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

Excipients: corn starch 56.8 mg, silicon dioxide colloid 2 mg, croscarmellose sodium 29 mg, magnesium stearate 4 mg, cellulose microcrystalline 72 mg;

film coating: Opadrai II white 22 mg, including: polyvinyl alcohol 10.32 mg, macrogol (polyethylene glycol) 5.19 mg, talc 3.83 mg, titanium dioxide 2.66 mg.

Description:

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

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.B.11 Valaciclovir

J.05.A.B Nucleosides and nucleotides

Pharmacodynamics:

In the human body valaciclovir quickly and completely turns into acyclovir under the influence of the enzyme valacyclovirhydrolase. Acyclovir possesses in vitro specific viral inhibitory activity: herpes simplex virus type 1 and type 2 virus, varicella zoster virus, varicella zoster virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes virus a man of the 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 requires the activity of a virus specific enzymes. For HSV, VZV, VEB, this enzyme is viral thymidine kinase, which is present in the cells infected by the virus.Partial selectivity of phosphorylation persists in the cytomegalovirus and is mediated through the product phosphotransferase gene UL 97. Activation of acyclovir with a specific viral enzyme to a great extent explains its selectivity.

The process of phosphorylation of acyclovir (conversion from mono- to triphosphate) is completed by cellular kinases. Acyclovir the nucleoside triphosphate is inserted into the viral DNA, which leads to an obligate rupture of the chain, the cessation of DNA synthesis and, consequently, to the blocking of viral replication.

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

Resistance is usually due to a deficiency of thymidine kinase, which leads to excessive spread of the virus in the host organism. Sometimes a decrease in sensitivity to acyclovir is due to the appearance of strains of the virus with a violation of the structure of viral thymidine kinase or DNA polymerase.The virulence of these varieties of the virus resembles that of its wild strain.

Pharmacokinetics:

General information

After oral administration valaciclovir well absorbed from the gastrointestinal tract. With the participation of the liver enzyme valaciclovirhydrolase quickly and almost completely turns into acyclovir and valine. After a single dose of valacyclovir in a dose of 250-2000 mg, the average maximum concentration of acyclovir in plasma in healthy volunteers with normal renal function is 10-37 μmol (2.2 - 8.3 μg / ml), and the median time to achieve this 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. The maximum concentration of valacyclovir in plasma is only 4% of the concentration of acyclovir, the average time to reach maximum concentration is 30-100 minutes after taking the dose, the limit of quantitative determination of valacyclovir in plasma is reached after 3 hours or earlier. Valaciclovir and acyclovir have similar pharmacokinetic parameters after oral administration.

Distribution

The degree of binding of valacyclovir to plasma proteins is very low (only 15%).

Excretion

In patients with normal renal function, the half-life of acyclovir from the plasma after taking valacyclovir is about 3 hours. Valaciclovir is excreted from the body with urine mainly in the form of acyclovir (more than 80% of the dose) and the metabolite of acyclovir

9-carboxymethoxymethylguanine, in an unchanged form is eliminated less than 1 % of the preparation.

Special patient groups

In patients with the final stage of renal failure, the average half-life is about 14 hours.

Characteristics of patients

The pharmacokinetics of valaciclovir and acyclovir are largely unaffected in patients infected with HSV and BWV viruses. In late pregnancy, a stable daily indicator "area under the concentration-time curve" (AUC) after taking 1000 mg Valaciclovir was more approximately 2 times than that with acyclovir at a dose of 1200 mg per day.

The use of valacyclovir in a dose of 1000 mg or 2000 mg does not disrupt the disposition and pharmacokinetic parameters of valacyclovir in HIV-infected patients compared to healthy individuals.

In transplant recipients of organs receiving valaciclovir in a dose of 2000 mg 4 times a day, the peak concentration of acyclovir is equal to or greater than that of healthy volunteers receiving the same dose of the drug, and the daily values AUC they are much higher.

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 caused by herpes zoster, including acute and postherpetic neuralgia).

- Treatment of infections of the skin and mucous membranes caused by the herpes simplex virus (HSV), including 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 HSV, including genital herpes. Prophylaxis of transmission of genital herpes to a healthy partner when taken as a suppressive therapy in conjunction with safe sex.

