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Valvir

Suction

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

When taking valacyclovir in a dose of 1000 mg, the bioavailability of acyclovir is 54% and is not reduced by food intake. The pharmacokinetics of valacyclovir is not dose-dependent.

The rate and extent of absorption decrease with increasing dose, resulting in a less proportionate increase in maximum plasma concentration (Cmax) compared to the therapeutic dose range and a decrease in bioavailability at doses above 500 mg.

Table 1. Results of assessing the pharmacokinetics of acyclovir when taking single doses of valacyclovir from 250 mg to 2000 mg in 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	9,7±1,71	15,0±4,23	23,1±8,53	36,9±6,36
µg/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	hxmmol/l	24,4±3,65	49,3±7,77	83,9±20,1	131±28,3
hxmkg/ml	5,50±0,82	11,1±1,75	18,9±4,51	29,5±6,36

Cmax - maximum concentration in blood plasma;

Tmax is the time until the maximum concentration in the blood plasma is reached;

AUC is the area under the concentration-time pharmacokinetic curve.

Cmax and AUC values reflect the average standard deviation.

Values for Tmax reflect the median value and range of values.

The maximum concentration of valacyclovir in blood plasma is only 4% of the concentration of acyclovir, the median time to reach it ranges from 30 to 100 minutes after taking the drug. 3 hours after dosing, the concentration of valacyclovir reaches the level of quantitative determination or below.

Valacyclovir and acyclovir have similar pharmacokinetic parameters after single and multiple doses. VZV and HSV do not significantly alter the pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir.

Distribution

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

Metabolism

After oral administration, valacyclovir is converted to acyclovir and L-valine through first-pass metabolism in the intestine and/or hepatic metabolism. Acyclovir is converted into small metabolites: CMMG under the influence of ethyl alcohol and aldehyde dehydrogenase: 8-OH-ACV under the influence of aldehyde oxidase. Approximately 88% of the total cumulative plasma exposure is due to acyclovir. 11% - CMMG and 1% - 8-OH-ACV.

Valacyclovir and acyclovir are not metabolized by isoenzymes of the cytochrome P450 system.

Removal

In patients with normal renal function, the half-life of acyclovir from blood plasma after a single or multiple doses of valacyclovir is about 3 hours. Less than 1% of the administered dose of valacyclovir is excreted unchanged by the kidneys. Valaniclovir is excreted from the body by the kidneys mainly in the form of acyclovir (more than 80% of the dose taken) and the metabolite of acyclovir - CMMG

Special patient groups

Patients with impaired renal function

The elimination of acyclovir correlates with renal function, and acyclovir exposure increases with the severity of renal failure.

In patients with end-stage renal disease, the mean T1/2 of acyclovir after administration of valacyclovir is approximately 14 hours, compared to approximately 3 hours with normal renal function.

Plasma and CSF exposures to acyclovir and its metabolites CMMG and 8-OH-ACV were assessed 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). receiving 2000 mg every 6 hours, and 3 patients with severe renal impairment (mean creatinine clearance 26 ml/min, range 17-31 ml/min) receiving 1500 mg every 12 hours. In severe versus normal renal impairment renal function in the blood plasma, as well as in the 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 extent of acyclovir CSF penetration (defined as the ratio of CSF AUC to plasma AUC), CMMG, or 8-GH-ACV between the two populations with severe renal impairment and normal renal function.

Patients with liver dysfunction

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 liver function.

Pregnancy

A study of the pharmacokinetics of valacyclovir and acyclovir in late pregnancy found an increase in the daily AUC value at steady state when taking valacyclovir daily at a dose of 1000 mg per day, which was approximately 2 times higher than the AUC when taking oral 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 valacyclovir remain unchanged compared to healthy volunteers.

Organ transplantation

The maximum concentration of acyclovir in organ transplant patients receiving 2000 mg valacyclovir 4 times a day 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 noticeably higher.

Valvir tablets 1000 mg No. 7

Compound

Active substance: valacyclovir hydrochloride hydrate 1223.4 mg, which corresponds to the content of valacyclovir 1000 mg.
Excipients: microcrystalline cellulose - 119.2 mg, povidone-K30 - 49 mg, magnesium stearate - 8.4 mg. Film coating composition: Opadry white Y-5-7068 (hypromellose 3cP - 14.7 mg, hyprolose - 12.6 mg, titanium dioxide - 8.4 mg, macrogol/PEG 400 - 4.2 mg, hypromellose 50cP - 2.1 mg) - 42 mg.

