Valvir pills 500mg, 10pcs

Composition

1 film-coated tablet contains:  

Active ingredient:  

valacyclovir hydrochloride hydrate 611.70 mg corresponding to 500 mg of valacyclovir; 

auxiliary substances:

microcrystalline cellulose 59.60 mg,

povidone-K 30 24.50 mg,

magnesium stearate 4.20 mg;

film coating:  

Opadray white Y-5-7068 (hypromellose ZsR 7.35 mg, hyprolose 6.3 mg, titanium dioxide 4.2 mg, macrogol/PEG 400 2.1 mg, hypromellose 50 cP 1.05 mg) – 21 mg

Pharmacological action

Pharmacodynamics

Valvir is an antiviral drug. In humans, valacyclovir is rapidly and completely converted to acyclovir and L-valine by valacyclovir hydrolase. Acyclovir in vitro has specific inhibitory activity against Herpes simplex viruses types 1 and 2, Varicella zoster and Epstein-Barr, cytomegalovirus (CMV) and human herpes virus type 6.

Acyclovir inhibits the synthesis of viral deoxyribonucleic acid (DNA) immediately after phosphorylation and conversion to the active form of acyclovir triphosphate. The first stage of phosphorylation occurs with the participation of virus-specific enzymes.

For Herpes simplex, Varicella zoster, and Epstein-Barr viruses, such an enzyme is viral thymidine kinase, which is present in virus-affected cells. Partial phosphorylation selectivity is preserved in CMV and is mediated through the phosphotransferase gene product UL 97. Activation of acyclovir by a specific viral enzyme greatly explains its selectivity.

The process of phosphorylation of acyclovir (conversion from mono – to triphosphate) is completed by cellular kinases. Acyclovir triphosphate competitively inhibits viral DNA polymerase and, being a nucleoside analog, is incorporated into viral DNA, which leads to an obligate (complete) chain break, stopping DNA synthesis and, consequently, blocking viral replication.

In immunocompromised patients, Herpes simplex and Varicella zoster viruses with reduced sensitivity to valacyclovir are extremely rare (less than 0.1%), but can sometimes be detected in patients with severe immune disorders, such as those with a bone marrow transplant, those receiving chemotherapy for malignancies, and those infected with the human immunodeficiency virus (HIV).

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

Pharmacokinetics

Valacyclovir and acyclovir have similar pharmacokinetic parameters after oral use.

Suction

After oral use, valacyclovir is well absorbed from the gastrointestinal tract( GIT), quickly and almost completely converted to acyclovir and L-valine. This transformation is catalyzed by the enzyme valacyclovir hydrolase, isolated from the human liver.

After a single dose of 0.25-2 g of valacyclovir, the maximum plasma concentration (Cmax) of acyclovir in healthy volunteers with normal renal function averages 10-37 mmol / l (2.2-8.3 mcg / ml), and the median time to reach this concentration is 1-2 hours. When taking valacyclovir at a dose of 1 g or more, the bioavailability of acyclovir is 54% and does not depend on food intake.

The cmax of valacyclovir in plasma is only 4% of the concentration of acyclovir and is reached on average 30-100 minutes after taking the drug; after 3 hours, the Cmax level remains the same or decreases.

Distribution

The degree of binding of acyclovir to plasma proteins is very low – about 15%. Acyclovir is rapidly distributed throughout the body’s tissues, especially to the liver, kidneys, muscles, and lungs. It also penetrates the vaginal secretions, cerebrospinal fluid, and herpetic vesicle fluid.

Deduction

In patients with normal renal function, the half-life (T 1/2) of acyclovir after a single dose and repeated use is approximately 3 hours. Valacyclovir is excreted in the urine, mainly in the form of acyclovir (more than 80% of the dose) and its metabolite 9-carboxymethoxymethylguanine, and less than 1% of the drug is excreted unchanged.

Pharmacokinetics in special clinical cases

In patients with end-stage renal failure, the T 1/2 of acyclovir is approximately 14 hours.

The pharmacokinetics of acyclovir are largely unaffected in patients infected with Herpes simplex and Varicella zoster viruses, as well as in elderly patients and patients with cirrhosis of the liver.

In patients with severe renal impairment, the Cmax of acyclovir is approximately twice as high as in healthy patients, and the T 1/2 of acyclovir increases 5-fold. Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk.

After oral use of valacyclovir at a dose of 500 mg, the cmax of acyclovir in breast milk was 0.5-2.3 times (on average,1.4 times) higher than the corresponding concentrations in maternal plasma. The ratio of the area under the concentration-time curve (AUC) of acyclovir in breast milk to the AUC of acyclovir in maternal plasma was 1.4-2.6 (average 2.2).

The average acyclovir concentration in breast milk is 2.24 mcg / ml. When the mother is prescribed valacyclovir at a dose of 500 mg 2 times a day, the child will be exposed to the same effect of acyclovir as when taking it orally at a dose of about 0.61 mg / kg / day. T 1/2 of acyclovir from breast milk is the same as from blood plasma. Valacyclovir is not detected unchanged in the mother’s plasma, breast milk, or baby’s urine.

In late pregnancy, the sustained daily AUC after taking 1 g of valacyclovir was approximately 2 times higher than that when taking acyclovir at a dose of 1.2 g per day. During pregnancy, the pharmacokinetic characteristics of valacyclovir do not change.