Adults and adolescents aged 12 years and over

- Prevention of cytomegalovirus (CMV) infection, as well as reactions of acute graft rejection (in patients with kidney transplants).

- Prevention of opportunistic infections and other herpesvirus infections (HSV, VZV) after organ transplantation.

Contraindications:

· Hypersensitivity to valaciclovir, acyclovir and any auxiliary component included in the preparation.

· Clinically expressed forms of HIV infection with Cd4+ lymphocytes less than 100 / μl.

· Children's age (up to 12 years with the goal of preventing cytomegalovirus infection, up to 18 years - for the rest of the indications).

Carefully:

- renal and hepatic impairment;

- elderly age;

- hypohydration;

- simultaneous administration of nephrotoxic drugs;

- pregnancy and the period of breastfeeding.

Pregnancy and lactation:

Pregnancy

Data on the use of valacyclovir in pregnancy is not enough. Valaciclovir The canon should be used during pregnancy only if the expected effect of therapy for the substance exceeds the potential risk to the fetus.

Data of registration records on the outcome of pregnancy in women who took valaciclovir, did not show 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, excreted with breast milk. After administration of valaciclovir in a dose of 500 mg, the maximum concentration of acyclovir (C_m_Oh) in breast milk was 0.5-2.3 times (1.4 times on average) than the corresponding concentrations of acyclovir in the mother's plasma. Attitude AUC acyclovir, which is in breast milk, to AUC Acyclovir maternal plasma ranged from 1.4 to 2.6 (mean 2.2). The average concentration of acyclovir in breast milk was 2.24 μg / ml (9.95 μmol / L). When taking materio valaciclovir in a dose of 500 mg 2 times a day, the child will undergo the same effect of acyclovir as when taking it inside at a dose of about 0.61 mg / kg / day. The half-time of elimination of acyclovir from breast milk is the same as from plasma of blood. Valaciclovir in unmodified form was not determined in the plasma of the mother, breast milk or urine of the child.

During the period of breastfeeding, use only if the intended benefit to the mother exceeds the potential risk to the child.

Dosing and Administration:

Inside, regardless of food intake, the tablets should be washed down with water.

Treatment of herpes zoster

Adults: 1000 mg 3 times a day for 7 days.

Treatment of infections caused by HSV

Adults: 500 mg twice a day for 5 days.

In more severe primary cases, treatment should be started as early as possible, and its duration should be increased from 5 to 10 days. In the case of relapses treatment should last 3 or 5 days, ideal is the appointment of valaciclovir in the prodromal period or immediately after the appearance of the first symptoms of the disease.

As an alternative for the treatment of labial herpes, valacyclovir is effectively administered at a dose of 2000 mg twice daily. The second dose should be taken after approximately 12 hours (but not earlier than 6 hours) after taking the first dose. When using this dosing regimen, the duration of treatment should not exceed 1 day, as this has not been shown to provide additional clinical benefits. Therapy should be started when the earliest symptoms of labial herpes (ie tingling, itching, burning) occur.

Prevention (suppression) of recurrences of infections caused by HSV

Adults: in patients with preserved immunity valaciclovir is prescribed in a dose of 500 mg once a day.

In patients with very frequent relapses (10 or more per year), an additional effect can be achieved with the appointment of valacyclovir in a daily dose of 500 mg divided into 2 divided doses (250 mg twice a day).

For adult patients with immunodeficiency, the recommended dose of valacyclovir is 500 mg 2 times a day.

Duration of treatment 4-12 months.

Prevention of infection with genital herpes healthy partner

Infected adults with preserved immunity and with number of exacerbations up to 9 per year valaciclovir should be taken at 500 mg once a day for a year or more, every day with regular sexual activity, with irregular sexual intercourse, valaciclovir should be taken 3 days before the alleged sexual contact.

Data on the prevention of patients in other populations does not exist.

Prevention of CMV infection after transplantation

Adults and adolescents aged 12 years and over: 2000 mg 4 times a day 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 at high risk, treatment may be longer.

