Valogard - instructions for use, doses, side effects, contraindications

Excipients: cellulose microcrystalline 101 - 227 mg, povidone - 26.1 mg, silicon dioxide colloidal anhydrous - 8.7 mg, crospovidone - 43.5 mg, magnesium stearate - 8.7 mg, Sepifilm 050 of which: methylhydroxypropylcellulose, microcrystalline cellulose, acetylated mono- and diglycerides - 16 mg, candurin including: potassium aluminum silicate, titanium dioxide - 4 mg.

Description:

Tablets of oblong form, with a biconvex surface, with a risk, covered with a film of pearl shell, almost white. On the fracture, the core is white or almost white.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.B.11 Valaciclovir

J.05.A.B Nucleosides and nucleotides

Pharmacodynamics:

Valacyclovir is an antiviral agent, is a L-valine new ester of acyclovir. Acyclovir is an analogue of a purine nucleoside (guanine).

In the human body valaciclovir quickly and completely turns into acyclovir and valine, under the influence of the enzyme valacyclovirhydrolase. Acyclovir possesses in vitro specific inhibitory activity against herpes simplex virus (HSV) types 1 and 2, varicella zoster virus and herpes zoster (VARV-varicellazoster virus), cytomegalovirus (CMV), Epstein-Barr virus (VEB) and human herpesvirus 6- th type. Acyclovir inhibits the synthesis of viral DNA immediately after phosphorylation and conversion into an active form of acyclovir triphosphate.

The first stage of phosphorylation requires the activity of virus-specific enzymes.

For HSV, VZB, and VEB, such an enzyme is viral thymidine kinase, which is present in the cells infected with the virus. Partial selectivity of phosphorylation is maintained in the cytomegalovirus and is mediated through the product of the phosphotransferase gene UL 97. 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, consequently, to blocking the replication of the virus.

In patients with preserved immunity, HSV and VZV with reduced sensitivity to valaciclovir are extremely rare, but can sometimes be found in patients with severe immune impairment, for example, with bone marrow transplant, in chemotherapy for malignant neoplasms and in HIV-infected patients.

Resistance is usually due to a deficiency of thymidine kinase, 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 oral administration valaciclovir well absorbed from the gastrointestinal tract, quickly and almost completely turning into a acyclovir and valine. This transformation is catalyzed by the enzyme of the liver with valaciclovirhydrolase.

After a single administration of valaciclovir 250-2000 mg, the maximum concentration (C_m_Oh) of acyclovir in plasma in healthy volunteers with normal renal function is 10-37 μmol / L (2.2-8.3 μg / ml), and the time to reach the maximum concentration (TC_m_Oh) 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.

The maximum concentration of valacyclovir in plasma is only 4% of the concentration of acyclovir, the average time to reach the maximum concentration of valacyclovir in plasma is 30-100 minutes after the dose,the limit of quantitative determination of valacyclovir in plasma is reached after 3 hours or earlier.

Valaciclovir and acyclovir have similar pharmacokinetic parameters after oral administration.

Distribution

The degree of binding of acyclovir to plasma proteins is low - 15%.

Excretion

In patients with normal renal function, the half-life of acyclovir from the plasma after taking valaciclovir is approximately 3 hours, and in patients with the final stage of renal failure, the average half-life is about 14 hours. Valaciclovir is excreted from the body by the kidneys, mainly in the form of acyclovir (more than 80% of the dose) and the metabolite of acyclovir 9-carboxymethoxymethylguanine, in unchanged form less than 1% of valaciclovir is excreted.

Special patient groups

The pharmacokinetics of valaciclovir and acyclovir are largely unchanged in patients infected with HSV and BWB.

In late pregnancy, the daily indicator of the area under the concentration-time curve (AUC) in the equilibrium state after administration of 1000 mg of valaciclovir was more approximately 2 times that of acyclovir in a dose of 1200 mg / day.

In HIV-infected patients, the pharmacokinetic parameters of acyclovir after ingestion of valacyclovir in a dose of 1000 mg or 2000 mg are comparable to those observed in healthy volunteers.

In transplant recipients of organs receiving valaciclovir in a dose of 2000 mg 4 times / day, the maximum concentration of acyclovir was comparable or exceeded the concentration observed in healthy volunteers after taking the same doses, while the daily area under the pharmacokinetic curve was significantly higher.

Indications:

Adults:

- Treatment of herpes zoster (Herpes zoster). Valogard contributes to the relief of pain syndrome, reduces its duration and the percentage of patients with pain caused by herpes zoster, including acute and postherpetic neuralgia.

