Product Overview
Structure
active ingredient:
- valaciclovir hydrochloride 1112.40 mg, in terms of valaciclovir 1000.00 mg;
- corn starch 113.60 mg,
- silicon dioxide colloidal 4.00 mg,
- croscarmellose sodium 58.00 mg,
- magnesium stearate 8.00 mg,
- microcrystalline cellulose 144.00 mg;
- Opadry II white 44.00 mg, including: macrogol (polyethylene glycol) 10.38 mg, polyvinyl alcohol 20.64 mg, talcum 7.66 mg, titanium dioxide 5.32 mg.
pharmachologic effect
antiviral agent.
ATX Code:
J05AB11
Pharmacological propertiesPharmacodynamics
Mechanism of action
Valaciclovir is an antiviral agent, is an acyclovir L-valine ester. Acyclovir is an analogue of purine nucleotide (guanine).
In the human body, valacyclovir is rapidly and almost completely converted to acyclovir and valine, presumably under the influence of the enzyme valacyclovir hydrolase.
Acyclovir is a specific inhibitor of herpes viruses with in vitro activity against herpes simplex viruses (HSV) types 1 and 2, varicella-zoster virus (BBZ) (Varicella zoster virus), 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, acyclovir triphosphate. The first stage of phosphorylation requires the activity of virus-specific enzymes. For HSV, VZV and EBV, such an enzyme is viral thymidine kinase, which is present only in virus-infected cells.
Partially, 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 cell kinases. Acyclovirtriphosphate competitively inhibits viral DNA polymerase and, being a nucleoside analogue, integrates into viral DNA, which leads to obligate breaking of the chain, termination of DNA synthesis and, consequently, to block virus replication.
Resistance to acyclovir is usually due to a deficiency of thymidine kinase, which leads to an excessive spread of the virus in the host body. In rare cases, a decrease in sensitivity to acyclovir is due to the appearance of virus 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.
According to the results of an extensive study of HSV and VZV strains selected from patients treated with acyclovir or used for prophylaxis, it was found that viruses with reduced sensitivity to valacyclovir are extremely rare, which can be detected in rare cases in patients with severely impaired immunity, for example, bone marrow or organ transplant recipients, patients receiving chemotherapy for malignant tumors, 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 postherpetic neuralgia.
PharmacokineticsSuction
After oral administration, valaciclovir is well absorbed from the gastrointestinal tract (GIT), quickly and almost completely turns into acyclovir and valine. This conversion is probably carried out by the liver enzyme valacyclovirhydrolase.
When taking valaciclovir in a dose of 1000 mg, the bioavailability of acyclovir is 54% and does not decrease with food intake.
The pharmacokinetics of valaciclovir is not dose-dependent. The rate and degree of absorption decrease with increasing dose, leading to a less proportional increase in the maximum plasma concentration (Cmax) compared with the therapeutic dose range and a decrease in bioavailability at doses above 500 mg.
Table 1. The results of the assessment of the pharmacokinetics of acyclovir when taking single doses of valaciclovir from 250 mg to 2000 mg by healthy volunteers with normal liver function
| Pharmacokinetic parameters of acyclovir | 250 mg (N = 15) | 500 mg (N = 15) | 1000 mg (N = 15) | 2000 mg (N = 8) | |
| Cmax | μmol / l | 9.78 ± 1.71 | 15.0 ± 4.23 | 23.1 ± 8.53 | 36.9 ± 6.36 |
| mcg / ml | 2.20 ± 0.38 | 3.37 ± 0.95 | 5.20 ± 1.92 | 8.30 ± 1.43 | |
| Tmax | hours (h) | 0.75 (0.75-1.5) | 1.0 (0.75-2.5) | 2.0 (0.75-3.0) | 2.0 (1.5-3.0) |
| Auc | h · micromol / l | 24.4 ± 3.65 | 49.3 ± 7.77 | 83.9 ± 20.1 | 131 ± 28.3 |
| h · mcg / ml | 5.50 ± 0.82 | 11.1 ± 1.75 | 18.9 ± 4.51 | 29.5 ± 6.36 | |
Tmax - time to reach maximum plasma concentration;
AUC is the area under the concentration-time pharmacokinetic curve.
