Universal reference book for medicines
Product name: VALTREX ® (VALTREX ® )

Active substance: valaciclovir

Type: Antiviral drug

Manufacturer: GlaxoSmithKline Trading (Russia) manufactured by GlaxoSmithKline Pharmaceuticals (Poland)
Composition, form of production and packaging
The tablets covered with a film shell of
white color, oblong, biconcave, without risks, on one side the inscription "GX CF1" is engraved;
the core is from white to almost white.
1 tab.

valacyclovir hydrochloride 556 mg,

which corresponds to the content of valacyclovir 500 mg

Excipients: microcrystalline cellulose - 70 mg, crospovidone - 28 mg, povidone K90 - 22 mg, magnesium stearate - 4 mg, silicon dioxide colloid - 2 mg.

The composition of the film shell: opadrai white - about 14 mg (hypromellose - 9.48 mg, titanium dioxide - 3.26 mg, macrogol 400 - 1.12 mg, polysorbate 80 - 0.14 mg).

The composition of polishing: wax karnauba - about 0.016 mg.

6 pcs.
- blisters (7) - packs of cardboard.
10 pieces.
- blisters (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2017.

PHARMACHOLOGIC EFFECT

Valacyclovir is an antiviral agent, it is an L-valine ester of acyclovir.
Acyclovir is an analogue of a purine nucleoside (guanine).
In the human body, valacyclovir is quickly and almost completely converted into acyclovir and valine, presumably under the influence of the enzyme valacyclovirhydrolase.

Acyclovir is a specific inhibitor of herpes viruses with in vitro activity against Herpes simplex virus types 1 and 2, Varicella zoster virus, Varicella zoster, cytomegalovirus (CMV), Epstein-Barr virus (VEB) and virus herpes simplex type 6. Acyclovir inhibits the synthesis of viral DNA immediately after phosphorylation and conversion into an active form - acyclovir triphosphate.

The first stage of phosphorylation requires the activity of virus-specific enzymes.
For HSV, VZV and VEB, this enzyme is viral thymidine kinase, which is present only in the cells infected with the virus. Partially, the selectivity of phosphorylation is maintained in the cytomegalovirus indirectly through the product of the phosphotransferase gene UL97. This need to activate 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.
Acyclovir triphosphate competitively inhibits viral DNA polymerase and, being an analogue of a nucleoside, is inserted

into viral DNA, which leads to an obligate rupture of the chain, stopping the synthesis of DNA and, consequently, to blocking the replication of the virus.

Resistance to acyclovir is usually due to a deficiency of thymidine kinase, which leads to an excessive spread of the virus in the host.
In rare cases, a decrease in sensitivity to acyclovir is due to the appearance of strains of the virus 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.
Based on the results of an extensive study of HSV and VZV strains selected from patients treated with acyclovir or used for prevention, it was found that viruses with reduced sensitivity to valacyclovir are extremely rare, but can be detected in rare cases in patients with severe immunity, for example, bone marrow transplant recipients or organ, patients receiving chemotherapy for malignant neoplasms, and in HIV-infected patients.

Valaciclovir contributes to the relief of pain syndrome: reduces its duration and reduces the percentage of patients with pain caused by herpes zoster, including acute postherpetic neuralgia.

PHARMACOKINETICS

Suction

After ingestion, valacyclovir is well absorbed from the digestive tract, rapidly and almost completely turning into acyclovir and valine.
This transformation is probably carried out by the enzyme of the liver with valaciclovirhydrolase.
When taking valacyclovir in a dose of 1000 mg, the bioavailability of acyclovir is 54% and does not decrease with food intake.
The pharmacokinetics of valacyclovir are not dose-dependent. The rate and degree of absorption decrease with increasing dose, resulting in a less proportional increase in C max in plasma, but compared with the therapeutic range of doses and a decrease in bioavailability at doses above 500 mg.
Table 1. Results of assessing 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)

C max μmol / L 9.78 ± 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

T max 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? Μmol / l 24.4 ± 3.65 49.3 ± 7.77 83.9 ± 20.1 131 ± 28.3

h? μg / ml 5.50 ± 0.82 11.1 ± 1.75 18.9 ± 4.51 29.5 ± 6.36

C max - the maximum concentration in the blood plasma;

T max - the time until the maximum concentration in the blood plasma;

AUC is the area under the pharmacokinetic curve "concentration-time".
The C max and AUC values ​​reflect the average standard deviation.
The values ​​for T max reflect the median value and range of values.