Pharmacokinetics

After oral administration, valacyclovir is well absorbed from the gastrointestinal tract and is quickly and almost completely converted to acyclovir and L-valine by the enzyme valacyclovir hydrolase.

After a single dose of 0.25-2 g of valacyclovir, the Cmax of acyclovir in healthy volunteers with normal renal function averages 10-37 µmol (2.2-8.3 µg/ml) and is achieved after 1-2 hours.

The bioavailability of acyclovir when taken from 1 g of valacyclovir is 54% and does not depend on food intake.

The Cmax of valacyclovir in plasma is only 4% of the level of acyclovir and is achieved on average 30-100 minutes after taking the drug; after 3 hours, the Cmax level remains the same or decreases.

The binding of valacyclovir to plasma proteins is very low - 15%.

In patients with normal renal function, T1/2 of acyclovir is about 3 hours. 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 excreted unchanged.

In patients with end-stage renal failure, T1/2 of acyclovir is approximately 14 hours.

In late pregnancy, the steady-state daily AUC after taking 1 g of valacyclovir was approximately 2 times greater than that when taking acyclovir at a dose of 1.2 g/day.

In organ transplant recipients receiving valacyclovir at a dose of 2 g 4 times / day, the Cmax of acyclovir is equal to or greater than that in healthy volunteers receiving the same dose of valacyclovir, and their daily AUC values are significantly higher.

Indications for use

Treatment of herpes zoster;
treatment and prevention of recurrent infections of the skin and mucous membranes caused by the herpes simplex virus (including newly diagnosed and recurrent genital herpes);
treatment of labial herpes;
reduction of genital herpes infection in a healthy partner if taken as a suppressive therapy in combination with safe sex;
prevention of cytomegalovirus infection that occurs during organ transplantation (reduces the severity of acute graft rejection in patients with kidney transplants, the development of opportunistic infections and other viral infections caused by Herpes simplex and Varicella zoster viruses) in adults and children over 12 years of age.

Contraindications

Hypersensitivity to valacyclovir, acyclovir and other components of the drug,
clinically pronounced forms of HIV infection with a CD4+ lymphocyte count of less than 100/μl,
bone marrow transplantation,
kidney transplantation,
children's age (up to 12 years for CMV, up to 18 years for other indications).

With caution: liver failure (high doses of the drug), renal failure, pregnancy, lactation.

Directions for use and doses

Inside.
Adults. Herpes zoster - 1000 mg 3 times a day for 7 days.

Herpes simplex - 500 mg 2 times a day.

In case of relapses, the course should be 3 or 5 days. For the first severe episode, the duration of treatment can be increased to 10 days (for relapses, it is ideal to prescribe Valvir in the prodromal period or when the first symptoms of the disease appear, i.e. tingling, itching, burning).

For the treatment of labial herpes, it is effective to prescribe the drug at a dose of 2 g 2 times over 1 day: the second dose should be taken approximately 12 hours (but not earlier than 6 hours) after the first dose (do not use this dosage regimen for more than 1 day, since this has not been shown to provide additional clinical benefit).

Prevention of relapses of infections caused by the herpes simplex virus: in patients with preserved immunity - 500 mg 1 time per day; with very frequent relapses (10 or more per year) - 250 mg 2 times a day; for adult patients with immunodeficiency - 500 mg 2 times a day. Duration of the course is 4-12 months.

Prevention of infection with genital herpes in a healthy partner: infected heterosexual adults with preserved immunity and with up to 9 exacerbations per year - 500 mg 1 time per day for 1 year or more, every day with regular sexual activity; in case of irregular sexual intercourse, taking Valvir should be started 3 days before the intended sexual contact (there are no data on the prevention of infection in other patient populations).

Prevention of cytomegalovirus infection: adults and adolescents over 12 years of age - 2 g 4 times a day (as early as possible after transplantation). The course duration is 90 days, but in high-risk patients, treatment may be longer.