- Treatment of infections of the skin and mucous membranes caused by HSV, including first-time and recurrent genital herpes (Herpes genitalis), as well as labial herpes (Herpes labialis).

- Prevention (suppression) of recurrences of infections of the skin and mucous membranes caused by HSV, including genital herpes.

- Prophylaxis of transmission of genital herpes to a healthy partner when taken as a suppressive therapy in conjunction with safe sex.

Adults and adolescents aged 12 years and over:

- Prevention of cytomegalovirus (CMV) infection, as well as reactions of acute graft rejection (in patients with kidney transplants), opportunistic infections and other herpesvirus infections (HSV, VZV) after organ transplantation.

Contraindications:

- Hypersensitivity to valaciclovir, acyclovir and any auxiliary component included in the preparation;

- bVariability;

- dUp to 12 years of age in the prevention of cytomegalovirus infection (CMV), infection after transplantation;

- dUnder-18 for all other indications (due to insufficient data on clinical studies for this age group);

- HIV infection with C contentD4 + lymphocytes less than 100 / μl.

Carefully:

In patients with hepatic / renal insufficiency; patients with clinically expressed forms of HIV infection; with the simultaneous administration of nephrotoxic drugs; the period of breastfeeding; elderly age; hypohydration.

Pregnancy and lactation:

Pregnancy

Valogard is contraindicated during pregnancy.

Breastfeeding period

Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After using valaciclovir in a dose of 500 mg, the maximum concentration of acyclovir (C_m_Oh) in breast milk in 0,5-2,3 times (an average of 1,4 times) exceeded the corresponding concentrations of acyclovir in the blood plasma of the mother. The average concentration of acyclovir in breast milk was 2.24 μg / ml (9.95 μmol / L). When taking a valacyclovir mother at a dose of 500 mg 2 times a day, the child will undergo the same effect of acyclovir as if taking it inside at a dose of about 0.61 mg / kg / day. The half-life of acyclovir from breast milk is the same as from plasma.

Valacyclovir in unchanged form was not detected in the plasma of the mother, breast milk or urine of the child.

Valogard should be administered with caution to lactating women.

Dosing and Administration:

Valogard is taken regardless of the meal, the tablets should be taken with water.

Treatment of herpes zoster

Adults

The recommended dose is 1000 mg 3 times a day for 7 days.

Treatment of infections caused by HSV

Adults

The recommended dose for therapy of the episode is 500 mg 2 times a day for 5 days.In more severe cases of debility, treatment should be started as soon as possible, and its duration should be increased from 5 to 10 days. In case of relapse, treatment should last 3 or 5 days. With relapses of HSV, Valogard's appointment in the prodromal period or immediately after the appearance of the first symptoms of the disease is ideal.

As an alternative to the treatment of labial herpes, Valogarda is effectively administered at a dose of 2 g twice daily. 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 HSV

Adults

In patients with preserved immunity the recommended dose is 500 mg once a day.

In patients with immunodeficiency the recommended dose is 500 mg 2 times a day. Prevention of infection with genital herpes of a healthy partner

To infected immunocompetent persons with relapses no more than 9 times a year, the recommended dose of Valogard is 500 mg once a day for a year or more every day.

Data on the prevention of infection in other patient populations are not available. Prevention of cytomegalovirus (CMV) infection after transplantation

Adults and adolescents aged 12 years and over

The recommended dose is 2 g 4 times a day, prescribed as soon as possible after transplantation.

The dose should be lowered depending on the creatinine clearance.

The duration of treatment is 90 days, but in patients with high risk, the course of treatment can be extended.

Special patient groups

Patients with impaired renal function

Treatment of shingles and infections caused by HSV, prevention (suppression) of recurrences of infection caused by HSV, prevention of transmission of genital herpes to a healthy partner

Valogarda dose is recommended to be reduced in patients with a significant decrease in renal function (see doses in renal failure in the table). Such patients need to maintain adequate hydration.

The experience of Valogarda in children with creatinine clearance values less than 50 ml / min / 1.73 m² no.

