites CMMG and 8-OH-ACV in plasma and CSF was evaluated at steady state after multiple doses of valacyclovir in 6 patients with normal renal function (mean creatinine clearance 111 mL/min, range 91-144 mL/min) who received 2,000 mg every 6 hours and in 3 patients with severe renal impairment (mean creatinine clearance 26 mL/min, range 17-31 mL/min) who received 1,500 mg every 12 hours.

In severe renal failure compared with normal renal function, plasma concentrations of acyclovir, CMMG, and 8-OH-ACV were 2, 4, and 5-6 times higher in plasma as well as in CSF, respectively. There was no difference in the penetration of acyclovir in CSF (defined as the ratio of AUC in CSF to AUC in plasma), CMMG, or 8-OH-ACV between the two populations with severe renal failure and normal renal function.

Patients with impaired hepatic function

Pharmacokinetic data show that in patients with hepatic impairment the rate of conversion of valacyclovir to acyclovir is reduced, but not the extent of this conversion. The half-life of acyclovir is independent of hepatic function.

Pregnancy

A study of the pharmacokinetics of valacyclovir and acyclovir in late pregnancy found an increase in the steady state daily AUC of valacyclovir at a daily dose of 1000 mg daily, which was approximately 2 times the AUC when acyclovir was taken orally at a dose of 1200 mg daily.

HIV infection

In patients with HIV infection, the distribution and pharmacokinetic characteristics of acyclovir remain unchanged after oral administration of one or more doses of 1000 mg or 2000 mg of valacyclovir compared with healthy volunteers.

Organ transplantation

The maximum concentration of acyclovir in patients after organ transplantation receiving 2000 mg valacyclovir 4 times daily was comparable to or higher than the maximum concentration observed in healthy volunteers receiving the same dose. The established daily AUC values can be characterized as markedly higher.

Indications

Skin itching, Cytomegalovirus infection, Herpes, Colds

Adults and adolescents aged 12 to 18 years

• treatment of skin and mucous membrane infections caused by HPV, including newly detected 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 HPV, including genital herpes, including in immunodeficient adults;
• prevention of infections caused by cytomegalovirus (CMV) and diseases after parenchymal organ transplants.

Adults

• treatment of herpes zoster and ophthalmic herpes zoster

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Active ingredient

Valacyclovir

Composition

1 film-coated tablet contains:
active ingredient:

• valacyclovir hydrochloride in terms of valacyclovir 500 mg;

excipients:

• corn starch,
• silica colloidal dioxide,
• croscarmellose sodium,
• magnesium stearate,
• microcrystalline cellulose;

coating composition:

• Opadray II white, including: macrogol (polyethylene glycol), polyvinyl alcohol, talc, titanium dioxide.

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How to take, the dosage

The drug Valacyclovir Canon can be taken regardless of meals, the tablets should be washed with water.
Treatment of infections of the skin and mucous membranes caused by HPV, including newly detected and recurrent genital herpes (Herpes genitalis), as well as herpes labialis (Herpes labialis)/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 cases of primary herpes, which may be more severe, treatment should be started as soon as possible and the duration should be increased from 5 to 10 days.

In relapses of 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 use can prevent lesions from developing if used at the first signs and symptoms of relapse caused by HPV.

As an alternative treatment for labial herpes, Valacyclovir Canon 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, since 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.

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

Adults with immunodeficiency

In adult patients with immunodeficiency, the recommended dose is 500 mg 2 times daily.
After 6-12 months of treatment it is necessary to evaluate the effectiveness of therapy.

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

Adults and adolescents aged 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.

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 must be taken into account; the dose of Valacyclovir Canon should be adjusted accordingly.

The adequate water-electrolyte balance should be maintained.

Patients with impaired renal function

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

Table 2. Dose adjustment of Valacyclovir Canon for use in adults and adolescents aged 12 to 18 years with impaired renal function

Interaction

No clinically significant interactions have been established.