Storage conditions

At a temperature not higher than 25 °C. Keep out of the reach of children.

Best before date

2 years. Do not use after expiration date.

special instructions

Patients with renal failure have an increased risk of developing neurological complications.

In case of liver dysfunction in patients with mild or moderate liver cirrhosis (the synthetic function of the liver is preserved), no dose adjustment of Valvir is required. When studying pharmacokinetics in patients with severe liver cirrhosis (with impaired synthetic function of the liver and the presence of shunts between the portal system and the general vascular bed), there was also no data indicating the need for correction of the dosage regimen; however, clinical experience with the use of Valvir in this category of patients is limited.

There is no data on the use of Valvir in high doses (4 g/day or more) in patients with liver disease, so the drug should be prescribed with caution in high doses to this category of patients.

Elderly patients do not require dose adjustment, except in cases of significant impairment of renal function. It is necessary to maintain adequate water and electrolyte balance.

No special studies have been conducted to study the effect of the drug Valvir in patients undergoing liver transplantation. However, prophylactic administration of high doses of acyclovir has been shown to reduce cytomegalovirus infection.

Suppressive therapy with Valvir reduces the risk of transmission of genital herpes, but does not completely eliminate it and does not lead to a complete cure. During therapy with Valvir, the patient must take measures to ensure the safety of the partner during sexual intercourse.

Description

Antiviral agent.

Use in children

There is no clinical experience of use in children.

Pharmacodynamics

Antiviral agent of the group of nucleoside analogues. Valacyclovir is the L-valine ester of acyclovir, thus being a prodrug.

After absorption into the blood, valacyclovir is almost completely converted to acyclovir under the influence of the liver enzyme valacyclovir hydrolase. Acyclovir, formed from valacyclovir, in turn, penetrates into cells affected by the virus, where, under the influence of the viral enzyme thymidine kinase, it is converted into monophosphate, then, under the influence of cellular kinases, into diphosphate and active triphosphate. Acyclovir triphosphate inhibits DNA polymerase and thus disrupts viral DNA replication. In addition, disruption of viral DNA replication may result from the incorporation of acyclovir into its structure. Thus, the high selectivity of valacyclovir for tissues affected by the virus is explained by the fact that stage I of the chain of phosphorylation reactions is mediated by an enzyme produced by the virus itself.

Active against Herpes simplex viruses types 1 and 2, Varicella zoster, cytomegalovirus, Epstein-Barr virus, human herpes virus 6.

Side effects

The most common adverse reactions with valacyclovir are headache and nausea; more serious adverse reactions are thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, acute renal failure and neurological disorders.

Adverse reactions are listed below according to the classification by main systems and organs and by frequency of occurrence: very often - ≥ 1/10; often - ≥1/100 or <1/10; uncommon - ≥1/1000 or <1/100; rarely - ≥ 1/10000 or <1/1000; very rarely - <1/10000.

From the gastrointestinal tract: often - nausea; rarely - abdominal discomfort, including abdominal pain; vomiting, diarrhea; very rarely - reversible abnormalities in liver function tests, which are sometimes regarded as manifestations of hepatitis.

From the blood and lymphatic system: very rarely - leukopenia (mainly in patients with reduced immunity), thrombocytopenia.

From the immune system: very rarely - anaphylaxis.

Mental disorders and disorders of the nervous system: often - headache; infrequently - agitation, including aggressive behavior; rarely - dizziness, confusion, hallucinations, decreased mental abilities; very rarely - agitation, tremor, ataxia, dysarthria; psychotic symptoms including mania; depression, seizures, encephalopathy, coma. These symptoms are reversible and are usually observed in patients with impaired renal function or against the background of other diseases. In organ transplant patients receiving high doses of valacyclovir (8 g/day) for the prevention of CMV infection, neurological reactions develop more often than when taking lower doses.

From the respiratory system and mediastinum: infrequently - dyspnea.

From the skin and subcutaneous tissue: infrequently - rashes, including manifestations of photosensitivity; rarely - itching.

Allergic reactions: very rarely - urticaria, angioedema.

From the urinary system: infrequently - hematuria (often associated with other renal disorders); rarely - renal dysfunction; very rarely - acute renal failure, renal colic (may be associated with impaired renal function).