C max and AUC values ​​reflect the standard deviation. Values ​​for Tmax reflect the median value and range of values.
The maximum concentration of valaciclovir in plasma is only 4% of the concentration of acyclovir, the median time to reach it is from 30 to 100 minutes after taking the drug.
3 hours after taking the drug, the concentration of valaciclovir reaches a level of quantification or lower. Valaciclovir and acyclovir have similar pharmacokinetic parameters after a single and multiple doses. VZV and HSV do not significantly change the pharmacokinetics of valaciclovir and acyclovir after oral administration of valaciclovir.
Distribution
The degree of binding of valaciclovir to plasma proteins is very low (15%). The degree of penetration into the cerebrospinal fluid (CSF) is defined as the ratio of AUC in CSF to AUC in blood plasma and is about 25% for acyclovir and a metabolite of 8-hydroxyacyclovir (8-OH-ACV); about 2.5% for the metabolite of 9- (carboxymethoxy) methyl guanine (CMMG).
Metabolism
After oral administration, valaciclovir is converted to acyclovir and L-valine through presystemic metabolism in the intestine and / or liver metabolism.
Acyclovir is converted into small metabolites: CMMG under the influence of ethyl alcohol and aldehyde dehydrogenase; 8-OH-ACV by aldehyde oxidase. Approximately 88% of the total cumulative plasma exposure is attributed to acyclovir, 11% to CMMG and 1% to 8-OH-ACV. Valaciclovir and acyclovir are not metabolized by isoenzymes of the cytochrome P450 system.
Breeding
In patients with normal renal function, the half-life of acyclovir from blood plasma after a single or multiple administration of valaciclovir is about 3 hours. Less than 1% of the accepted dose of valaciclovir is excreted by the kidneys unchanged.
Valacyclovir is excreted from the body by the kidneys mainly in the form of acyclovir (more than 80% of the accepted dose) and the metabolite of acyclovir - CMMG.
Special patient groups
Patients with impaired renal function
Excretion of acyclovir correlates with renal function, exposure to acyclovir increases with increasing severity of renal failure. In patients with end-stage renal failure, the average half-life of acyclovir after valacyclovir is about 14 hours, compared to about 3 hours with normal kidney function.
Exposure of acyclovir and its metabolites CMMG and 8-OH-ACV in blood plasma and CSF were evaluated in a stable state after repeated administration of valacyclovir in 6 patients with normal renal function (average creatinine clearance 111 ml / min, range 91-144 ml / min), receiving 2000 mg every 6 hours, and in 3 patients with severe renal failure (average creatinine clearance 26 ml / min, range 17-31 ml / min), receiving 1500 mg every 12 hours.
In severe renal failure compared with normal renal function in blood plasma, as well as in CSF, the concentrations of acyclovir, CMMG and 8-OH-ACV were 2, 4 and 5-6 times higher, respectively. There was no difference in the degree of penetration of acyclovir into CSF ​​(defined as the ratio of AUC in CSF to AUC in blood plasma), CMMG, or 8-OH-ACV between two populations with severe renal failure and normal renal function.
Patients with impaired liver function
Pharmacokinetic data show that in patients with liver failure, the rate of conversion of valaciclovir to acyclovir is reduced, but not the degree of this conversion. The half-life of acyclovir is independent of liver function.
Pregnancy
A study of the pharmacokinetics of valaciclovir and acyclovir in late pregnancy showed an increase in the value of the daily AUC in a stable state with daily intake of valaciclovir at a dose of 1000 mg per day, which was approximately 2 times higher than AUC when ingested with acyclovir at a dose of 1200 mg per day.
HIV infection
In patients with HIV infection, the distribution and pharmacokinetic characteristics of acyclovir after oral administration of one or more doses of 1000 mg or 2000 mg of valaciclovir remain unchanged compared with healthy volunteers.
Organ transplantation
The maximum concentration of acyclovir in patients after organ transplantation receiving 2000 mg of valaciclovir 4 times a day was comparable to or higher than the maximum concentration observed in healthy volunteers who received the same dose. The established daily AUC values ​​can be characterized as significantly higher.
