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

Excipients: microcrystalline cellulose - 95.00 mg; giprolose (hydroxypropyl cellulose) - 14.00 mg; crospovidone - 28.00 mg; magnesium stearate - 7.00 mg;

film sheath: [hypromellose - 10.50 mg, giprolose (hydroxymropylcellulose) - 4.07 mg,talc (4,12 mg, titanium dioxide -2,31 mg) or [dry mixture for film coating - white containing hypromellose (50%), giprolose (hydroxypropyl cellulose) (19.4%), talc (19.6%) , titanium dioxide (11%)] - 21.00 mg.

Description:

Round, biconvex tablets, covered with a film shell of white or almost white color. On the cross section, the nucleus is white or almost white in color.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.B.11 Valaciclovir

J.05.A.B Nucleosides and nucleotides

Pharmacodynamics:

Valaciclovir is a nucleoside inhibitor of DNA polymerase of herpes viruses. It blocks the synthesis of viral DNA and the replication of viruses. In the human body valaciclovir completely turns into acyclovir and L-valine. Acyclovir in vitro has a specific inhibitory activity against herpes simplex virus (HSV) 1, 2 types (Herpes simplex 1, 2 types), varicella zoster virus and herpes zoster (varicella zoster virus (VZB)), 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 in virus-infected cells. 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 glueexact 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 viruses with reduced sensitivity to valacyclovir are extremely rare (less than 0.1%), but can sometimes be found in patients with severe impairment of immunity, for example, with bone marrow transplant, in patients receiving chemotherapy for malignant neoplasms, and in HIV-infected patients.

Resistance is caused by a deficiency of thymidine kinase of the virus, 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 transformed into a acyclovir and L-valine. This transformation is catalyzed by the enzyme of the liver - valaciclovirhydrolase.

After a single dose of 250-2000 mg valacyclovir, the mean maximum concentration (C_mOh) of acyclovir in blood plasma in healthy volunteers with normal kidney function averages 10-37 μmol / l (2,2-8,3 μg / ml), and the average time to reach maximum concentration is 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. FROM_mOhValacyclovir in blood plasma is only 4% of the concentration of acyclovir and is achieved on average 30-100 minutes after taking the drug; 3 hours later_mOhremains the same or decreases. Valaciclovir and acyclovir have similar pharmacokinetic parameters after oral administration.

Distribution

The connection with the proteins valacyclovir - 13-18%, acyclovir - 9-33%. Acyclovir is well distributed in the tissues and body fluids, including the brain, kidneys, lungs, liver, watery moisture, tear fluid, intestines, muscles, spleen, uterus, cca mucous membrane and secret of the vagina, sperm, amniotic fluid, cerebrospinal fluid (50% of the concentration in the plasma), a liquid of herpetic vesicles. The highest concentrations are created in the kidneys, liver and intestines. Penetrates through the placenta and into breast milk.

Excretion

Valacyclovir is excreted by the kidneys, mainly in the form of acyclovir (more than 80% of the dose) and its metabolite 9-carboxymethoxymethylguanine, less than 1% of the drug is unchanged. The half-life (T_1/2) Valaciclovir is less than 30 minutes, acyclovir is 2.5-3.3 hours.

Pharmacokinetics in specific patient groups

In elderly patients (65-83 years) T_1/2Acyclovir is 3.3-3.7 hours, and in patients with terminal stage of renal failure - approximately 14 hours.

The pharmacokinetics of valaciclovir and acyclovir are largely unaffected in patients infected with HSV and BWV viruses.

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

In recipients of organ transplants with valacyclovir in a dose of 2000 mg 4 times a day C_mOhacyclovir is equal to or greater than that of healthy volunteers who received the same dose of the drug, and the daily area indices under the "concentration-time" curve (AUC) were significantly higher.

In late pregnancy, a steady daily rate AUC after taking 1000 mg of valaciclovir was more than approximately 2 times that of acyclovir at a dose of 1200 mg per day.

Indications:

Adults:

- treatment of herpes zoster (Herpes zoster) (the drug contributes to the relief of pain syndrome, reduces its duration and the percentage of patients with pain due to herpes zoster, including acute and postherpetic neuralgia);

- treatment of infections of the skin and mucous membranes caused by the virus Herpes simplex Type 1,2, including the newly diagnosed 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 the virus Herpes simplex Type 1,2, including genital herpes;

- prevention of transmission of the genital herpes virus to a healthy partner when using the drug as a suppressive therapy in combination with safe sex.