Precipitation of acyclovir crystals in the lumen of the renal tubules is possible.

It is necessary to maintain an adequate drinking regime during treatment.

Other: In patients with severe immune impairment, especially Nazis with advanced acquired immune deficiency syndrome, receiving high doses of valacyclovir (8 g/day) for a long time, cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination) have been observed ). Similar complications have been noted in patients with the same diseases but not receiving valacyclovir.

It is not possible to determine the frequency of occurrence of some adverse reactions based on the available data.

From the senses: visual impairment.

From the hematopoietic organs: neutropenia. aplastic anemia, leukoclastic vasculitis, thrombotic thrombocytopenic purpura.

From the skin: erythema multiforme.

Laboratory indicators: decreased hemoglobin, hypercreatininemia.

Other: dysmenorrhea, arthralgia, nasopharyngitis, respiratory tract infections, facial swelling, increased blood pressure, tachycardia, fatigue; additionally in children - fever, dehydration, rhinorrhea.

Use during pregnancy and breastfeeding

Adequate and strictly controlled studies of the safety of valacyclovir during pregnancy and lactation have not been conducted. Use in this category of patients is possible in cases where the expected benefit of therapy for the mother outweighs the potential risk for the fetus or infant.

It is known that acyclovir, which is a metabolite of valacyclovir, is excreted in breast milk in concentrations 0.6-4.1 times higher than its concentration in plasma. T1/2 of acyclovir from breast milk is 2.8 hours, which is comparable to T1/2 from blood plasma.

Interaction

Concomitant use of valacyclovir with nephrotoxic drugs, including aminoglycosides, organic platinum compounds, iodinated contrast agents, methotrexate, pentamidine, foscarnet, cyclosporine and tacrolimus, should be used with caution, especially in patients with impaired renal function, and requires regular monitoring of renal function.
No clinically significant interactions have been established.

Cimetidine and probenecid after taking 1 g of valacyclovir increase the AUC of acyclovir, reducing its renal clearance (however, dose adjustment of valacyclovir is not required due to the wide therapeutic index of acyclovir).

Caution must be exercised in the case of simultaneous use of valacyclovir in high doses (4 g / day) and drugs that compete with acyclovir for the elimination route (the latter is eliminated in the urine unchanged as a result of active tubular secretion), since there is a potential threat of increased plasma levels of concentrations of one or both drugs or their metabolites.

With simultaneous use of acyclovir with mycophenolate mofetil, an increase in the AUC of acyclovir and the inactive metabolite mycophenolate mofetil was observed.

Overdose

Currently, there is insufficient data on overdose with valacyclovir.
Symptoms: A single dose of acyclovir up to 20 g, which was partially absorbed from the gastrointestinal tract, was not accompanied by a toxic effect of the drug. When ingesting ultra-high doses of acyclovir for several days, nausea, vomiting, headache, and confusion developed; with intravenous administration - an increase in serum creatinine concentration, the development of renal failure, confusion, hallucinations, agitation, convulsions, coma.

Treatment: Patients should be under close medical supervision for signs of toxicity. Hemodialysis significantly enhances the removal of acyclovir from the blood and can be considered the treatment of choice in the management of patients with an overdose of valacyclovir.

Impact on the ability to drive vehicles and operate machinery

Caution should be exercised in the event of the development of adverse reactions that affect the speed of psychomotor reactions.

Valvir 1000 mg n7 tab.

Compound

1 film-coated tablet contains:
active substance:
valacyclovir hydrochloride hydrate 611.70 mg or 1223.40 mg, corresponding to 500 mg or 1000 mg valacyclovir;
excipients:
microcrystalline cellulose 59.60/119.20 mg, povidone-K30 24.50/49.00 mg, magnesium stearate 4.20/8.40 mg;
film coating:
Opadry white Y-5-7068 (hypromellose ZsP 7.35/14.7 mg, hyprolose 6.3/12.6 mg, titanium dioxide 4.2/8.4 mg, macrogol/PEG 400 2.1 /4.2 mg, hypromellose 50cP 1.05/2.1 mg) - 21/42 mg.

Description

500 mg tablets: white or off-white, oval, biconvex tablets marked VC2 on one side. 1000 mg tablets: white or off-white, oval, biconvex tablets marked VC3 on one side.