Indications
Adults and adolescents aged 12 to 18 years
- treatment of infections of the skin and mucous membranes caused by HSV, including newly diagnosed and recurrent genital herpes (Herpes genitalis), as well as labial herpes (Herpes labialis);
- prevention (suppression) of recurrence of infections of the skin and mucous membranes caused by HSV, 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 (Herpes zoster) and ophthalmic herpes zoster.
Pregnancy and lactation
In animal studies, valaciclovir did not affect fertility. However, the use of high doses of acyclovir for parenteral administration caused testicular effects in rats and dogs. Studies of the effects of valaciclovir on fertility in humans have not been conducted.
However, no changes were recorded in the number, motility and morphology of spermatozoa in 20 patients after 6 months of daily use of valaciclovir in doses from 400 mg to 1000 mg.
Pregnancy
There is limited evidence on the use of valaciclovir during pregnancy.
The drug should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.
Pregnancy registers documented pregnancy outcomes in women taking valaciclovir or other drugs containing acyclovir (acyclovir is an active metabolite of valaciclovir), 111 and 1246 cases, respectively (of which 29 and 756 took drugs in the first trimester of pregnancy), represented pregnancy outcomes registered prospectively.
Analysis of the data presented in the register of pregnant women exposed to acyclovir did not reveal an increase in the number of birth defects in their children compared to the general population, and no specific defects or patterns were revealed for any of the malformations indicating a common cause.
Since a small number of women who took valaciclovir during pregnancy were included in the pregnant register, reliable and definite conclusions about the safety of using valaciclovir during pregnancy cannot be made.
Breastfeeding
Acyclovir, the main metabolite of valaciclovir, passes into breast milk. After taking valaciclovir in a dose of 500 mg by mouth, Cmax in breast milk was 0.5–2.3 times (on average 1.4 times) higher than the corresponding concentration of acyclovir in maternal blood plasma. The ratio of AUC values ​​of acyclovir in breast milk to AUC in maternal blood serum ranged from 1.4 to 2.6 (average value 2.2).
The mean concentration of acyclovir in breast milk was 2.24 μg / ml (9.95 μmol / L). When the mother takes valaciclovir at a dose of 500 mg 2 times a day, breast-fed children are exposed to the same effects of acyclovir as when taken 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 unchanged was not detected in maternal blood plasma, breast milk or urine. The drug Valacyclovir Canon should be prescribed with caution to women during breastfeeding.
However, acyclovir for intravenous administration is used to treat HSV in infants at a dose of 30 mg / kg / day.
Contraindications
- Hypersensitivity to valaciclovir, acyclovir or any other component that is part of the drug;
- children under 12 years old;
- children's age up to 18 years in the treatment of herpes zoster and ophthalmic herpes zoster.
Side effects
From the digestive system: nausea, abdominal pain, vomiting, diarrhea, increased activity of ALT, AST, alkaline phosphatase, hepatitis.
From the side of the nervous system: headache, dizziness, depression, aggressive behavior, agitation, ataxia, coma, confusion or depression of consciousness, dysarthria, encephalopathy, mania, psychosis, including auditory and visual hallucinations, convulsions, tremors.
From the sensory organs: impaired vision.
From the urinary system: pain in the projection of the kidneys, acute renal failure.
From the hemopoietic organs: neutropenia, thrombocytopenia, aplastic anemia, leukoclastic vasculitis, thrombotic thrombocytopenic purpura.
From the skin: erythema multiforme, rash, photosensitivity, alopecia.
Allergic reactions: angioedema, shortness of breath, itching, rash, urticaria, anaphylactic reactions.
Laboratory findings: Hb reduction, hypercreatininemia.
Other: dysmenorrhea, arthralgia, nasopharyngitis, respiratory tract infections, facial edema, increased blood pressure, tachycardia, fatigue; additionally in children - fever, dehydration, rhinorrhea.
Interaction
Clinically significant interactions have not been established.
Acyclovir is excreted by the kidneys, mainly unchanged through active renal secretion. The combined use of drugs with this excretion mechanism can lead to an increase in the concentration of acyclovir to blood plasma.