C max valaciclovir in blood plasma is only 4% of the concentration of acyclovir, the median time to achieve it is 30 to 100 min after taking the drug.
After 3 hours after taking the drug, the valacyclovir concentration reaches the level of quantitation or lower.
Valaciclovir and acyclovir have similar pharmacokinetic parameters after a single and multiple administration.
VZV and HSV significantly do not change the pharmacokinetics of valaciclovir and acyclovir after taking valacyclovir inwards.
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 8-hydroxyacyclovir metabolite (8-OH-ACV); about 2.5% for the metabolite 9- (carboxymethoxy) methyl guanine (CMMG).
Metabolism

After ingestion, valaciclovir is converted into acyclovir and L-valine through presystemic metabolism in the intestine and / or hepatic metabolism.
Acyclovir is converted into small metabolites: CMMG under the influence of ethyl alcohol and aldehyde dehydrohease; 8-OH-ACV under the influence of aldehyde oxidase.Approximately 88% of the total cumulative effect on blood plasma is accounted for by acyclovir, 11% by CMMG and 1% by 8-OH-ACV. Valaciclovir and acyclovir are not metabolized by isoenzymes of the cytochrome P450 system.
Excretion

In patients with normal renal function T 1/2 acyclovir from the 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.
Valaniclovir 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 - CMMG
Special patient groups

Patients with impaired renal function.
Excretion of adiklovir correlates with renal function, the exposure of acyclovir increases with increasing severity of renal failure. In patients with terminal renal failure, the mean T 1/2 acyclovir after valaciclovir is approximately 14 hours compared to approximately 3 hours with normal renal function.
Exposure of aciclovir and its metabolites CMMG and 8-OH-ACV in blood plasma and CSF were evaluated in stable state after multiple administration of valaciclovir in 6 patients with normal renal function (mean CC 111 ml / min, range 91-144 ml / min) 2000 mg every 6 hours, and in 3 patients with severe renal failure (mean SC 26 ml / min, range 17-31 ml / min) receiving 1500 mg every 12 hours. With severe renal failure compared with normal renal function in blood plasma, as well as in the CSF, the concentrations of acyclovir, CMMG and 8-OH-ACV would be
whether in 2, 4 and 5-6 times higher, respectively. There was no difference in the degree of penetration of acyclovir in the CSF (defined as the ratio of AUC to CSF ​​to AUC in plasma), CMMG or 8-GH-ACV between two populations with severe renal failure and normal renal function.
Patients with impaired liver function.
Pharmacokinetic data show that in patients with hepatic insufficiency, the rate of conversion of valaciclovir to acyclovir is reduced, but not the degree of this transformation. T 1/2 acyclovir does not depend on liver function.
Pregnancy.
A study of the pharmacokinetics of valaciclovir and acyclovir in late pregnancy established an increase in the daily AUC value in a stable state with a daily intake of valacyclovir at a dose of 1000 mg per day, which was approximately 2 times higher than the AUC when administered at the dose of 1200 mg per acyclovir.
HIV infection.
In patients with HIV infection, the distribution and pharmacokinetic characteristics of acyclovir following oral administration of one or more doses of 1000 mg or 2000 mg of valacyclovir remain unchanged compared to healthy volunteers.
Organ transplantation.
With max acyclovir in patients after organ transplantation, those receiving 2000 mg of valaciclovir 4 times / day were comparable or higher than C max 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 the newly identified and recurring 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, incl.
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.

DOSING MODE

The drug Valtrex ® can be taken regardless of the meal, the tablets should be washed down with water.

Treatment of infections of the skin and mucous membranes caused by HSV, including the newly identified and recurring genital herpes (Herpes genitalis), as well as the labial herpes (Herpes labialis)

Immunocompetent adults and adolescents aged 12 to 18 years

The recommended dose is 500 mg 2 times / 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. With relapses of HSV, the most valid treatment is Valtrex ® in the prodromal period or immediately after the appearance of the first symptoms of the disease. The use of valaciclovir can prevent the development of the lesion if it is used at the first signs of symptoms of a recurrence caused by HSV.
As an alternative treatment for labial herpes, valtrex ® is effectively administered at a dose of 2000 mg 2 times / day for 1 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 should not exceed 1 day, because The excess of 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 (ie tingling, itching, burning) occur.

