Valaciclovir - instructions for use, dose, side effects, contraindications

In the human body valaciclovir quickly and completely turns into acyclovir and the lump, under the influence of the enzyme valacyclovirhydrolase. Acyclovir possesses in vitro specific inhibitory activity against herpes simplex virus (HSV) 1th and 2 nd types,virus varicella zoster and herpes zoster (VARV-varicella-zoster virus), cytomegalovirus (CMV), the Epstein-Barr virus (EBV) and the human herpes virus 6th 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 occurs with the participation of virus-specific enzymes. For HSV, VZV, and VEB, such an enzyme is viral thymidine kinase, which is present only in virus-infected cells. Partial selectivity of phosphorylation is maintained in the cytomegalovirus and is mediated through the product of the phosphotransferase gene UL97. 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 to acyclovir is usually due to a deficiency of thymidine kinase of the virus, which leads to an 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 viral thymidine kinase or DHK-polymerase. The virulence of these varieties of the virus resembles that of its wild strain.

Pharmacokinetics:

Suction

PAfter ingestion of the shaft acyclovir well absorbed from the gastrointestinal tract, quickly and almost completely transformed into a acyclovir and L-valine. This transformation is catalyzed by the enzyme of the liver - valaciclovirhydrolase.

When taking valaciclovir in a dose of 1000 mg, the bioavailability of acyclovir is 54% independent of food intake. The pharmacokinetics of valaciclovir are dose-dependent.The rate and degree of absorption decreases with increasing dose, resulting in an increase in the mean maximum concentration (C_max) occurs less proportionately in the range of therapeutic doses, and a decrease in bioavailability in doses above 500 mg is also observed.

The pharmacokinetic parameters (FKP) of acyclovir after a single intake of 250-2000 mg valacyclovir by healthy volunteers with normal renal function are given in the table 1.

Table 1. Pharmacokinetic parameters of acyclovir.

Acyclovir FKP		250 mg (N = 15)	500 mg (N = 15)	1000 mg (N = 15)	2000 mg (N =8)
FROM_max	m to g / ml	2,20 ± 0,38	3,37 ± 0,95	5,20 ±1.92	8,30 ±1,43
T_max*	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.mkg / ml	5,50 ±0,82	11,1 ± 1,75	18,9 ± 4,51	29,5 ±6,36

* - time to reach the maximum concentration;

** - the area under the pharmacokinetic curve "concentration-time".

Values for C_mOh and the area under the "concentration-time" curve (AUC) are given as mean ± standard deviation, values for the time to reach the maximum concentration (TFROM_mOh) are given in the form of mean values and a range of values.

FROM_mOh Valacyclovir in blood plasma is 4% of the concentration of acyclovir and is achieved on average 30-100 min after taking the drug: after 3 hours C_max remains the same or decreases. Valaciclovir and acyclovir have similar pharmacokinetic parameters after a single or multiple administration.

Distribution

The binding of valaciclovir to plasma proteins is very low (15%). Penetration into the cerebrospinal fluid (CSF), defined as the ratio AUC in the CSF to AUC at blood plasma, does not depend on renal function and is about 25% for acyclovir and metabolite 8-hydroxy-acyclovir (8-ON-ACV), and about 2.5% for metabolites 9- (carboxymethoxy) methylguanine (CMMH).

Metabolism

After oral administration valaciclovir is turning at acyclovir and L-valine through presystemic metabolism in the intestine and / or hepatic metabolism. Acyclovir is converted to an insignificant degree in metabolites-9- (carboxymethoxy) methylguanine with the participation of alcohol and aldehyde dehydrogenase and in 8-hydroxy-acyclovir with the participation of aldehyde oxidase. About 88% of the total combined effect of blood plasma is due to acyclovir, 11% KMMG and 1% 8-ON-ACV. Neither valaciclovir, nor acyclovir It is not metabolized by cytochrome P450 isoenzymes.

Excretion

Valacyclovir is excreted in the urine, mainly in the form of acyclovir (more than 80% of the dose) and its metabolite KMMG (about 14% of the dose). Metabolite 8-OH-AAB is detected in the urine only in small amounts (less than 2% of the dose).Less than 1% of the accepted dose of valaciclovir is excreted through the urine unchanged. In patients with normal renal function, the half-life of acyclovir from blood plasma after a single or repeated use of valaciclovir is approximately 3 hours.

Special patient groups

Renal insufficiency

Excretion of acyclovir correlates with renal function and the effect of acyclovir will increase with an increase in renal failure. In patients with end-stage renal failure, the half-life of acyclovir after valacyclovir is on average 14 hours compared to approximately 3 hours with normal renal function.