Pharmacotherapeutic group

: antiviral agent

Pharmacological properties
Pharmacodynamics
Antiviral drug.
In the human body, valacyclovir is quickly and completely converted into acyclovir and L-valine under the influence of valacyclovir hydrolase. Acyclovir in vitro has specific inhibitory activity against Herpes simplex viruses types 1 and 2, Varicella zoster and Epstein-Barr, cytomegalovirus (CMV) and human herpes virus type 6. Acyclovir inhibits the synthesis of viral deoxyribonucleic acid (DNA) immediately after phosphorylation and conversion to active form of acyclovir triphosphate. The first stage of phosphorylation occurs with the participation of virus-specific enzymes. For Herpes simplex, Varicella zoster and Epstein-Barr viruses, this enzyme is viral thymidine kinase, which is present in cells affected by the virus. Partial phosphorylation selectivity is conserved in CMV and is mediated through the phosphotransferase gene product UL 97. Activation of acyclovir by a specific viral enzyme largely explains its selectivity. The process of phosphorylation of acyclovir (conversion from mono-to triphosphate) is completed by cellular kinases. Acyclovir triphosphate competitively inhibits viral DNA polymerase and, being a nucleoside analogue, is incorporated into viral DNA, which leads to obligate (complete) chain breakage, cessation of DNA synthesis and, consequently, blocking viral replication. In patients with preserved immunity, Herpes simplex and Varicella zoster viruses with reduced sensitivity to valacyclovir are extremely rare (less than 0.1%), but can sometimes be detected in patients with severe immune disorders, for example, with a bone marrow transplant, in those receiving chemotherapy for malignant diseases. neoplasms and in those infected with the human immunodeficiency virus (HIV). Resistance is caused by a deficiency of the virus' thymidine kinase, which leads to excessive spread of the virus in the host. Sometimes a decrease in sensitivity to acyclovir is due to the emergence of virus strains with a violation of the structure of the viral thymidine kinase or DNA polymerase. The virulence of these variants of the virus resembles that of the wild strain. Pharmacokinetics
Valacyclovir and acyclovir have similar pharmacokinetic parameters after oral administration.
Absorption
After oral administration, valacyclovir is well absorbed from the gastrointestinal tract (GIT), quickly and almost completely converted to acyclovir and L-valine.
This transformation is catalyzed by the enzyme valacyclovir hydrolase, isolated from human liver. After a single dose of 0.25-2 g of valaciclovir, the maximum plasma concentration (Cmax) of acyclovir in healthy volunteers with normal renal function averages 10-37 µmol/l (2.2-8.3 µg/ml), and the median time to reach this concentration is 1 - 2 hours. When taking valacyclovir in a dose of 1 g, the bioavailability of acyclovir is 54% and does not depend on food intake. Cmax of valacyclovir in 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 Cmax level remains the same or decreases. Distribution
The degree of binding of acyclovir to plasma proteins is very low - about 15%.
Acyclovir is quickly distributed throughout the tissues of the body, especially to the liver, kidneys, muscles, and lungs. It also penetrates vaginal secretions, cerebrospinal fluid and herpetic vesicle fluid. Excretion
In patients with normal renal function, the half-life (T1/2) of acyclovir after a single dose and repeated use is approximately 3 hours. Valacyclovir is excreted in the urine, mainly in the form of acyclovir (more than 80% of the dose) and its metabolite 9-carboxymethoxymethylguanine, in Less than 1% of the drug is excreted unchanged.
Pharmacokinetics in special clinical situations
In patients with end-stage renal failure, T1/2 of acyclovir is approximately 14 hours. The pharmacokinetics of acyclovir is not significantly affected in patients infected with Herpes simplex and Varicella zoster viruses, as well as in elderly patients and patients with cirrhosis of the liver. In patients with severely impaired renal function, the Cmax of acyclovir is approximately two times greater than in healthy patients and the T1/2 of acyclovir increases 5 times. Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After administration of valacyclovir orally at a dose of 500 mg, the Cmax of acyclovir in breast milk was 0.5-2.3 times (on average 1.4 times) higher than its corresponding concentration in maternal plasma. The ratio of the area under the concentration-time curve (AUC) of acyclovir found in breast milk to the AUC of acyclovir in maternal plasma was 1.4-2.6 (average 2.2). The average concentration of acyclovir in breast milk is 2.24 mcg/ml. When the mother is given valaciclovir at a dose of 500 mg twice a day, the child will be exposed to the same amount of acyclovir as if it was taken orally at a dose of about 0.61 mg/kg/day. T1/2 of acyclovir from breast milk is the same as from blood plasma. Valacyclovir in unchanged form is not detected in maternal plasma, breast milk or infant urine. In late pregnancy, the steady-state daily AUC after taking 1 g of valacyclovir was approximately 2 times greater than that when taking acyclovir at a dose of 1.2 g per day. During pregnancy, the pharmacokinetic characteristics of valacyclovir do not change. Taking valacyclovir at a dose of 1 g and 2 g does not affect the distribution and pharmacokinetic parameters of valacyclovir in HIV-infected patients compared to healthy individuals. In organ transplant recipients receiving valacyclovir at a dose of 2 g 4 times daily, the Cmax of acyclovir is equal to or greater than that of healthy volunteers receiving the same dose of the drug, and their daily AUC values are significantly higher.

