Composition, form of production and packaging
The tablets covered with a film membrane of white or almost white color, round, biconcave; on the cross section - the core is white or almost white.
1 tab.
valacyclovir hydrochloride 556 mg,
in terms of valacyclovir 500 mg
Excipients: microcrystalline cellulose - 95 mg, giprolase (hydroxypropyl cellulose) - 14 mg, crospovidone - 28 mg, magnesium stearate - 7 mg.
The composition of the film shell: (hypromellose - 10.5 mg, giprolose (hydroxypropylcellulose) - 4.07 mg, talc - 4.12 mg, titanium dioxide - 2.31 mg) or (dry film coating - white, containing hypromellose - 50%, hydroxypropyl cellulose - 19.4% talc - 19.6%, titanium dioxide - 11%) - 21 mg.
5 pieces. - packings cellular planimetric (2) - packs cardboard.
14 pcs. - packings cellular planimetric (3) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Antiviral drug. Valaciclovir is a nucleoside inhibitor of DNA polymerase of herpes viruses. It blocks the synthesis of viral DNA and the replication of viruses. In the human body, valaciclovir is completely converted into 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 type 6.Acyclovir inhibits the synthesis of viral DNA immediately after phosphorylation and conversion into an 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, such an enzyme is viral thymidine kinase, which is present in virus-infected cells. Partial selectivity of phosphorylation persists in the cytomegalovirus and is mediated through the product of the phosphotransferase UL 97 gene. Activation of acyclovir with a specific viral enzyme largely explains its selectivity.
The process of phosphorylation of acyclovir (conversion from mono- to triphosphate) is completed by cellular kinases. Acyclovirurt phosphate competitively inhibits the viral DNA polymerase and, being an analogue of the nucleoside, is inserted into the viral DNA, which leads to obligate rupture of the chain, termination of DNA synthesis and, therefore, to blocking the replication of the virus.
In patients with preserved immunity, Herpes simplex and Varicella zoster viruses with a low sensitivity to valacyclovir are extremely rare (less than 0.1%), but can sometimes be found in patients with severe impairment of immunity, for example, with bone marrow transplant, in chemotherapy for malignant neoplasms and in HIV-infected people.
Resistance is caused by a deficiency of thymidine kinase of the virus, which leads to excessive spread of the virus in the host organism. Sometimes a decrease in sensitivity to acyclovir is due to the appearance of strains of the virus with a violation of the structure of the viral thymidine kinase or DNA polymerase. The virulence of these varieties of the virus resembles that of its wild strain.
PHARMACOKINETICS
Suction
After ingestion, valaciclovir is absorbed well from the digestive tract, quickly and almost completely turns into acyclovir and valine. This transformation is catalyzed by the enzyme of the liver - valaciclovirhydrolase.
After a single dose of 250-2000 mg valacyclovir C max acyclovir in blood plasma in healthy volunteers with normal renal function averages 10-37 Ојmol / L (2.2-8.3 Ојg / ml), and the average time to reach C max is 1-2 hours. When taking valaciclovir in a dose of 1000 mg, the bioavailability of acyclovir is 54% and does not depend on the intake of food. C max 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 C max level remains the same or decreases. Valaciclovir and acyclovir have similar pharmacokinetic parameters after oral administration.
Distribution
The connection with the proteins valacyclovir - 13-18%, acyclovir - 9-33%. Acyclovir is well distributed in tissues and body fluids, including the brain, kidneys, lungs, liver, watery moisture, tear fluid, intestines, muscles, spleen, uterus, mucous membrane and vaginal secretion, sperm, amniotic fluid, cerebrospinal fluid (50% of concentration in plasma), a liquid of herpetic vesicles. The highest concentrations are created in the kidneys, liver and intestines. Penetrates through the placenta and into breast milk.
Excretion
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 unchanged. T 1/2 valacyclovir is less than 30 min, acyclovir is 2.5-3.3 h.
Pharmacokinetics in special clinical cases
In elderly patients (65-83 years old), T 1/2 acyclovir is 3.3-3.7 hours, and in patients with terminal stage of renal insufficiency it is approximately 14 hours.
The pharmacokinetics of valaciclovir and acyclovir are largely unaffected in patients infected with Herpes simplex and Varicella zoster viruses.
In HIV-infected patients, the pharmacokinetic parameters of acyclovir after ingestion of valacyclovir in a dose of 1000 mg and 2000 mg are comparable to those observed in healthy volunteers.