Adults and children 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 other component included in the preparation;

- HIV infection with a CD4 + lymphocyte content of less than 100 in 1 μl;

- Children's age (up to 12 years in the prevention of cytomegalovirus infection after transplantation, up to 18 years - for the rest of the indications).

Carefully:

- Hepatic and / or renal insufficiency;

- elderly age;

- hypohydration;

- simultaneous use of nephrotoxic drugs;

- Pregnancy;

- the period of breastfeeding;

- clinically expressed forms of HIV infection.

Pregnancy and lactation:

Pregnancy

There are limited data on the use of valacyclovir in pregnancy. Valaciclovir apply only in cases where the potential benefit to the mother exceeds the possible risk to the fetus.

Registered data on the outcome of pregnancy in women who took valaciclovir or acyclovir (active metabolite of valacyclovir) did not show an increase in the number of birth defects in children compared to the general population. Because the register includes a small number of women who valaciclovir when pregnancy, it is impossible to make reliable and definite conclusions about the safety of valaciclovir during pregnancy.

Breastfeeding period

Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After taking valaciclovir inside at a dose of 500 mg 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 a mother valacyclovir is taken inside at a dose of 500 mg 2 times a day, the child will undergo the same effect of acyclovir as when taking acyclovir orally at a dose of about 0.61 mg / kg / day. T_1/2from breast milk is the same as from blood plasma. The drug Valcicon ® should be administered with caution to lactating women.

Dosing and Administration:

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

Treatment of herpes zoster (Herpes zoster)

Adults:

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

Treatment of infections caused by HSV (Herpes simplex)

Adults:

The recommended dose for therapy of the episode is 500 mg twice a day for 5 days.

In more severe cases of debility of the disease, 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, valacyclovir is effectively administered at a dose of 2 g 2 times a 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 is 1 day.Therapy should be started with the earliest symptoms of labial herpes: tingling, itching and / or burning.

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 twice a day.

Prophylaxis of transmission of genital herpes to a healthy partner

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, daily.

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 reduced depending on the creatinine clearance (CK). 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:

- treatment of herpes zoster and infections caused by HSV, prevention (suppression) of recurrences of infection caused by HSV, 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 dosing regimen in Table 1). Such patients need to maintain adequate hydration.

The experience of valaciclovir in children with CC values less than 50 ml / min / 1.73 m²no.

Table 1

Indications	CK, ml / min	Valacyclovir dose
Shingles Herpes (Herpes zoster)	15-30	1 g 2 times a day
	less than 15	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 a day for one day)	31-49	1 g twice within 24 hours
	15-30	500 mg twice daily
	less than 15	500 mg once
Prevention (suppression) of recurrences of infections caused by HSV: - Patients with normal immunity - Patients with reduced immunity - reduced risk of transmission of genital herpes
	less than 15	250 mg once a day
	less than 15	500 mg once a day
	less than 15	250 mg once a day

Patients on hemodialysis are recommended to use valaciclovir immediately after the end of the hemodialysis session at the same dose as patients with QC 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 installed in accordance with Table 2.

table 2

CK, 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 daily
less than 10 or hemodialysis *	1.5 g once a day

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

It is often necessary to determine QC, especially during a period when the kidney function changes rapidly, for example, immediately after transplantation or engraftment of the graft, with a dose of valaciclovir adjusted according to QC values.

Patients with impaired hepatic function

In adult patients with a mild and moderate liver function disorder with a conservative synthetic dose correction function, valacyclovir 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 portocaval anastomoses also do not indicate the need to adjust the dose of valacyclovir, but the clinical experience for this pathology is limited.

Children under the age of 12 years

There is no data on the use of Valcicon® in children.

Elderly patients

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

Side effects:

Classification of the incidence of adverse events according to recommendations World Health Organization (WHO):

very often> 1/10;

often from> 1/100 to <1/10;

infrequently from> 1/1000 to <1/100;

rarely from> 1/10000 to <1/1000;

very rarely <1/10000, including individual messages;

the frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

From the hematopoiesis:

very rarely - leukopenia (mainly observed in patients with reduced immunity), thrombocytopenia.

Allergic reactions:

very rarely - anaphylaxis, rash.

From the nervous system:

often - headache;

rarely - dizziness, confusion, hallucinations, depression of consciousness, decreased mental abilities;

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 grams per day) of valaciclovir for the prevention of CMV infection, neurologic reactions develop more often than with lower doses.

From the respiratory system:

infrequently - shortness of breath;

frequency unknown - nasopharyngitis, respiratory tract infection.

From the digestive system:

often - nausea;

rarely - discomfort in the abdomen, vomiting, diarrhea, abdominal pain.

