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

Excipients: cellulose microcrystalline - 84.3 mg, hypromellose - 42.0 mg, crospovidone - 7.0 mg, magnesium stearate - 7.0 mg, silicon dioxide colloid - 3.5 mg.

Composition of the tablet shell:

Opaprai II white (33G28435) - 25.0 mg (hypromellose 40.0%, titanium dioxide 25.0%, macrogol 3350 8.0%, lactose monohydrate 21.0%, triacetin 6.0%).

Description:

The tablets are oval, biconvex, covered with a film shell of white color with a risk on one side and engraving "fOn the other side, the core is white or almost white in cross section.

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 almost completely turns into acyclovir and L-valine is presumably influenced by the enzyme valacyclovirhydrolase.

Acyclovir in vitro has a specific inhibitory activity against herpes simplex virus (HSV) 1, 2 types (Herpes simplex 1, 2 types), the virus of chickenpox and herpes zoster (VZV - varicella-zoster virus, Varicella zoster virus), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpesvirus type 6. Acyclovir inhibits the synthesis of viral DNA immediately after phosphorylation and conversion into an active form of acyclovir triphosphate.

The first stage of phosphorylation occurs with the participation of virus-specific enzymes. For viruses of HSV, VZV and VEB, this enzyme is viral thymidine kinase, which is present only 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 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. Acyclovirrythophosphate competitively inhibits viral DNA polymerase and, being an analogue of a nucleoside, is inserted into 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 viruses with reduced sensitivity to valacyclovir are extremely rare, but can sometimes be found in patients with severe impairment of immunity, for example, with a bone marrow transplant,who are receiving chemotherapy for malignant neoplasms and for HIV-infected people.

Resistance to acyclovir is 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 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 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% and does not depend on the intake of food. 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.

Pharmacokinetic parameters (FKP) of acyclovir after a single intake of 250-2000 mg Valacyclovir by healthy volunteers with normal function of night are given in 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 kg / 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_maxand AUC are given as mean values ± standard deviation, values for T_maxare presented as mean values and range of values.

FROM_max Valacyclovir in blood plasma is 4% of the concentration of acyclovir and is achieved at average after 30-100 minutes after taking the drug; in 3 hours C_maxremains the same or decreases. Valaciclovir and acyclovir have analoguespenniese 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 in blood plasma, does not depend on kidney function and is about 25% for acyclovir and metabolite 8-hydroxyacyclovir (8-OH-ACV),and about 2.5% for the metabolite 9- (carboxymethoxy) methylguanine (CMMD).

Metabolism

After oral administration valaciclovir turns into 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 into 8-hydroxyacyclovir with the participation of aldehyde oxidase. Approximately 88% of the total combined effect of blood plasma is due to acyclovir, 11% KMMG and 1% 8-OH-ACV. Neither valaciclovir, nor acyclovir are not metabolized by isoenzymes of the cytochrome P450 system.

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-ACV is detected in urine only in small amounts (less than 2% of the dose). Less than 1% of the accepted dose of valaciclovir is excreted through the kidneys 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 CMMG and 8-OH-ACV 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) , who received 2000 mg every 6 hours and 3 patients 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 function kidney in the blood plasma, also ka to and in the cerebrospinal fluid, the concentration of acyclovir, CMMH and 8-OH-ATSB 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.

Indications:

Adults and adolescents aged 12 to 18 years

- Treatment of infections of the skin and mucous membranes caused by TIG, including the first time Revealed 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, including 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.

Contraindications:

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

- HIV infection with content Cd4+ lymphocytes less than 100 in 1 μl;

- Children up to 12 years;

- Children under 18 years of age in the treatment of herpes zoster and ophthalmic herpes zoster.

Carefully:

Renal failure, elderly age, patients at risk of dehydration, simultaneous use of nephrotoxic drugs, pregnancy, lactation, clinically expressed forms of HIV infection in patients.

Pregnancy and lactation:

Pregnancy

There are limited data on the use of valaciclovir and small data on the use of acyclovir (an active metabolite of valacyclovir) in pregnancy in women. Registered data on the outcome of pregnancy in women who took valaciclovir or acyclovir, did not show an increase in the number of birth defects in their children compared to the general population. Valaciclovir apply only in cases where the potential benefit to the mother exceeds the possible risk to the fetus.

Breastfeeding period

Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After administration of valaciclovir in a dose of 500 mg inside C_mOh Acyclovir 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 twice a day, the child is exposed to the same effects of acyclovir as if ingested 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 determined in the blood plasma of the mother, thoracic milk or urine of the child.

A drug Valaciclovir should be administered with caution to women during breastfeeding.

Dosing and Administration:

Inside, regardless of food intake, washing down with water.