Indications for use

treatment of herpes zoster;
treatment and prevention of recurrent infections of the skin and mucous membranes caused by the herpes simplex virus (including newly diagnosed and recurrent genital herpes);
treatment of labial herpes;
reduction of genital herpes infection in a healthy partner if taken as a suppressive therapy in combination with safe sex;
prevention of cytomegalovirus infection that occurs during organ transplantation (reduces the severity of acute graft rejection in patients with kidney transplants, the development of opportunistic infections and other viral infections caused by Herpes simplex and Varicella zoster viruses) in adults and children over 12 years of age.

Contraindications

Hypersensitivity to valacyclovir, acyclovir and other components of the drug, clinically pronounced forms of HIV infection with a CO4+ lymphocyte content of less than 100/μl, bone marrow transplantation, kidney transplantation, children's age (up to 12 years for CMV, up to 18 years for other indications) . With caution: liver failure (high doses of the drug), renal failure, pregnancy, lactation.

Use during pregnancy and lactation

Use during pregnancy is possible if the expected effect of therapy for the mother exceeds the potential risk to the fetus (there is insufficient information on use during pregnancy). Acyclovir is the main metabolite of valacyclovir and is excreted in breast milk. During therapy with valacyclovir, breastfeeding is possible if the expected effect of therapy for the mother outweighs the potential risk for the child.

Directions for use and doses

Inside. Adults. Herpes zoster - 1000 mg 3 times a day for 7 days. Herpes simplex - 500 mg 2 times a day. In case of relapses, the course should be 3 or 5 days. For the first severe episode, the duration of treatment can be increased to 10 days (for relapses, it is ideal to prescribe Valvir in the prodromal period or when the first symptoms of the disease appear, i.e. tingling, itching, burning). For the treatment of labial herpes, it is effective to prescribe the drug at a dose of 2 g 2 times for 1 day: the second dose should be taken approximately 12 hours (but not earlier than 6 hours) after the first dose (do not use this dosage regimen for more than 1 day, as it has not been shown to provide additional clinical benefit). Prevention of relapses of infections caused by the herpes simplex virus: in patients with preserved immunity - 500 mg 1 time per day; with very frequent relapses (10 or more per year) - 250 mg 2 times a day; for adult patients with immunodeficiency - 500 mg 2 times a day. Course duration is 4-12 months. Prevention of infection with genital herpes of a healthy partner: infected heterosexual adults with preserved immunity and with the number of exacerbations up to 9 per year - 500 mg 1 time per day for 1 year or more, every day with regular sexual activity, with irregular sexual intercourse, Valvir must be taken start 3 days before expected sexual intercourse (data on the prevention of infection in other patient populations are not available). Prevention of cytomegalovirus infection: adults and adolescents over 12 years of age - 2 g 4 times a day (as early as possible after transplantation). The course duration is 90 days, but in high-risk patients, treatment may be longer. It is recommended to reduce the dose of Valvir in patients with a significant decrease in renal function (see table).