From the liver and bile ducts:

very rarely - increased activity of "liver" enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (AFP)), hepatitis.

From the skin:

infrequent - rashes, including manifestations of photo sensitivity; rarely - itching;

very rarely - hives, angioedema.

From the urinary system:

rarely - renal dysfunction;

very rarely - renal colic (may be associated with impaired renal function), acute renal failure;

the frequency is unknown - hematuria (often associated with other disorders on the part of the kidneys).

Cases of precipitation of acyclovir crystals in the lumen of renal tubules have been reported. It is necessary to observe the drinking regime during the treatment.

Co cardiovascular system:

frequency unknown - hypertension, tachycardia.

Other:

chaStomata is unknown - edema of the face, dysmenorrhea, fatigue.

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

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 coma; nausea and vomiting are also noted.

To prevent an overdose, use caution when application of the drug. Many cases of overdose were 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 (who received a dose of valaciclovir exceeding the recommended dose).

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:

Nephrotoxic drugs increase the risk of kidney dysfunction. The simultaneous use of valaciclovir with nephrotoxic drugs, including aminoglycosides, organic compounds of platinum, 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 renal function.

Acyclovir is excreted by the kidneys, mostly unchanged, through active renal secretion. Joint 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 Valcicon® in a dose of 1000 mg, cimetidine and probenecid, which are derived in the same way as valaciclovir, increase the value AUC acyclovir and thatthus reducing its kidney clearance. In view of the wide therapeutic index of acyclovir, the dose adjustment of Valcicon^®in this case is not required.

Caution should be exercised in case of simultaneous use of valaciclovir in higher doses (4 g per day and above) and drugs that compete with acyclovir for elimination, as there is a potential threat of a rise in plasma levels of one or both drugs or their metabolites. An increase in AUC acyclovir and an inactive metabolite of mycophenolate mofetil with simultaneous application of these drugs.

Special instructions:

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

Because the acyclovir is excreted by the kidneys, the dose of Valcicon ® should be adjusted depending on the degree of renal function impairment. 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 reversible and disappear after the drug is discontinued.

In patients with chronic renal insufficiency, it is recommended to frequently determine QC, especially during a period when the kidney function changes rapidly (in particular, immediately after transplantation or engraftment of a transplant), while the valaciclovir dose is adjusted in accordance with QC values.

There are no data on the use of valacyclovir in high doses (4 g per day or more) in patients with liver disease, so high doses of Valcicon® should be given to such patients with caution.

Special studies to study the effects of valaciclovir in liver transplant were 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 exclude the risk of infection and does not lead to complete cure. Therapy with Valcicon ® is recommended in combination with safe sex.

The use of valaciclovir in high doses for a long time under conditions accompanied by severe immunodeficiency (bone marrow transplantation, clinically expressed forms of HIV infection, kidney transplantation) led to the development of thrombocytopenic purpura and hemolytic-uremic syndrome, up to a lethal outcome.

When there are side effects from the central nervous system (including agitation, hallucinations, confusion, delirium, seizures and encephalopathy), the drug is canceled.

Cases of acute renal failure were recorded:

- in elderly patients with or without kidney function (caution should be exercised when using valacyclovir in elderly patients, and a dose reduction in patients with impaired renal function is recommended);

- in patients with concomitant renal disease who received high doses of valaciclovir (a dose reduction of valacyclovir to patients with renal insufficiency is recommended);

- in patients taking other nephrotoxic drugs (caution should be exercised while using valaciclovir and nephrotoxic drugs);

- in patients without adequate hydration.

Adequate hydration should be maintained for all patients.

In the case of acute renal failure and anuria, it is possible to use hemodialysis, 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:

There is no evidence of the effect of valaciclovir, used in therapeutic doses, on the ability to drive vehicles and mechanisms. However, when assessing the ability of a patient to drive a car or moving machinery it should be taken into account that there may be side effects from the central nervous system, so you should be careful.

Form release / dosage:

Tablets, film-coated, 500 mg.

Packaging:

5, 10 or 14 tablets in a contour cell box made of a polyvinylchloride film and aluminum foil.

42, 50 or 60 tablets in a can of high-density polyethylene.

2 or 4 contourcell packs of 5 tablets, 1, 2, 3, 4, 5 or 6 contiguous cell packs of 10 tablets, 3 contour packs of 14 tablets, or odeson the bank together with instructions for use 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 expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002186

Date of registration:20.08.2013 / 31.08.2015

Expiration Date:20.08.2018

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia

Information update date: & nbsp03.02.2017

Illustrated instructions

Instructions

Valcicon® (Valcycon)