After the administration of the drug Valaciclovir Canon at a dose of 1000 mg and cimetidine preparations, probenecid, which are excreted in the same way, a decrease in renal clearance and an increase in AUC of acyclovir are observed. However, due to the wide therapeutic index of acyclovir, dose adjustment of valaciclovir ns is required.
In the treatment of labial herpes, in the prevention and treatment of diseases caused by CMV, caution should be exercised in the case of simultaneous use of valaciclovir in higher doses (4000 mg per day and higher) and drugs that compete with acyclovir for the elimination route, since there is a potential the threat of an increase in plasma concentrations of one or both drugs or their metabolites.
An increase in the AUC of acyclovir and an inactive metabolite of mycophenolate mofetil (an immunosuppressant used in patients after organ transplantation) was noted with the simultaneous use of these drugs.
The simultaneous use of the drug Valaciclovir Canon with nephrotoxic drugs, including aminoglycosides, organic platinum compounds, iodinated contrast medium, methotrexate, pentamidine, foscarnet, cyclosporine and tacrolimus, should be carried out with caution, especially in patients with impaired renal function, and requires regular monitoring of function the kidneys.
How to take, course of administration and dosage
The drug Valacyclovir Canon can be taken regardless of the meal, tablets should be washed down with water.
Treatment of infections of the skin and mucous membranes caused by HSV, 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
recommended dose is 500 mg 2 times a day.
In case of relapse, treatment should last 3 or 5 days. In the case of primary herpes, which can occur in a more severe form, treatment should be started as early as possible, and its duration should be increased from 5 to 10 days.
In relapses of HSV, prescribing Valacyclovir Canon in the prodromal period or immediately after the onset of the first symptoms of the disease is considered the most accurate. The use of valaciclovir can prevent the development of damage if it is used at the first signs and symptoms of relapse caused by HSV.
As an alternative treatment for labial herpes, the administration of the drug Valaciclovir Canon at a dose of 2000 mg 2 times a day for 1 day is effective. The second dose should be taken approximately 12 hours (but not earlier than 6 hours) after taking the first dose. When using this dosing regimen, the duration of treatment should not exceed 1 day, since exceeding the duration of this course of treatment does not lead to additional clinical benefit.
Therapy should be started when the earliest symptoms of labial herpes appear (i.e., pinching, itching, burning).
Prevention (suppression) of recurrence of skin and mucous membrane infections caused by HSV, including genital herpes, including in adults with immunodeficiency
Immunocompetent adults and adolescents aged 12 to 18 years
In immunocompetent patients, the recommended dose is 500 mg 1 time per day.
After 6-12 months of treatment, it is necessary to cordon off the effectiveness of therapy.
Immunodeficiency Adults
In adult patients with immunodeficiency, the recommended dose is 500 mg 2 times a day.
After 6-12 months of treatment, it is necessary to cordon off the effectiveness of therapy.
Prevention of CMV infections and diseases after transplantation of parenchymal organs
Adults and adolescents aged 12 to 18 years
The recommended dose is 2000 mg 4 times a day, prescribed as soon as possible after transplantation. The dose should be reduced depending on the clearance of creatinine. The duration of treatment is usually 90 days, but in patients at high risk, the course of treatment can be extended.
Treatment of herpes zoster (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 effectiveness of treatment with Valaciclovir Canon in children has not been investigated.
Elderly patients
It is necessary to take into account possible impaired renal function in elderly patients; the dose of Valaciclovir Canon should be adjusted accordingly.
An adequate water-electrolyte balance must be maintained.
Patients with impaired renal function
The dose of Valaciclovir Canon is recommended to be reduced in patients with severe renal impairment (see dosing regimen in Table 2). In such patients, it is necessary to maintain an adequate water-electrolyte balance.