Indications	Clearance creatinine, ml / min	Valogarda dose
Shingles	15-30 less than 15	1 g 2 times a day 1 g once a day
Treatment of infection caused by HSV (according to the scheme 500 mg twice a day)	less than 15	500 mg once a day
Treatment of labial herpes (according to the scheme 2 g 2 times during one day)	31-49 15-30 less than 15	1 g twice for 1 day 500 mg twice for 1 day 500 mg once
Prevention (suppression) of recurrences of infections caused by HSV:
- patients with normal immunity - patients with reduced immunity -Reduction of the risk of transmission of genital herpes	less than 15 less than 15 less than 15	250 mg once a day 500 mg Once a day 250 mg 1 time per day

Patients on hemodialysis are recommended to use Valogard immediately after the end of the hemodialysis session at the same dose as patients with creatinine clearance less than 15 ml / min.

Prevention of cytomegalovirus (CMV) infection after transplantation

The appointment of Valogarda in patients with impaired renal function should installed in accordance with the table below.

Creatinine clearance, ml / min	Valogarda dose
75 and more	2 g 4 times a day
from 50 to less than 75	1.5 g 4 times a day
from 25 to less than 50	1.5 g 3 times a day
from 10 to less than 25	1.5 g 2 times a day
less than 10 or dialysis *	1.5 g once a day

* In patients on hemodialysis, Valogard should be prescribed after the end of the hemodialysis session.

It is often necessary to determine the clearance of creatinine, especially during periods when the kidney function changes rapidly, for example, immediately after transplantation or engraftment of the graft, with Valogard's dose adjusted according to the creatinine clearance rates.

Patients with impaired hepatic function

In adults with a mild or moderate degree of liver function disorder with a preserved synthetic function, the dose adjustment for Valogard 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 Valogard, but the clinical experience for this pathology is limited.

Children under the age of 12 years

There is no data on Valogard's use in children.

Elderly patients

Dose adjustments are not required, except for a significant impairment of kidney function. It is necessary to maintain an adequate water-electrolyte balance.

Side effects:

Undesirable reactions are listed below in accordance with the classification of the main systems and organs and the frequency of occurrence, which was defined as follows: very often: ≥ 1 on 10: often: ≥1 for 100 or <1 for 10: infrequently: ≥ 1 for 1000 or <1 for 100, rarely: ≥ 1 for 10000 or <1 for 1000, very rarely: <1 per 10000.

Clinical Trials Data

Disturbances from the nervous system

Often: headache.

Disorders from the gastrointestinal tract

Often: nausea.

Postmarketing data research

From the blood system and hematopoiesis

Rarely: leukopenia, thrombocytopenia, mainly leukopenia was noted in patients with reduced immunity.

From the immune system

Rarely: anaphylaxis.

From the nervous system and the psyche

Rarely: dizziness, confusion consciousness, hallucinations, oppression of consciousness.

Rarely: agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma.The above symptoms are generally reversible and are usually observed in patients with impaired function of the nights or against a background of other predisposing conditions. In adult patients with a transplanted organ who receive high doses (8 g per day) of valaciclovir for the prevention of CMV infection, neurologic reactions develop more often than with lower doses.

From the respiratory system and the mediastinum

Infrequently: dyspnea.

From the gastrointestinal tract

Rarely: discomfort in the abdomen, vomiting, diarrhea.

From the liver and biliary tract

Rarely: reversible violations functional hepatic tests, which are sometimes regarded as manifestations of hepatitis.

From the side leather and subcutaneous fat

Infrequently: Rashes, including photosensitivity manifestations.

Rarely: itching.

Rarely: urticaria, angioedema.

From the urinary system

Infrequently: hematuria (often associated with other disorders of the kidneys).

Rarely: impaired renal function.

Rarely: acute renal insufficiency, renal colic (may be associated with impaired renal function).In addition, precipitation of acyclovir crystals in the lumen of the renal tubules was observed. Adequate drinking regimen should be observed during treatment.

Other

In patients with severe impairment of immunity, especially in adults with advanced HIV infection receiving high doses of valaciclovir (8 g daily) for a long period of time, there were cases of renal failure, microangiopathic hemolytic anemia, and thrombocytopenia (sometimes in combination). Similar complications were observed in patients with the same underlying and / or concomitant diseases, but not receiving valaciclovir.

Overdose:

Symptoms: acute renal failure and neurological disorders, including confusion, hallucinations, agitation, oppression and coma, as well as nausea and vomiting, were observed in patients who received doses of valaciclovir exceeding recommended. Similar conditions were more frequent in patients with impaired renal function and elderly patients who received repeated higher recommended doses of valaciclovir due to non-compliance with the dosing regimen.

Treatment: patients should be under close medical supervision. Hemodialysis greatly contributes to the excretion of acyclovir from the blood and can be considered a method of choice in managing patients with Valogard overdose.