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

Immunocompetent adults and adolescents aged 12 to 18 years

The recommended dose is 500 mg 2 times a 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. In cases of recurrence of HSV, valaciclovir administration in the prodromal period or immediately after the appearance of the first symptoms of the disease is considered to be the most correct. The use of valaciclovir can prevent the development of the lesion if it is used at the first signs and symptoms of a relapse caused by HSV.

As an alternative treatment for labial herpes, valacyclovir is effectively administered at a dose of 2000 mg 2 times a 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 such a dosing regimen, the duration of treatment should not exceed 1 day, as exceeding 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, including in adults with immunodeficiency

Immunocompetent adults and adolescents aged 12 to 18 years

In immunocompetent patients, the recommended dose is 500 mg once a day. After 6-12 months of treatment, it is necessary to evaluate the effectiveness of therapy.

Adults with immunodeficiency

In adults with immunodeficiency, the recommended dose is 500 mg twice a 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 Herpes

Adults

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

Special patient groups

Patients with impaired renal function

Valaciclovir dose is recommended to be reduced in patients with marked renal dysfunction (see dosing regimen in Table 2). Such patients need to maintain an adequate water-electrolyte balance.

Valacyclovir should be used after hemodialysis in patients undergoing periodic hemodialysis.

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

Experience with valaciclovir in children with creatinine clearance values less than 50 ml / min / 1.73 m² absent.

Table 2. Correction of the dose of the drug Valaciclovir for use in adults and adolescents aged 12 to 18 years with impaired renal function

Indications	Creatinine clearance, ml / min	Dose of the drug Valacyclovir
Herpes zoster and ophthalmic herpes zoster in immunocompetent adults (treatment)	not less than 50	1000 mg 3 times a day
	from 30 to 49	1000 mg twice a day
	from 10 to 29	1000 mg once a day
	less than 10	500 mg once a day
HSV (treatment)
Immunocompetent adults and adolescents aged 12 to 18 years	not less than 30	500 mg twice a day
	less than 30	500 mg 1 time per day
Labial herpes in immunocompetent adults and adolescents aged 12 to 18 years (treatment)	not less than 50	2000 mg twice daily
	from 30 to 49	1000 mg twice a day
	from 10 to 29	500 mg twice a day
	less than 10	500 mg once a day
HSV (prevention (suppression))
Immunocompetent adults and adolescents aged 12 to 18 years	not less than 30	500 mg 1 time per day
Immunocompetent adults and adolescents aged 12 to 18 years	less than 30	500 mg once every two days
Adults with immunodeficiency	not less than 30	500 mg twice a day
	less than 30	500 mg once a day
Prevention of infections caused by CMV, in adults and adolescents in ages 12 to 18 years	not less than 75	2000 mg 4 times a day
	from 50 to 75	1500 mg 4 times a day
	from 25 to 50	1500 mg 3 times a day
	from 10 to 25	1500 mg twice a day
	less than 10 or in patients on hemodialysis	1500 mg once a day

Patients with impaired hepatic function

According to available data on the use of a single dose of acyclovir, 1000 mg, in adult patients with hepatic cirrhosis of mild and moderate severity (with preserved synthetic function of the liver) correction of the dose of the drug Valaciclovir not required.

Pharmacokinetic data in adult patients with severe degree of liver dysfunction (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 dose of the drug Valaciclovir, but the clinical experience with these pathologies is limited.

Children under the age of 12 years

There is no data on the use of valacyclovir in children under 12 years of age.

Elderly patients

It is necessary to take into account the possible violation of kidney function in elderly patients, the dose of the drug Valaciclovir should be adjusted accordingly (see para.Table 2). It is necessary to maintain an adequate water-electrolyte balance.

Side effects:

Categories of incidence of side effects: very often (≥1 / 10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10000 up to <1/1000), very rarely (<1/10000).

From the gastrointestinal tract: often - nausea; rarely - discomfort in the abdomen, vomiting, diarrhea.

On the part of the blood system and hemopoiesis: very rarely - leukopenia (mainly observed in patients with reduced immunity), thrombocytopenia.

From the immune system: rarely anaphylaxis.

From the nervous system and psyche: often - a headache: rarely - dizziness, confusion, hallucinations, depression of consciousness; very rarely - tremor, agitation, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma. The symptoms listed above are mostly reversible and are usually observed in patients with renal insufficiency or other predisposing conditions.

In patients with a transplanted organ receiving valaciclovir in high doses (8 g/ day) for the prevention of CMV infection, neurological reactions develop more often than when taken in lower doses.

From the respiratory system: infrequently - shortness of breath.