Special patient groups

Patients with impaired renal function

Treatment of herpes zoster and infections caused by BPG, prevention (suppression) and reduction in infection of a healthy partner.

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

Therapeutic readings	Clearance creatinine, ml / min	Valacyclovir dose
Shingles Herpes	15-30 less than 15	1000 mg twice a day 1000 mg once a day
Herpes simplex (treatment)	less than 15	500 mg once a day
Labial herpes (treatment) (2000 mg in 2 divided doses for 1 day)	31-49 15-30 less than 15	1000 mg twice for 1 day 500 mg twice for 1 day 500 mg once
Herpes simplex prevention (suppression): - Patients with preserved immunity - patients with reduced immunity	less than 15 less than 15	250 mg once a day 500 mg once a day
Reduced infection with genital herpes	less than 15	250 mg once a day

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

Prevention of CMV infections after transplantation

Mode of administration of the drug Valacyclovir Canon in patients with impaired renal function should be established in accordance with the table below.

Creatinine clearance, ml / min

The dose of valaciclovir

75 and more

from 50 to 74 inclusive

from 25 to 49 inclusive

from 10 to 24 inclusive

less than 10 or dialysis

2000 mg 4 times a day

1500 mg 4 times a day

1500 mg 3 times a day

1500 mg twice a day

1500 m g once a day

In patients on hemodialysis, the preparation of Valaciclovir canon should be prescribed after the end of the hemodialysis session.

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

Patients with impaired hepatic function

In patients with mild to moderate liver cirrhosis (the synthetic function of the liver is preserved), the adjustment of the dose of Valacyclovir Kanon is not required. Pharmacokinetic data in patients with severe hepatic cirrhosis (with a violation of the syntheticliver function and the presence of shunts between the portal system and the common vascular bed) also do not indicate the need to adjust the dose of the drug, however, the experience of its clinical use in 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:

Undesirable reactions are listed below in accordance with the classification of the main systems and organs and the frequency of occurrence.

Classification of WHO frequency of development of side effects:

very often ≥1 / 10 appointments (> 10%)

often from ≥1 / 100 to <1/10 of prescriptions (> 1% and <10%)

infrequently from ≥1 / 1000 to <1/100 of prescriptions (> 0.1% and <1%)

rarely from ≥1 / 10000 to <1/1000 assignments (> 0.01% and <0.1%)

very rarely <1/10000 prescriptions (<0.01%)

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

Infectious and parasitic diseases

Frequency unknown: respiratory tract infection.

Violations of the blood and lymphatic system

Very rarely: leukopenia, thrombocytopenia. Most of the leukopenia was

was noted in patients with reduced immunity.

The frequency is unknown: neutropenia, aplastic anemia, leukoplastic vasculitis, thrombocytopenic purpura.

Immune system disorders

Very rarely: anaphylaxis.

Disorders of the psyche

Uncommon: agitation, including aggressive behavior.

Rarely: hallucinations.

Very rarely: psychotic symptoms, including mania, depression.

Disorders from the nervous system and the psyche

Rarely: dizziness, confusion, decreased mental

abilities, oppression of consciousness.

Rarely:excitation, tremor, ataxia, dysarthria, convulsions,encephalopathy, coma.

Disturbances on the part of the organ of sight

Frequency unknown: impaired vision.

Hearing disorders and labyrinthine disorders

The frequency is unknown: nasopharyngitis, rhinorrhea.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequent: shortness of breath.

Heart Disease

The frequency is unknown: tachycardia.

Vascular disorders

Frequency unknown: increased blood pressure.

Disorders from the gastrointestinal tract

Often: nausea.

Rarely: abdominal discomfort, vomiting, diarrhea.

Disturbances from the liver and bile ducts

Very rare: reversible disturbances of liver function tests, which are sometimes regarded as manifestations of hepatitis.

Disturbances from the skin and subcutaneous tissues

Infrequent: rashes, including photosensitivity.

Rarely: itching.

Very rarely: urticaria, angioedema.

The frequency is unknown: erythema multiforme.

Disturbances from musculoskeletal and connective tissue

Frequency unknown: arthralgia.