Prevention (suppression) of recurrences of infections of the skin and mucous membranes caused by HSV, including genital herpes, incl.
in adults with immunodeficiency
Immunocompetent adults and adolescents aged 12 to 18 years

In immunocompetent patients, the recommended dose is 500 mg 1 time / day.
After 6-12 months of treatment, it is necessary to evaluate the effectiveness of therapy.
Adults with immunodeficiency

In adults with immunodeficiency recommended, the dose is 500 mg 2 times / day.
After 6-12 months of treatment, it is necessary to evaluate the effectiveness of therapy.
Prevention of infections caused by CMV 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 lowered depending on the creatinine clearance. The duration of treatment is usually 90 days, but in patients with high-risk treatment can be extended.
Treatment of herpes zoster (Herpes zoster) and ophthalmic herpes zoster

Adults

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

Special patient groups

Children

The effectiveness of treatment with Valtrex ® in children has not been studied.

Elderly patients

It is necessary to take into account the possible violation of kidney function in elderly patients, the dose of Valtrex ® should be adjusted accordingly.
It is necessary to maintain an adequate water-electrolyte balance.
Patients with impaired renal function

Valtrex ® is recommended to reduce the dose in patients with severe renal dysfunction (see dosing regimen in Table 2).
Such patients need to maintain an adequate water-electrolyte balance.
Table 2. Correction of a dose of Valtrex ® for use in adults and adolescents aged 12 to 18 years with impaired renal function

Indications Clearance of creatinine, ml / min Valtrex ®

Herpes zoster and ophthalmic herpes zoster in immunocompetent adults (treatment) not less than 50 1000 mg 3 times / day

from 30 to 49 1000 mg 2 times / day

from 10 to 29 1000 mg 1 time / day

less than 10 500 mg 1 time / day

HSV (treatment)

Immunocompetent adults and adolescents aged 12 to 18 years at least 30 500 mg 2 times / day

less than 30 500 mg 1 time / day

Labial herpes in immunocompetent adults and adolescents aged 12 to 18 years (treatment) at least 50 2000 mg 2 times / day

from 30 to 49 1000 mg 2 times / day

from 10 to 29 500 mg 2 times / day

less than 10 500 mg 1 time / day

HSV (prevention (suppression))

Immunocompetent adults and adolescents aged 12 to 18 years at least 30 500 mg 1 time / day

less than 30 500 mg once every two days

Adults with immunodeficiency not less than 30 500 mg 2 times / day

less than 30 500 mg 1 time / day

Prevention of infections caused by CMV, in adults and adolescents aged 12 to 18 years, not less than 75 2000 mg 4 times / day

from 50 to 75 1500 mg 4 times / day

from 25 to 50 1500 mg 3 times / day

from 10 to 25 1500 mg 2 times / day

less than 10 or in patients on hemodialysis 1500 mg 1 time / day

Additional information for indications: 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)

The experience of using Valtrex ® in children with CC values ​​less than 50 ml / min / 1.73 m2 is absent.

Additional information for indications: prevention of infections caused by CMV and diseases after transplantation of parenchymal organs

It is often necessary to determine QC, especially during the period when the kidney function changes rapidly, for example, immediately after transplantation or engraftment of the transplant, while the dose of Valtrex ® is adjusted in accordance with the QC indices.

Additional information for indications: treatment of herpes zoster (Herpes zoster) and ophthalmic herpes zoster

Valtrex ® should be used after hemodialysis in patients undergoing periodic hemodialysis .

Patients with impaired hepatic function

Based on the study using a single dose of valaciclovir 1000 mg in adult patients with cirrhosis of the liver of mild or moderate severity (with preserved synthetic function of the liver), the dose adjustment of Valtrex ® is not required.

Pharmacokinetic data in adult patients with severe liver function impairment (decompensated cirrhosis), with a violation of the synthetic function of the liver and the presence of portocaval anastomoses also do not indicate the need for correction of the Valtrex® dose, however, the clinical experience with these pathologies is limited.

Information on doses more than 4000 mg / day for patients with infections caused by HSV and CMV is indicated in the section "Special instructions".

SIDE EFFECT

Undesirable reactions are listed below in accordance with the classification of the main systems and organs and the frequency of occurrence, which is defined as follows: very often (? 1/10), often (? 1/100, <1/10), infrequently (? 1 / 1000, <1/100), rarely (? 1/10 000, <1/1000), very rarely (<10 000).