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

After administration of Valacyclovir Canon at a dose of 1000 mg and the drugs cimetidine, probenecid, which are excreted by the same route, a decrease in renal clearance and increase in AUC of acyclovir was observed. However, due to the wide therapeutic index of acyclovir there is no need to adjust the dose of valacyclovir.

In the treatment of labial herpes, in the prevention and treatment of diseases caused by CMV, caution should be exercised when using valacyclovir at higher doses (4000 mg daily or higher) and drugs that compete with acyclovir for the excretion route, since there is a potential risk of increased plasma concentrations of one or both drugs or their metabolites.

The AUC of acyclovir and the inactive metabolite mycophenolate mofetil (an immunosuppressant used in patients after organ transplantation) have been observed to increase when these drugs are used simultaneously.

The concomitant use of Valacyclovir Canon 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.

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Special Instructions

In elderly patients, persons with dehydration during treatment it is necessary to increase fluid intake (risk of acute renal failure).

In the treatment of genital herpes, sexual intercourse should be avoided, since the drug does not protect against transmission.

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

In case of CNS side effects (including agitation, hallucinations, confusion, delirium, seizures and encephalopathy) the drug is stopped.

Contraindications

Hypersensitivity, HIV infection with CD4+ lymphocytes less than 100/μL, childhood (under 12 years for CMV, under 18 years for other indications).

With caution. Hepatic/renal insufficiency, elderly age, hypohydration, concomitant use of nephrotoxic drugs, pregnancy, lactation, children.

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Side effects

Digestive system disorders: nausea, abdominal pain, vomiting, diarrhea, increased ALT, AST, ALP activity, hepatitis.

Nervous system disorders: headache, dizziness, depression, aggressive behavior, agitation, ataxia, coma, confusion or depression of consciousness, dysarthria, encephalopathy, mania, psychosis, including auditory and visual hallucinations, seizures, tremor.

Sensory organs: visual impairment.

Urinary system disorders: pain in the renal projection, acute renal failure.

Hematopoietic disorders: neutropenia, thrombocytopenia, aplastic anemia, leukoclastic vasculitis, thrombotic thrombocytopenic purpura.

Skin disorders: erythema multiforme, rash, photosensitization, alopecia.

Allergic reactions: angioedema, dyspnea, itching, rash, urticaria, anaphylactic reactions.

Laboratory measures: decreased Hb, hypercreatininemia.

Others: dysmenorrhea, arthralgia, nasopharyngitis, respiratory tract infections, facial edema, increased BP, tachycardia, fatigue; additionally in children, fever, dehydration, rhinorrhea.

Overdose

Symptoms: possible deposition of acyclovir in the renal tubules, with the development of acute renal failure and anuria.

Treatment: hemodialysis.

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Pregnancy use

Fertility

In animal studies valacyclovir had no effect on fertility. However, the use of high doses of acyclovir when administered parenterally 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 the number, motility and morphology of spermatozoa in 20 patients after 6 months of daily use of valacyclovir in doses from 400 mg to 1000 mg were registered.

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 registries have documented pregnancy outcomes in women taking valacyclovir or other drugs containing acyclovir (acyclovir is the active metabolite of valacyclovir), 111 and 1246 observations, respectively (of which 29 and 756 took the drugs in the first trimester of pregnancy), representing prospectively reported pregnancy outcomes.

Analysis of data reported in the registry of pregnant women exposed to acyclovir showed no increase in birth defects in their children compared with the general population, with no specificity or pattern indicating a common cause for any of the malformations.

Because the pregnancy registry included a small number of women who took valacyclovir during pregnancy, reliable and definitive conclusions about the safety of valacyclovir in pregnancy cannot be drawn.

Breastfeeding period

Acyclovir, the main metabolite of valacyclovir, penetrates into breast milk. After oral administration of valacyclovir at a dose of 500 mg the 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 value 2.2).

The mean value of acyclovir concentration 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 amount of 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 from 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.

Nevertheless, acyclovir for intravenous administration is used to treat HPV in infants at a dose of 30 mg/kg/day.

Similarities

Valtrex, Valacyclovir, Valcicon, Valvir, Valacyclovir Canon