The effect of acyclovir and its metabolites CMMH and 8-OH-AEC in plasma and cerebrospinal fluid was evaluated in a stable state after repeated use of valaciclovir in 6 volunteers with normal renal function (mean creatinine clearance 111 ml / min, range 91-144 ml / min) receiving 2000 mg every 6 h, and 3 volunteers with severe renal failure (mean creatinine clearance 26 ml / min, range 17-31 ml / min), receiving 1500 mg every 12 hours.In severe renal failure compared with normal renal function in blood plasma, as well as in cerebrospinal fluid, the concentration of acyclovir, CMMG and 8-ON-AEC was on average 2, 4 and 5-6 times higher, respectively.

Liver failure

Pharmacokinetic data show that hepatic insufficiency reduces the rate of conversion of valaciclovir into acyclovir, but not the degree of transformation. The half-life of acyclovir does not depend on the presence of liver failure.

Indications:

Adults:

- Treatment of herpes zoster (Herpes zoster). A drug Valaciclovir 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 the first time detected and recurrent genital herpes (Herpes genitalis), as well as labial herpes (Herpes labialis).

- Preventive maintenance (suppression) of relapses of infections of a skin and mucous membranes caused or called SH1G, 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 about the age of 12 years and older:

- Prevention of infections caused by cytomegalovirus (CMV) and diseases after organ transplantation.

Contraindications:

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

- dUp to 12 years of age in the prevention of infections caused by cytomegalovirus (CMV) and diseases after organ transplantation;

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

- HIV infection with a CD4 + lymphocyte content of less than 100 / μL.

Carefully:

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

Pregnancy and lactation:

Pregnancy

Data on the use of valacyclovir in pregnancy is not enough. A drug Valaciclovir should be used during pregnancy only in the event that,if the potential benefit to the mother exceeds the potential risk to the fetus. Data of registration records on the outcome of pregnancy in women who took valaciclovir and other preparations containing acyclovir (acyclovir is an active metabolite of the drug Valaciclovir), did not reveal an increase in the number of birth defects in their children compared to the general population. Because the register includes a small number of women who valaciclovir during pregnancy, it is impossible to make reliable and definite conclusions about the safety of valacyclovir in pregnancy.

Breastfeeding period

Acyclovir, the main metabolite of valacyclovir, is decreed by breast milk. After using valaciclovir in a dose of 500 mg, the maximum concentration of acyclovir (Cmah) in breast milk in 0,5-2,3 times (on average, 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. Valaciclovir in unmodified form was not determined in the plasma of the mother, breast milk, or urine of the child.

Valaciclovir should be administered with caution to lactating women.

Dosing and Administration:

Inside. A drug Valaciclovir is taken regardless of the meal, tablets should be washed down 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 HIV

Adults

The recommended dose for therapy of the episode is 500 mg 2 times a day.

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 can be increased from 5 to 10 days. In case of relapse, treatment should last 3 or 5 days. In cases of recurrence of HSV, valacyclovir is considered ideal in the prodromal period or immediately after the appearance of the first symptoms of the disease.

As an alternative to the treatment of labial herpes, valaciclovir is effectively administered at a dose of 2 g twice daily. The second dose should be taken approximately after 12 hours (but not earlier than 6 hours) after taking the first dose.When using such a dosing regimen, the duration of treatment should not exceed 1 day, as exceeding the duration of treatment does not lead to an additional clinical effect. Therapy should be started when the earliest symptoms of labial herpes (ie tingling, itching, burning) occur.

Prevention (suppression) of recurrent 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 twice a day.

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

To infected immunocompetent persons with relapses no more than 9 times a year, the recommended dose of valacyclovir 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 infections caused by cytomegalovirus (CMV) and diseases after organ 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 treatment can be extended.

Special patient groups

Patients with impaired renal function

The curing of herpes zoster and infections caused by HSV, 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 doses for renal failure in the table). Such patients need to maintain an adequate water-electrolyte balance.

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

Indications	Creatinine clearance, ml / min	Dose of the drug Valacyclovir
Shingles Herpes	15-30	1 g 2 times and days
Shingles Herpes	less than 15	1 g 5 times a day
Treatment of infection caused by HSV (but the scheme of 500 mg 2 times a day)	less than 15	500 mg once a day
	31-49	1 g twice in one day
Treatment of labial herpes (according to the scheme 2 g 2 times during one day)	15-30	500 mg twice daily for one day
	less than 15	500 mg once
ProfilesActs (suppression) of recurrences of infections caused by HSV:
- Patients with normal immunity	less than 15	250 mg once a day
- Patients with reduced immunity	less than 15	500 mg once a day
- reduced risk of transmission of genital herpes	less than 15	250 mg once a day

Patients on hemodialysis are recommended to use valaciclovir at once 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 mode of administration of valaciclovir in patients with impaired renal function should be established in accordance with the table below.

Creatinine clearance, ml / min	Valacyclovir 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
clearer 10 or dialysis *	1.5 g once a day

* In patients on hemodialysis, valaciclovir should be appointed after the end of the hemodialysis session.