Table

Valvir dosage regimens for various therapeutic indications depending on creatinine clearance

Therapeutic indications		Creatinine clearance (CC), ml/min	Dosage regimen
Shingles		15-30	1 g 2 times a day
Shingles		less than 15	1 g 1 time per day
Herpes simplex		less than 15	500 mg 1 time per day
Labial herpes		31-49	1 g 2 times for 1 day
		15-30	500 mg 2 times for 1 day
		less than 15	500 mg 1 time per day
Herpes simplex	patients with preserved immunity	less than 15	250 mg 1 time per day
Herpes simplex	patients with reduced immunity	less than 15	500 mg 1 time per day
Reducing genital herpes infections		less than 15	250 mg 1 time per day
cytomegalovirus infection		75 or more	2 g 4 times a day
		50-74	1.5 g 4 times a day
		25-49	1.5 g 3 times a day
		10-24	1.5 g 2 times a day
		less than 10 or hemodialysis	1.5 g 1 time per day

Patients on hemodialysis are recommended to use Valvir immediately after the end of the hemodialysis session in the same dose as patients with CC less than 15 ml/min.
Patients on dialysis should be prescribed Valvir after the end of the hemodialysis session.
It is necessary to determine QC frequently, especially during periods when renal function changes rapidly, such as immediately after transplantation or engraftment. In this case, the dose of Valvir is adjusted in accordance with the QC indicators.
Impaired liver function: in case of mild to moderate liver cirrhosis (the synthetic function of the liver is preserved), no dose adjustment is required. Pharmacokinetic data in patients with severe liver cirrhosis (with impaired synthetic function of the liver and the presence of shunts between the portal system and the general vascular bed) also do not indicate the need for dose adjustment of Valvir, however, the experience of its clinical use in this pathology is limited.
In elderly people, no dose adjustment is required, except for significant renal impairment. It is necessary to maintain adequate water and electrolyte balance.

Side effect

The most common adverse reactions with valacyclovir are headache and nausea, more serious adverse reactions are thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, acute renal failure and neurological disorders.
Adverse reactions are listed below in accordance with the classification by main systems and organs and by frequency of occurrence: very often - ≥1/10; often - ≥1/100 or <1/10; sometimes - ≥1/1000 or <1/100; rarely - 1/10000 or <1/1000; very rarely - <1/10000. From the gastrointestinal tract: often - nausea; rarely - abdominal discomfort, including abdominal pain; vomiting, diarrhea; very rarely - reversible abnormalities in liver function tests, which are sometimes regarded as manifestations of hepatitis. From the blood and lymphatic system:
very rarely - leukopenia (mainly in patients with reduced immunity), thrombocytopenia.
From the immune system:
very rarely - anaphylaxis.
Mental disorders and disorders of the nervous system:
often - headache;
sometimes - agitation, including aggressive behavior; rarely - dizziness, confusion, hallucinations, decreased mental abilities; very rarely - agitation, tremor, ataxia, dysarthria; psychotic symptoms including mania; depression, seizures, encephalopathy, coma. These symptoms are reversible and are usually observed in patients with impaired renal function or against the background of other diseases. In organ transplant patients receiving high doses of valacyclovir (8 g/day) for the prevention of CMV infection, neurological reactions develop more often than when taking lower doses. From the respiratory system and mediastinum:
sometimes - dyspnea.
From the skin and subcutaneous tissue:
sometimes - rashes, including manifestations of photosensitivity;
rarely - itching. Allergic reactions:
very rarely - urticaria, angioedema.
From the urinary system:
rarely - renal dysfunction;
very rare - acute renal failure, renal colic (may be associated with impaired renal function). Other:
In patients with severe immune impairment, especially in patients with advanced acquired immune deficiency syndrome, receiving high doses of valacyclovir (8 g/day) for a long time, cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination) have been observed. ).
Similar complications have been noted in patients with the same diseases but not receiving valacyclovir. It is not possible to determine the frequency of occurrence of some adverse reactions based on the available data. From the senses:
visual impairment.
From the hematopoietic organs:
neutropenia, aplastic anemia, leukoplastic vasculitis, thrombotic thrombocytopenic purpura.
From the skin:
erythema multiforme.
Laboratory indicators:
decreased hemoglobin, hypercreatininemia.
Other:
dysmenorrhea, arthralgia, nasopharyngitis, respiratory tract infections, facial swelling, increased blood pressure, tachycardia, fatigue; additionally in children - fever, dehydration, rhinorrhea.