From the side of the pension and biliary tract: very rarely - reversible violations of functional liver tests, which are sometimes regarded as a manifestation of hepatitis.

From the skin and subcutaneous fat: infrequent - rashes, including photosensitivity manifestations; rarely - itching; very rarely - hives, angioneurotic edema.

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

There was also a precipitation of acyclovir crystals in the lumen of the renal tubules. During treatment, adequate drinking regimen should be observed.

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

Overdose:

Symptoms

In case of an overdose of valacyclovir, acute renal failure may occur and the development of neurological symptoms, including confusion, hallucinations, agitation, oppression of consciousness and to whom, nausea and vomiting are also noted. To prevent an overdose, follow the dosing regimen. Many cases of overdose have been associated with the use of the drug to treat patients with impaired renal function and elderly patients due to non-compliance with the dosing regimen (re-received doses of valaciclovir exceeding recommended ones).

Treatment

Patients should be closely monitored for the timely diagnosis of toxic manifestations. Hemodialysis significantly accelerates the excretion of acyclovir from the blood plasma and can be considered the optimal method of treatment in case of an overdose.

Interaction:

Clinically significant interactions are not established.

Acyclovir is excreted by the kidneys, mostly unchanged, 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 prescribing the drug Valaciclovir in a dose of 1000 mg cimetidine and probenecid, which are derived in the same way as valaciclovirincrease AUC acyclovir and thus reduce its kidney clearance. However, in view of the wide therapeutic index of acyclovir, the dose adjustment of the drug Valaciclovir in this case is not required.

Care must be taken in case of simultaneous use of the drug Valaciclovir in higher doses (4000 mg per day and above) and are medicinalx drugs that 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. An increase was noted AUC acyclovir and an inactive metabolite of mycophenolate mofetil (an immunosuppressant used after organ transplantation) with simultaneous administration of these drugs.

The simultaneous use of valaciclovir with nephrotoxic drugs, including aminoglycosides, organic compounds of platinum, iodinated contrast medium, methotrexate, pentamidine, foscarnet, cyclosporin and tacrolimus should be carried out with caution,especially in patients with impaired renal function, and requires regular monitoring of kidney function.

Special instructions:

Hydration

In patients at risk of dehydration, especially in elderly patients, in the period of treatment is necessary to ensure adequate fluid replacement.

Use in patients with renal insufficiency and in elderly patients

Because the acyclovir is excreted by the kidneys, the dose of the drug Valaciclovir should be reduced depending on the degree of impaired renal function. In patients with renal insufficiency and in elderly patients have an increased risk of neurological complications, these patients must be thoroughly monitored. As a rule, these reactions are mostly reversible.

The use of doses of valaciclovir in cases of impaired liver function and after liver transplantation

No data on the use of valacyclovir in high doses (4000 mg per day and above) in patients with liver disease, such patients however high dose Valaciclovir should be administered with caution. Special studies to study the effects of valaciclovir in liver transplantation have not been conducted.However, it was found that the prophylactic administration of acyclovir in high doses reduces the manifestation of CMV infection and disease.

Use in genital herpes

Patients should refrain from having sex if symptoms occur, even if antiviral treatment is started. Suppressive therapy with valacyclovir reduces the risk of transmission of genital herpes, but does not exclude the risk of infection and does not lead to complete cure. Drug therapy Valaciclovir it is recommended in combination with reliable means of barrier contraception.

Application for CMV infections

The use of valaciclovir in high doses for the prevention of CMV infection leads to more frequent occurrence of side effects, including CNS disorders, than when used in lower doses for other indications. It is necessary to closely monitor the indicators of kidney function in such patients with the correction of the dose of the drug, if necessary.

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

There is no evidence of the effect of valaciclovir, used in therapeutic doses, on the ability to drive vehicles and mechanisms. However, when assessment of a patient's ability to drive or move vehicles It is necessary to take into account that there may be side effects from central nervous system, so you should be careful.

Form release / dosage:

Tablets, film-coated, 500 mg.

Packaging:

For 10 tablets in a contoured cell pack of PVC film and aluminum foil printed lacquered.

For 1, 2, 3, 4, 5 or 6 contour squares, together with the instruction for medical use, is placed in a pack of cardboard box.

Storage conditions:

In the 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.

Terms of leave from pharmacies:On prescription

Registration number:LP-003220

Date of registration:23.09.2015

Expiration Date:23.09.2020

The owner of the registration certificate:IZVARINO PHARMA, LLC IZVARINO PHARMA, LLC Russia

Manufacturer: & nbsp

IZVARINO PHARMA, LLC Russia

Information update date: & nbsp14.01.2017

Illustrated instructions

Instructions

Valaciclovir (Valacyclovir)