Interaction:

Clinically significant interactions are not established.

Acyclovir is excreted by the kidneys, mainly in unmodified form through active renal secretion. Combined use of drugs with this removal mechanism can lead to an increase in the concentration of acyclovir in the blood plasma. After the appointment of the drug Valogard at a dose of 1000 mg and drugs cimetidine, probenecid, which are excreted in the same way as the preparation Valogard, there is an increase in AUC acyclovir and, thus, decreases the renal clearance of acyclovir. Nevertheless, due to the wide therapeutic index of acyclovir, the dose adjustment of Valogard is not required.

In the treatment of labial herpes, the prevention and treatment of diseases caused by CMV, caution should be exercised when using Valogard at a higher dose (4000 mg per day or more) and medications,which compete with acyclovir for the route of excretion, because there is a potential threat of an increase in plasma concentrations of one or both drugs or their metabolites. There was an increase in the AUC of acyclovir and an inactive metabolite of mycophenolate mofetil (an immunosuppressant used in patients after organ transplantation) with osimultaneous application of of these drugs.

The simultaneous use of Valogard with nephrotoxic drugs, including aminoglycosides, organic compounds of the plugin, iodinated contrast agent, methotrexate, pentamidine, foscarnet, cyclosporine and tacrolimus should be performed with caution, especially in patients with impaired renal function, and requires regular monitoring of kidney function .

Special instructions:

In patients with a risk of dehydration, especially in elderly patients, adequate fluid replenishment must be ensured.

Because the acyclovir is excreted by the kidneys, Valogard's dose should be adjusted depending on the degree of renal dysfunction. 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, in general, are reversible after drug discontinuation. There is no data on the use of valaciclovir in higher doses (4 g per day or more) in patients with liver disease, therefore high doses of Valogard should be given with caution. Special studies on the study of the action

Valogarda during liver transplant was not performed. However, it has been shown that prophylactic intravenous administration of acyclovir in high doses reduces the manifestations of CMV infection.

Suppressive therapy Valogardom reduces the risk of transmission of genital herpes, but does not completely exclude the risk of infection and does not lead to a complete cure. Valotherapy therapy is recommended in combination with safe sex.

In clinical trials, in patients with advanced HIV-1 infection, as well as in allogeneic bone marrow transplantation in recipients of renal transplant receiving valaciclovir in a dose of 8 g per day, thrombotic thrombocytopenic purpura / hemolytic uremic syndrome was observed, in some cases fatal. The use of valacyclovir should be discontinued immediately,if there are clinical signs, symptoms and laboratory abnormalities characteristic of thrombotic thrombocytopenic purpura / hemolytic uraemic syndrome.

Cases of acute renal failure were recorded:

- in elderly patients with or without kidney function.

Caution should be exercised when using valaciclovir in elderly patients, and a dose reduction in patients with impaired renal function is also recommended.

- in patients with concomitant renal disease who received higher doses of valaciclovir.

It is recommended to reduce the dose of valacyclovir to patients with renal insufficiency.

- in patients taking other nephrotoxic drugs.

Care should be taken when using valaciclovir and nephrotoxic drugs concomitantly.

- in patients without adequate hydration.

Adequate hydration should be maintained for all patients.

In the case of acute renal failure and anuria, hemodialysis may be used until the kidney function is restored.

Side effects from the central nervous system have been reported, including agitation, hallucinations, confusion, delusions, convulsions and encephalopathy.These effects have been reported in adult patients and children with or without impaired renal function; in patients with concomitant renal disease who received higher doses of valaciclovir; in elderly patients. If these side effects occur, discontinuation of valacyclovir should be considered.

Effect on the ability to drive transp. cf. and fur:

The drug may cause dizziness, confusion. Therefore, the degree of restriction on driving and the work with the mechanisms the doctor must determine for each patient individually.

Form release / dosage:

Tablets, film-coated, 500 mg.

Packaging:

For 6 or 10 tablets in a blister of a film of PVC colorless and aluminum foil printed lacquered.

For 7 blisters (6 tablets) or 1 blister (10 tablets), together with the instruction for use, put in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002295

Date of registration:05.11.2013 / 02.04.2014

Expiration Date:05.11.2018

The owner of the registration certificate:FARMAK, PAO FARMAK, PAO Ukraine

Manufacturer: & nbsp

FARMAK, PAO Ukraine

Representation: & nbspFARMAK PAOFARMAK PAO

Information update date: & nbsp19.01.2017

Illustrated instructions

Instructions

Vałlogard (Valogard)