In recipients of organ transplants receiving valacyclovir at a dose of 2000 mg 4 times / day, C max of acyclovir is equal to or greater than that of healthy volunteers receiving the same dose of the drug, and daily AUC values ​​were significantly higher.
In late pregnancy, a steady daily area under the pharmacokinetic curve after taking 1000 mg of valaciclovir was approximately 2-fold greater than that of acyclovir at a dose of 1200 mg / day.
INDICATIONS
Adults:
- Treatment of herpes zoster (the drug contributes to the relief of pain syndrome, reduces its duration and the percentage of patients with pain caused by shingles, including acute and postherpetic neuralgia);
- treatment of infections of the skin and mucous membranes caused by the Herpes simplex virus type 1, type 2, including newly diagnosed and recurrent genital herpes, as well as labial herpes;
- prevention (suppression) of recurrences of infections of the skin and mucous membranes caused by the Herpes simplex virus type 1, type 2, including genital herpes;
- Prevention of transmission of the genital herpes virus to a healthy partner when using the drug as a suppressive therapy in combination with safe sex.
Adults and children aged 12 years and over:
- Prevention of cytomegalovirus infection, as well as reactions of acute graft rejection (in patients with kidney transplants), opportunistic infections and other herpesvirus infections after organ transplantation.
DOSING MODE
The drug is taken orally, regardless of food intake, with water.
Treatment of herpes zoster (Herpes zoster)
Recommended Adult Dose is 1000 mg 3 times / day for 7 days.
Treatment of infections caused by Herpes simplex
For adults, the recommended dose for therapy of the episode is 500 mg 2 times / day for 5 days. In more severe cases of debut, the disease should be started as soon as possible, and its duration can be increased from 5 to 10 days. In case of relapse, treatment should last 3 or 5 days. When relapses of infections caused by Herpes simplex, the ideal is the appointment of valaciclovir in the prodromal period or immediately after the appearance of the first symptoms of the disease.
As an alternative for the treatment of labial herpes, valacyclovir is effectively administered at a dose of 2 g 2 times / day. The second dose should be taken after approximately 12 hours (but not earlier than 6 hours) after taking the first dose. When using this mode of dosing, the duration of treatment is 1 day.
Therapy should be started when the earliest symptoms of labial herpes (ie tingling, itching, burning) occur.
Prevention (suppression) of recurrences of infections caused by Herpes simplex
In adult patients with preserved immunity, the recommended dose is 500 mg 1 time / day. In patients with immunodeficiency, the recommended dose is 500 mg 2 times / day.
Prophylaxis of transmission of genital herpes to a healthy partner
To infected immunocompetent persons with relapses no more than 9 times a year the recommended dose of valacyclovir is 500 mg 1 time / day during the year and more every day.
Data on the prevention of infection in other populations of patients are absent.
Prevention of cytomegalovirus infection after transplantation
The recommended dose for adults and adolescents aged 12 years and older is 2 g 4 times / day, prescribed as soon as possible after transplantation.
The dose should be reduced depending on the QC. The duration of treatment is 90 days, but in patients with high-risk treatment can be extended.
Patients with impaired renal function
Treatment of herpes zoster and infections caused by Herpes simplex, the prevention (suppression) of recurrences of infection caused by HSV, the prevention of transmission of genital herpes to a healthy partner
The dose of valaciclovir is recommended to be reduced in patients with a significant decrease in renal function (see dosing regimen in Table 1). Such patients need to maintain adequate hydration.
The experience of valaciclovir in children with CC values ​​less than 50 ml / min / 1.73 m 2 is not available.
Indications KK, ml / min Valaciclovir dose
Shingles (Herpes zoster) 15-30 1 g 2 times / day
less than 15 1 g 1 time / day
Treatment of infection caused by the Herpes simplex virus (according to the scheme 500 mg 2 times / day) less than 15 500 mg 1 time / day
Treatment of labial herpes (according to the scheme 2 g 2 times / day for one day) 31-49 1 g twice in one day
15-30 500 mg twice daily for one day
less than 15 500 mg once
Prevention (suppression) of recurrences of infections caused by HSV:
patients with normal immunity of less than 15 250 mg 1 time / day
patients with reduced immunity of less than 15 500 mg 1 time / day
decrease in the risk of transmission of genital herpes less than 15 250 mg 1 time / day
Patients on hemodialysis are recommended to use valaciclovir immediately after the end of the hemodialysis session at the same dose as patients with SC less than 15 ml / min.