Overdose

Currently, there is insufficient data on overdose with valacyclovir.
Symptoms:
A single dose of acyclovir up to 20 g, which was partially absorbed from the gastrointestinal tract, was not accompanied by a toxic effect of the drug.
When ingesting ultra-high doses of acyclovir for several days, nausea, vomiting, headache, and confusion developed; with intravenous administration - an increase in serum creatinine concentration, the development of renal failure, confusion, hallucinations, agitation, convulsions, coma. Treatment:
Patients should be under close medical supervision for signs of toxicity. Hemodialysis significantly enhances the removal of acyclovir from the blood and can be considered the treatment of choice in the management of patients with an overdose of valacyclovir.

Interaction with other drugs

No clinically significant interactions have been established. Cimetidine and probenecid after taking 1 g of valacyclovir increase the AUC of acyclovir, reducing its renal clearance (however, dose adjustment of valacyclovir is not required due to the wide therapeutic index of acyclovir). Caution must be exercised in the case of simultaneous use of valacyclovir in high doses (4 g / day) and drugs that compete with acyclovir for the elimination route (the latter is eliminated in the urine unchanged as a result of active tubular secretion), since there is a potential threat of increased plasma levels of levels of one or both drugs or their metabolites. With simultaneous use of acyclovir with mycophenolate mofetil, an increase in the AUC of the first and inactive metabolite of the second was noted. Caution must also be exercised when combining valacyclovir in high doses (4 g/day or higher) with drugs that affect renal function (for example, cyclosporine, tacrolimus).

special instructions

Taking the drug in high doses for a long time in conditions accompanied by severe immunodeficiency (bone marrow transplantation, clinical forms of HIV infection, kidney transplantation) led to the development of thrombocytopenic purpura and hemolytic-uremic syndrome, including death.
If side effects from the central nervous system occur (including agitation, hallucinations, confusion, delirium, convulsions and encephalopathy), the drug is discontinued. Patients at risk of dehydration, especially elderly patients, must ensure adequate body hydration during treatment with Valvir. Patients with renal failure have an increased risk of developing neurological complications. In case of liver dysfunction in patients with mild or moderate liver cirrhosis (the synthetic function of the liver is preserved), no dose adjustment of Valvir is required. When studying pharmacokinetics in patients with severe liver cirrhosis (with impaired synthetic function of the liver and the presence of shunts between the portal system and the general vascular bed), there was also no data indicating the need for correction of the dosage regimen; however, clinical experience with the use of Valvir in this category of patients is limited. There is no data on the use of Valvir in high doses (4 g/day or more) in patients with liver disease, so the drug should be prescribed with caution in high doses to this category of patients. Elderly patients do not require dose adjustment, except in cases of significant impairment of renal function. It is necessary to maintain adequate water and electrolyte balance. No special studies have been conducted to study the effect of the drug Valvir in patients undergoing liver transplantation. However, prophylactic administration of high doses of acyclovir has been shown to reduce cytomegalovirus infection. Suppressive therapy with Valvir reduces the risk of transmission of genital herpes, but does not completely eliminate it and does not lead to a complete cure. During therapy with Valvir, the patient must take measures to ensure the safety of the partner during sexual intercourse. Use in pediatrics
There is no experience of clinical use of the drug in children.

Effect on the ability to drive a car and/or other mechanisms

Caution should be exercised in the event of the development of adverse reactions that affect the speed of psychomotor reactions.

Release form

Film-coated tablets 500 mg and 1000 mg. 500 mg tablets: 10 or 14 tablets in PVC/Aluminum foil blisters. 1 blister (10 tablets each) or 3 blisters (14 tablets each) along with instructions for use in a cardboard box. Tablets 1000 mg: 7 tablets in PVC/Aluminum foil blisters. 1 or 4 blisters along with instructions for use in a cardboard box.

Storage conditions

At a temperature not higher than 30°C. Keep out of the reach of children!

Best before date

18 months. Do not use after expiration date.

Vacation conditions

Dispensed by prescription.