Disorders from the kidneys and urinary tract

Rarely: impaired renal function.

Very rarely, acute renal failure, renal colic (may be associated with impaired renal function).

Frequency unknown: acyclovir precipitation of crystals in the lumen of the renal tubules (observe adequate drinking regimen during treatment), haematuria (often associated with other disorders of the kidney).

Violations of the genitals and mammary gland The frequency is unknown: dysmenorrhea.

Laboratory and instrumental data

Very rarely: a reversible increase in functional liver tests, an increase in the concentration of bilirubin.

The frequency is not known: a decrease in hemoglobin, hypercreatininaemia.

General disorders and disorders at the site of administration

The frequency is not known: fatigue, fever (in children), dehydration.

Other

In patients with severe impairment of immunity, especially in patients with advanced AIDS, receiving high doses of valaciclovir (8000 mg daily) for a long period of time, there have been cases of renal failure, microangiopathic hemolytic anemia, and thrombocytopenia (sometimes in combination). Similar complications were observed in patients with the same diseases, but not receiving valaciclovir.

Overdose:

Symptoms and signs: acute renal failure and neurological disorders, including confusion, hallucinations, agitation, depression 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 in elderly patients who received repeated, exceeding recommended doses of valaciclovir, due to non-compliance with the dosing regimen.

Treatment: patients should be carefully monitored to identify signs of toxic effects. Hemodialysis significantly enhances the removal of acyclovir from the blood and can be considered a method of choice in managing patients with an overdose of valaciclovir.

Interaction:Clinically significant interactions are not established. Acyclovir is excreted by the kidneys mostly unchanged, actively secreted into the renal tubule. After the appointment of 1000 mg valacyclovir, cimetidine and probenecid, blocking tubular secretion, increase AUC acyclovir and reduce its renal clearance. However, this dose of valaciclovir does not require any correction due to the wide therapeutic index of acyclovir. Care should be taken when using valaciclovir at a higher dose (4000 mg per day or more) and medications that compete with acyclovir for the elimination pathway, 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 an inactive metabolite of mycopheolate mofetil, an immunosuppressive drug used in transplantation, while simultaneously using these drugs.Care should also be taken (monitoring kidney function) with simultaneous use of valaciclovir, particularly in patients with impaired renal function or when taking higher doses (4000 mg per day or more), as well as in combination with nephrotoxic drugs including aminoglyclazides, organic compounds of platinum, iodinated contrast medium, methotrexate, pentamidium, foscarnet, cyclosporin and tacrolimus.

Special instructions:

The use of the drug 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, delusions, seizures and encephalopathy), the drug is canceled. Patients with a risk of dehydration, especially elderly patients, during treatment with valaciclovir, must ensure adequate hydration of the body.

Patients with renal insufficiency have an increased risk of developing neurological complications. When violations of liver function in patients with mild to moderate liver cirrhosis, dose adjustment is not required.

There is no data on the use of valaciclovir in higher doses (4000 mg per day or more) in patients with liver disease, therefore high doses of valacyclovir should be given 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 CMV infection.

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

Effect on the ability to drive transp. cf. and fur:It is necessary to take into account the clinical state of the patient and the profile of adverse reactions of valacyclovir in assessing the patient's ability to drive vehicles or other mechanisms requiring rapidity of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 500 mg.

Packaging:

By 7, 10, 14, 15 tablets into a contoured cell packaging made of a polyvinylchloride film or a G1BX / PVDC film or a PVC / PCTFE film and an aluminum printed lacquered foil.

According to 1, 2, 3, 6 contour cell packs of 7 tablets or 1, 2, 3, 6 contiguous cell packs of 10 tablets, or 1.3 contour packs of 14 tablets, or 2, 4 circuit cell packs 15 tablets together with instructions for use are placed in a pack of cardboard.

Storage conditions:In a dry, protected from light 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-002013

Date of registration:26.02.2013 / 20.04.2015

Expiration Date:26.02.2018

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Information update date: & nbsp14.01.2017

Illustrated instructions

Instructions

Valaciclovir Canon (Valacyclovir Canon)