Prevention of cytomegalovirus infection after transplantation
The mode of administration of valaciclovir in patients with impaired renal function should be established in accordance with Table 2.
table 2
CK, ml / min Valaciclovir dose
? 75 2 g 4 times / day
from 50 to <75 1.5 g 4 times / day
from 25 to <50 1.5 g 3 times / day
from 10 to <25 1.5 g 2 times / day
<10 or dialysis * 1.5 g 1 time / day
* In patients on hemodialysis, valacyclovir should be administered after the end of the hemodialysis session.
It is often necessary to determine QC, especially during a period when the kidney function changes rapidly, for example, immediately after transplantation or engraftment of the graft, with a dose of valaciclovir adjusted according to QC values.
Patients with impaired hepatic function
In adult patients with a mild and moderate liver function disorder with a conservative synthetic valacyclovir dose adjustment function is not required.
Pharmacokinetic data in adult patients with severe impairment of liver function (decompensated cirrhosis), with a violation of the synthetic function of the liver and the presence of port-caval anastomoses also do not indicate the need to adjust the dose of valacyclovir, however, the clinical experience for this pathology is limited.
Children under the age of 12 years
There is no data on the use of Valcicon В® in children.
Elderly patients
Dose correction is not required except for a significant impairment of kidney function. It is necessary to maintain an adequate water-electrolyte balance.
SIDE EFFECT
From the side of the central nervous system: headache, dizziness, psychotic symptoms, agitation, mental decline, ataxia, coma, confusion or depression, dysarthria, encephalopathy, mania, hallucinations, convulsions, tremor. These reactions are reversible and are usually observed in patients with impaired renal function or against a background of other predisposing conditions. In patients with a transplanted organ who receive valaciclovir in high doses (8 g / day) for the prevention of cytomegalovirus infection, neurologic reactions develop more often than when taken in lower doses.
From the respiratory system: dyspnoea.
On the part of the digestive system: nausea, a feeling of discomfort in the abdomen, vomiting, diarrhea, reversible violations of functional hepatic tests (increased ALT, AST, APP), which are sometimes regarded as manifestations of hepatitis.
On the part of the hematopoiesis system: leukopenia (mainly observed in patients with reduced immunity), thrombocytopenia, anemia, thrombotic thrombocytopenic purpura.
From the skin: erythema multiforme, rashes, photosensitivity, alopecia.
Allergic reactions: itching, hives, angioedema, anaphylaxis.
From the urinary system: pain in the projection of the kidneys, impaired renal function, incl. acute renal failure, renal colic. Renal colic can be associated with impaired renal function.
From the senses: a blurred vision.
On the part of laboratory indicators: a decrease in hemoglobin, hypercreatininaemia.
Other: dysmenorrhea, nasopharyngitis, respiratory tract infections, increased blood pressure, tachycardia, fatigue.
In patients with severe impairment of immunity, especially in adult patients with advanced HIV infection, receiving valacyclovir in high doses (8 g / day daily) for a long time, there have been cases of renal failure, microangiopathic hemolytic anemia, and thrombocytopenia (sometimes in combination ). Similar adverse reactions were observed in patients with the same diseases, but not receiving valaciclovir.
CONTRAINDICATIONS
- HIV infection with a CD4 + lymphocyte content of less than 100 in 1 Ојl;
- Children's age (up to 12 years in the prevention of cytomegalovirus infection after transplantation, up to 18 years - for other indications);
- Hypersensitivity to valaciclovir, acyclovir and any other component included in the preparation.
With caution should be used in patients with hepatic / renal failure, hypohydration, in elderly patients, while taking nephrotoxic drugs, during pregnancy and lactation, with clinically expressed forms of HIV infection in patients.
PREGNANCY AND LACTATION
There are limited data on the use of valacyclovir in pregnancy. Valacyclovir is used only in cases where the potential benefit to the mother exceeds the possible risk to the fetus.
Registered data on the outcome of pregnancy in women taking valaciclovir or acyclovir (active metabolite valatsiklovira), did not show an increase in the number of birth defects in their children compared with the general population. Since a small number of women taking valaciclovir during pregnancy are included in the register, it is impossible to make reliable and definite conclusions about the safety of valaciclovir during pregnancy.
Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After taking valaciclovir inward at a dose of 500 mg, C max of acyclovir in breast milk was 0.5-2.3 times (1.4 times on average) higher than the corresponding concentrations of acyclovir in the blood plasma of the mother. The mean concentration of acyclovir in breast milk was 2.24 Ојg / ml (9.95 Ојmol / L). When a valaciclovir mother is taken inside at a dose of 500 mg 2 times a day, the child will undergo the same effect of acyclovir as with taking acyclovir orally at a dose of about 0.61 mg / kg / day.