Table 2. Dose adjustment of Valaciclovir Canon for use in adults and adolescents aged 12 to 18 years with impaired renal function
| Indications | Creatinine clearance, ml / min | Dose of Valaciclovir Canon |
| Herpes zoster and ophthalmic herpes zoster in immunocompetent adults (treatment) | not less than 50 | 1000 mg 3 times a day |
| from 30 to 49 | 1000 mg 2 times a day | |
| from 10 to 29 | 1000 mg once daily | |
| less than 10 | 500 mg once daily | |
| HSV (treatment) | ||
| Immunocompetent adults and adolescents aged 12 to 18 years | not less than 30 | 500 mg 2 times a day |
| less than 30 | 500 mg once daily | |
| Labial herpes in immunocompetent adults and adolescents aged 12 to 18 years (treatment) | not less than 50 | 2000 mg 2 times a day |
| from 30 to 49 | 1000 mg 2 times a day | |
| from 10 to 29 | 500 mg 2 times a day | |
| less than 10 | 500 mg once daily | |
| HSV (prevention (suppression)) | ||
| Immunocompetent adults and adolescents aged 12 to 18 years | not less than 30 | 500 mg once daily |
| less than 30 | 500 mg once every two days | |
| Immunodeficiency Adults | not less than 30 | 500 mg 2 times a day |
| less than 30 | 500 mg once daily | |
| Prevention of CMV infections in adults and adolescents aged 12 to 18 | not less than 75 | 2000 mg 4 times a day |
| from 50 to 75 | 1500 mg 4 times a day | |
| from 25 to 50 | 1500 mg 3 times a day | |
| from 10 to 25 | 1500 mg 2 times a day | |
| less than 10 or in patients on hemodialysis | 1500 mg once daily | |
Additional information for indication: treatment of infections of the skin and mucous membranes caused by HSV, including newly diagnosed and recurrent genital herpes (Herpes genitalis), as well as labial herpes (Herpes labialis)
There is no experience with the use of Valaciclovir Canon in children with creatinine clearance values ​​of less than 50 ml / min / 1.73 m².
Additional information for indication: prevention of CMV infections and diseases after transplantation of parenchymal organs
It is often necessary to determine creatinine clearance, especially at a time when kidney function changes rapidly, for example, immediately after transplantation or graft engraftment, while the dose of Valaciclovir Canon is adjusted in accordance with creatinine clearance indicators.
Additional information for indications: treatment of herpes zoster (Herpes zoster) and ophthalmic herpes zoster
The drug Valacyclovir Canon should be used after hemodialysis in patients undergoing periodic hemodialysis.
Patients with impaired liver function
Based on a study using a single dose of valaciclovir 1000 mg in adult patients with mild or moderate liver cirrhosis (with preserved synthetic liver function), dose adjustment of the drug Valaciclovir Canon is not required.
Pharmacokinetic data in adult patients with a severe degree of impaired liver function (uncompensated cirrhosis), with impaired synthetic liver function and the presence of portocaval anastomoses also do not indicate the need for dose adjustment of Valacyclovir Canon, however, clinical experience with these pathologies is limited.
Information on doses greater than 4000 mg per day for patients with infections caused by HSV and CMV is indicated in the Special Instructions section.
Overdose
Similar conditions were more often observed in patients with impaired renal function and elderly patients who received repeated exceeding the recommended doses of valaciclovir, due to non-compliance with the dosage regimen.
Treatment: Patients should be under close medical supervision. Hemodialysis significantly contributes to the elimination of acyclovir from the blood and can be considered the method of choice in the management of patients with an overdose of the drug.
Special instructions
In patients at risk of dehydration, especially in elderly patients, it is necessary to ensure an adequate water-electrolyte balance.
Use in patients with impaired renal function and in elderly patients
Since acyclovir is excreted by the kidneys, it is necessary to reduce the dose of Valacyclovir Canon in patients with impaired renal function. In elderly patients, impaired renal function may be observed, therefore, a dose reduction for this group of patients should be considered. Both elderly patients and patients with impaired renal function are at increased risk of developing
neurological complications, such patients need to ensure careful medical supervision. As a rule, these reactions are mainly reversible in case of drug withdrawal.
Treatment of labial herpes and prevention of CMV infections and diseases.
The use of high doses of the drug Valaciclovir Canon for impaired liver function and after a liver transplant
There is no data on the use of Valacyclovir Canon in high doses (
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