HIt is often necessary to determine the clearance of creatinine, especially in periods when the kidney function changes rapidly, for example,immediately after transplantation or engraftment of the graft, with a dose of valaciclovir adjusted according to Pcreatinine clearance.

Patients with impaired hepatic function

In adult patients with impaired liver function of mild or moderate severity with a preserved synthetic function, dose adjustment of the drug Valaciclovir 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 portocaval anastomoses also do not indicate the need to adjust the dose of the drug Valaciclovir, but the clinical experience with this pathology is limited.

Children under the age of 12 years

There is no data on the use of valacyclovir in children.

Elderly patients

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

Side effects:

The frequency of adverse reactions was determined in accordance withe with recommendationsand the World Health Organization: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); rarely (≥1/10000, <1/1000); very rarely (<1/10000), including individual messages; frequency (frequency ire can be calculated by available data there).

Clinical Trials Data

From the nervous system

Often: headache.

From the gastrointestinal tract

Often: nausea.

Post-registration research data

From the blood system and hematopoiesis

Very rarely: thrombocytopenia, leukopenia. In general, leukopenia was observed in patients with reduced immunity.

From the immune system

Very rarely: anaphylaxis.

From the nervous system and the 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 receiving high doses (8 g per day) for the prevention of CMV infection, neurological reactions develop more often than when taking lower doses.

From the respiratory system and the mediastinum

Infrequent: shortness of breath.

From the gastrointestinal tract

Rarely: diarrhea, vomiting, discomfort in the abdomen.

From the liver and biliary tract

Very rarely: reversible abnormalities of functional hepatic samples, which are sometimes regarded as manifestations of hepatitis.

From the skin and subcutaneous fat

Infrequent: rashes, including photosensitivity.

Rarely: itching.

Very rarely: urticaria, angioedema.

From the urinary system

Rarely: impaired renal function.

Very rarely: acute renal failure, renal colic. Renal colic can be associated with impaired renal function. Precipitation of acyclovir crystals in the lumen of the renal tubules. Adequate drinking regimen should be observed during treatment. Hematuria (often associated with other disorders of the kidneys).

Other

In patients with severe impairment of immunity, especially in adult patients with advanced HIV infection receiving high doses of acyclovir (8 g daily) for a long period of time, there were cases of kidney 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 an overdose of acyclovir.

Interaction:

Clinically significant interactions are not established. Acyclovir is excreted by the kidneys, basically, unchanged through active renal secretion. The combined use of drugs with this removal mechanism can lead to an increase in the concentration of acyclovirin the plasma. After the appointment of 1 g valacyclovir, cimetidine and probenecid, which are derived in the same way as valaciclovirincrease AUC acyclovir and thus reduce one hundred of kidney clearance. But, inup of a wide therapeutic index of acyclovir, dose adjustment valaciclovir in this case is not required.

Care should be taken when using valaciclovir at a higher dose (4 grams per day or more) and medications that compete with acyclovir for the route of withdrawal, because there is a potential threat of a rise in plasma concentrations of one or both drugs or their metabolites. An increase was noted AUC acyclovir and inactive metabolite of mycophenolate mofetil, an immunosuppressive drug used in transplantation, while using these drugs.

Care must be taken (monitoring of kidney function) especially in patients with renal dysfunction when using valaciclovir concomitantly with nephrotoxic drugs, including aminoglycosides, organic compounds platinum, iodinated contrast medium, methotrexate, pentamidine, foscarnet, cyclosporin and tacrolimus.

Special instructions:

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

Because the acyclovir is excreted by the kidneys, the dose of the drug Valaciclovir should be adjusted depending on the degree of impaired renal function. 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 mainly elkable reversible after drug discontinuation.

Het data on the use of the drug Valaciclovir in high doses (4 g per day and above) in patients with liver disease, so high doses of the drug Valaciclovir they should be administered with caution. Special studies to study the effect of the drug Valaciclovir when a 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 with valacyclovir reduces the risk of transmission of genital herpes, but does not completely eliminate the risk of infection and does not lead to complete cure. Drug therapy Valaciclovir it is recommended in combination with safe sex.

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

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

Form release / dosage:

Tablets, film-coated, 500 mg, 1000 mg.

Packaging:

By 7, 10, 28, 30 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

By 7, 10, 20, 28, 30, 40, 42, 50, 60 or 100 tablets into cans of polyethylene terephthalate, sealed with caps screwed on with the first opening control or by a "push-turn" system of polypropylene or polyethylene, or in polymer cans polypropylene for medicinal products, sealed with lids tightened with the control of the first opening of polyethylene according to TU 9464-002-95202676-2011.

One bank or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 contour packagings together with instructions for useis placed in a cardboard package (bundle).

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-003188

Date of registration:10.09.2015

Expiration Date:10.09.2020

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Representation: & nbspOZONE LLC OZONE LLC Russia

Information update date: & nbsp14.01.2017

Illustrated instructions

Instructions

Valaciclovir (Valacyclovir)