APPLICATION FOR FUNCTIONS OF THE LIVER
Carefully The drug should be used for renal failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution should be used in patients with liver failure
APPLICATION FOR CHILDREN
There is no data on the use of Valcicon В® 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.
APPLICATION IN ELDERLY PATIENTS
In elderly patients correction of the dose is not required except for a significant impairment of kidney function. It is necessary to maintain an adequate water-electrolyte balance.
SPECIAL INSTRUCTIONS
In patients at risk of dehydration, especially in elderly patients, adequate fluid replenishment must be ensured during treatment.
Since acyclovir is excreted by the kidneys, the dose of Valcicon В® should be adjusted in depending on the degree of renal function impairment. In patients with renal insufficiency, there is an increased risk of developing neurological complications, such patients need to be closely monitored. As a rule, these reactions are reversible and disappear after the drug is discontinued.
In patients with chronic renal insufficiency, it is recommended to frequently determine QC, especially during a period when the kidney function changes rapidly (in particular, immediately after transplantation or engraftment of the graft), while the valaciclovir dose is adjusted in accordance with the QC indices. There is no data on the use of valacyclovir in high doses (? 4 g / day) in patients with liver disease, therefore high doses of Valcicon В® should be given with caution.
Suppressive therapy with valacyclovir reduces the risk of transmission of genital herpes, but does not exclude the risk of infection and does not lead to complete cure.Therapy with Valcicon В® is recommended in combination with safe sex.
The drug in high doses for long time under conditions involving severe immunodeficiency (bone marrow transplantation, symptomatic forms of HIV infection, kidney transplantation), led to the development thrombocytopenic purpura and hemolytic-uremic syndrome, until death.
At occurrence of side effects of the central nervous system (including agitation, hallucinations, confusion, delirium, seizures and encephalopathy) drug overturned.
Impact on the management of vehicles and mechanisms
No data on the effect of valacyclovir used in therapeutic doses, the ability to drive vehicles and mechanisms. However, in assessing the patient's ability to drive a car or moving machinery should be aware that you may experience side effects of the central nervous system, so be careful.
OVERDOSE
Symptoms: an overdose of valacyclovir may cause acute renal failure and the development of neurological symptoms, including confusion, hallucinations, agitation, depression of consciousness and coma, nausea, and vomiting are also marked. To prevent overdosing Caution should be exercised when using the drug. Many cases of overdose have been associated with the use of a drug for the treatment of patients with impaired renal and elderly patients function due to non-compliance with the dosing regimen (repeatedly received valaciclovir dose exceeding the recommended).
Treatment.Patients subject to careful monitoring for timely diagnosis toxic manifestations. Hemodialysis greatly accelerates the removal of acyclovir from the blood plasma and can be considered an optimal treatment method in case of symptomatic overdose.
DRUG INTERACTION
Cimetidine and tubular secretion blockers reduce the effect (reduced rate but not the completeness of the conversion to acyclovir). Correction of dosing regimen in people with normal QA is needed.
Nephrotoxic drugs increase the risk of renal dysfunction. Care must be taken (observe the change of renal function) when combined preparation Valtsikon В® at higher doses (4 g / day or more) with drugs that affect the other kidney (e.g., cyclosporine, tacrolimus).
Acyclovir is excreted by the kidneys, in largely unaltered by the active renal secretion. The combined use of drugs with the same mechanism of elimination can lead to increased concentration of acyclovir in plasma. After drug administration Valtsikon В® 1000 mg probenecid and cimetidine, are derived in the same manner as valaciclovir, aciclovir AUC value is increased and thus reduce its renal clearance. Given the wide therapeutic range acyclovir, drug dosage adjustment Valtsikon В® in this case is not required.
Care must be taken in the case of simultaneous use of valaciclovir at higher doses (4 g / day or higher) and drugs that compete with acyclovir for elimination pathway, since There is a potential threat increase in blood plasma levels of one or both drugs or their metabolites. It was noted an increase in magnitude AUC acyclovir and mycophenolate mofetil inactive metabolite while the use of these drugs.
The pharmacokinetics of valaciclovir does not change when concomitantly with digoxin, aluminum / magnesium-containing antacids, thiazide diuretics.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of the reach of children, protected from light at a temperature not higher than 25 В° C. Shelf life - 2 years.