Clinical Trials Data

From the nervous system: often - a headache.

From the side of the digestive system: often - nausea.

Post-marketing research data

On the part of the blood system and hemopoiesis: very rarely - leukopenia, thrombocytopenia.
In general, leukopenia was observed in patients with reduced immunity.
From the immune system: very rarely - anaphylaxis.

From the nervous system and psyche: rarely - dizziness, confusion, hallucinations, depression of consciousness;
very rarely - agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma. The symptoms listed above are mostly reversible and are usually observed in patients with impaired renal function or against a background of other predisposing conditions. In adult patients with a transplanted organ who receive high doses (8 g / day) of Valtrex ® for the prevention of CMV infection, neurologic reactions develop more often than with lower doses.
From the respiratory system and mediastinal organs: infrequently - shortness of breath.

From the digestive system: rarely - discomfort in the abdomen, vomiting, diarrhea.

Of the liver and biliary tract: rarely - reversible damage liver function tests, which are sometimes regarded as manifestations of hepatitis.
Skin and subcutaneous tissue: rare - rash, including photosensitivity manifestations; rarely - itching; very rarely - urticaria, angioedema.
From the urinary system: infrequently - haematuria (often associated with other disorders of the kidney); rarely - renal dysfunction; very rarely - acute renal failure, renal colic. Renal colic may be associated with renal impairment .Reported cases acyclovir deposition of crystals in the lumen of the renal tubules. Care must be adequate drinking regime during treatment.
Miscellaneous: patients with severely impaired immune system, especially in adult patients with advanced stages of HIV infection receiving high doses of valaciclovir (8 g / day) for a long period of time, there have been cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes combination). These complications have been observed in patients with the same primary and / or concomitant diseases, but do not receive valacyclovir.
CONTRAINDICATIONS

- Hypersensitivity to valaciclovir, aciclovir and any other component, part of the drug;
- children's age till 12 years;

- Children up to age 18 years in the treatment of herpes zoster and ophthalmic zoster.
With caution: in patients with renal insufficiency; patients with symptomatic forms of HIV infection; while receiving nephrotoxic drugs.
PREGNANCY AND LACTATION

Fertility
In animal studies, valacyclovir had no effect on fertility. However, use of high doses of acyclovir when administered parenterally caused testicular effects in rats and dogs.
Studies of the effect of valaciclovir on fertility have not been conducted in humans. However, no changes were registered in an amount motility and morphology of spermatozoa in 20 patients after 6 months of daily application of valaciclovir at doses of 400 mg to 1000 mg.
Pregnancy

There are limited data on the use of Valtrex ® during pregnancy. The drug should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.
In pregnancy registries have been documented pregnancy outcomes in women taking Valtrex ® or other preparations containing acyclovir (acyclovir is an active metabolite of the drug Valtrex ®), 111, and 1246 observations, respectively (of which 29 and 756 take I preparations trimester) pregnancy outcomes were recorded prospectively. Analysis of the data in the register pregnant women exposed to acyclovir, showed no increase in the number of birth defects in children as compared with the general population, none of malformations revealed no specificity or patterns, indicating a common cause. Since pregnancy registries small number of women were included who received valacyclovir during pregnancy, the accurate and definite conclusions about the safety of valaciclovir in pregnancy can not be done.
Breastfeeding period

Acyclovir, the main metabolite of valaciclovir, enters the breast milk. Upon receiving valaciclovir dose of 500 mg orally C max in breast milk in 0.5-2.3 fold (an average 1.4 times) higher than the corresponding concentration of acyclovir in plasma, maternal blood. The ratio of AUC values of acyclovir in breast milk to AUC in maternal serum ranged from 1.4 to 2.6 (mean 2.2).
The mean value of the concentration of acyclovir in breast milk was 2.24 micrograms / ml (9.95 micromol / L). When receiving valaciclovir mother at a dose of 500 mg of 2 times / day children who are breast-fed, subjected to the same effects of acyclovir as when taking it orally at a dose of about 0.61 mg / kg / day. T 1/2 of acyclovir from breast milk is the same as from blood plasma.
Valacyclovir in unchanged form was not detected in the plasma of the mother's blood, breast milk and urine of a child. The drug Valtrex ® should be used with caution in women during breast-feeding. However, acyclovir for on / in the treatment of HSV used for infants at a dose of 30 mg / kg / day.
APPLICATION FOR FUNCTIONS OF THE LIVER

When renal failure dosage regimen set depending on creatinine clearance and evidence.
APPLICATION FOR CHILDREN

Contraindications:

- children's age till 12 years;

- Children up to age 18 years in the treatment of herpes zoster and ophthalmic zoster.
APPLICATION IN ELDERLY PATIENTS

elderly patients dose adjustment is required, except in cases of significant renal dysfunction. It is necessary to maintain an adequate fluid and electrolyte balance.
SPECIAL INSTRUCTIONS

Hydration
in patients at risk of dehydration, especially in elderly patients, it is necessary to provide adequate water and electrolyte balance.
The use in patients with impaired renal function, elderly patients
Because acyclovir is excreted by the kidneys, the dose should be reduced Valtrex ®in patients with impaired renal function. Elderly patients may be a violation of nochek function, so you should consider reducing the dose for this patient group. As elderly patients and patients with impaired renal function are at increased risk of developing neurological complications in these patients is necessary to provide a thorough medical control. As a rule, these reactions generally are reversible in case withdrawal of the drug.
Treatment of herpes labialis and prophylaxis of CMV infections and diseases
The use of high doses of Valtrex ® with abnormal liver function after a liver transplant. No data on the use Valtrex ®in high doses (4000 mg / day and above) in patients with liver disease, such patients however high dose Valtrex ® should be used with caution. Special studies on the effect of Valtrex ® not conducted for liver transplantation. However, it was found that the prophylactic high dose acyclovir reduces the manifestations of CMV infection and disease.
Use in genital herpes
Patients should be advised to abstain from sex when symptoms are present even if treatment is the antiviral drug Valtrex ® has been started. Suppressive therapy with Valtrex ®It 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. Therapy with Valtrex ® recommended in combination with a reliable means of barrier contraception.
Effects on ability to drive vehicles and management mechanisms
necessary to consider the clinical condition of the patient and the adverse reaction profile of valaciclovir in assessing a patient's ability to drive a car or moving machinery.
OVERDOSE

Symptoms: acute renal failure and neurological disorders, including confusion, hallucinations, agitation, depression of consciousness and coma, as well as nausea and vomiting, were observed in patients who received a dose of valaciclovir, exceeding recommended. Such conditions were more common in patients with renal impairment and elderly patients function who received repeated doses of valaciclovir exceeding recommended, due to non-compliance with the dosing regimen.
Treatment: Patients should be under close medical supervision. Hemodialysis largely contributes to the removal of acyclovir from the blood and may be considered the method of choice in the management of patients with an overdose Valtrex ® .
DRUG INTERACTION

Clinically significant interactions have not been established.
Acyclovir is excreted by the kidneys, substantially unaltered by the active renal secretion. The combined use of drugs with the same mechanism of elimination can lead to increased concentrations of acyclovir in the plasma.
After drug administration Valtrex ® in a dose of 1000 m and cimetidine preparations and probenecid, which are derived in the same manner as the preparation Valtrex® , observed an increase in AUC of acyclovir and thus reduced renal clearance of acyclovir. However, because of the wide therapeutic index acyclovir correction dose Valtrex ® is required.
When treating labial herpes prevention and treatment of diseases caused by CMV, care must be taken in the case of simultaneous application Valtrex ® at higher doses (4000 mg / day or higher) and drugs that compete with acyclovir for deducing path since there increasing the potential threat in blood plasma concentration of one or both drugs or their metabolites. AUC increase was noted acyclovir and inactive metabolite mycophenolate mofetil (immunosuppressant used in organ transplant patients) while the application of these drugs.
It should also be taken (monitoring of renal function) when combined Valtrex ®at higher doses (4 g / day and above) with drugs that affect the other kidney (e.g., cyclosporine, tacrolimus).
Simultaneous use of the drug Valtrex ® with nephrotoxic drugs, including aminoglycosides, organic platinum compounds, iodinated contrast agent, methotrexate, pentamidine, foscarnet, cyclosporin and tacrolimus, should be carried out with care, particularly in patients with impaired kidney function and require regular monitoring of renal function.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored at temperatures not above 30 ° C in the reach of children.
Shelf life - 3 years.
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