Taking valacyclovir at a dose of 1 g and 2 g does not affect the distribution and pharmacokinetic parameters of valacyclovir in HIV-infected patients compared with healthy individuals.

In organ transplant recipients receiving valacyclovir at a dose of 2 g 4 times a day, the Cmax of acyclovir is equal to or exceeds that of healthy volunteers receiving the same dose of the drug, and their daily AUC values are significantly higher.

Indications

• Treatment and prophylaxis of recurrent infections of the skin and mucous membranes caused by the herpes simplex virus (including first diagnosed and recurrent genital herpes);
• the treatment of herpes zoster;
• the treatment of herpes labiales;
• reduction of genital herpes infection of a healthy partner, if taken as a suppressive therapy in combination with safe sex,
• prevention of cytomegalovirus infection occurring in organ transplantation (reduces the severity of the reaction is acute transplant rejection in patients with kidney transplants, development of opportunistic infections and drogichinsky infections caused by viruses Herpes simplex and Varicella zoster) for adults and children over 12 years of age.

Use during pregnancy and lactation

Use during pregnancy is possible if the expected effect of therapy for the mother exceeds the potential risk to the fetus (there is not enough information about use during pregnancy).

Acyclovir is the main metabolite of valacyclovir and is excreted in breast milk.

During valacyclovir therapy, breast-feeding is possible if the expected effect of therapy for the mother exceeds the potential risk for the child.

Contraindications

• Hypersensitivity to valacyclovir, acyclovir and other components of the drug,
• clinically expressed forms of HIV infection with a C4+ – lymphocyte content of less than 100 / µl, bone marrow
• transplantation, kidney transplantation,
• children (up to 12 years with CMV, up to 18 years – for other indications).

With caution: hepatic insufficiency (high doses of the drug), renal failure, pregnancy, lactation.

Side effects

The most common adverse reactions that occur with valacyclovir are headache and nausea, more serious adverse reactions: thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, acute renal failure and neurological disorders.

Adverse reactions are listed below in accordance with the classification by major systems and organs and by frequency of occurrence: very common – ≥1/10; often – ≥1/100 or From the blood and lymphatic system: very rare-leukopenia (mainly in patients with reduced immunity), thrombocytopenia.

Immune system disorders: very rare-anaphylaxis.

Mental and nervous system disorders: often-headache; sometimes-agitation, including aggressive behavior; rarely-dizziness, confusion, hallucinations, decreased mental abilities; very rarely — agitation, tremor, ataxia, dysarthria; psychotic symptoms, including mania; depression, convulsions, encephalopathy, coma.

These symptoms are reversible and usually occur in patients with impaired renal function or other diseases. In organ transplant patients receiving high doses of valacyclovir (8 g/day) for the prevention of CMV infection, neurological reactions develop more often than with lower doses.

Respiratory and mediastinal disorders: sometimes dyspnoea.

From the skin and subcutaneous tissue: sometimes-rashes, including manifestations of photosensitivity; rarely-itching.

Allergic reactions: very rarely — urticaria, angioedema.

From the urinary system: rarely-impaired renal function; very rarely-acute renal failure, renal colic (may be associated with impaired renal function).

Other services: Cases of renal failure, microangiopathic hemolytic anemia, and thrombocytopenia (sometimes in combination) have been reported in patients with severe immune disorders, especially in patients with advanced acquired immune deficiency syndrome who receive high doses of valacyclovir (8 g/day) for a long time. Similar complications were reported in patients with the same medical conditions, but not receiving valacyclovir.

According to the available data, it is not possible to determine the frequency of some adverse reactions.

From the side of the senses: visual impairment.

Hematopoietic disorders: neutropenia, aplastic anemia, leukoplastic vasculitis, thrombotic thrombocytopenic purpura.

Skin disorders: erythema multiforme.

Laboratory parameters: decreased hemoglobin, hypercreatininemia.

Others: dysmenorrhea, arthralgia, nasopharyngitis, respiratory tract infections, facial edema, high blood pressure, tachycardia, fatigue; in addition, children have fever, dehydration, rhinorrhea.

Interaction

No clinically significant interactions have been established.

Cimetidine and probenecid after taking 1 g of valacyclovir increase the AUC of acyclovir, reducing its renal clearance (however, dose adjustment of valacyclovir is not required due to the wide therapeutic index of acyclovir).

Caution should be exercised in the case of concomitant use of valacyclovir in high doses (4 g / day) and drugs that compete with acyclovir for the elimination pathway (the latter is eliminated unchanged in the urine as a result of active tubular secretion), since there is a potential threat of an increase in plasma levels of one or both drugs or their metabolites.

When acyclovir was co-administered with mycophenolate mofetil, an increase in the AUC of the first and inactive metabolite of the second was noted.

Caution should also be exercised when combining valacyclovir in high doses (4 g/day or higher) with drugs that affect renal function (for example, cyclosporine, tacrolimus).

How to take, course of use and dosage

Valvir is taken orally. Adults.

Herpes zoster — 1000 mg 3 times a day for 7 days.

Herpes simplex — 500 mg 2 times a day. In case of relapses, the course should be 3 or 5 days. In the first episode with a severe course, the duration of treatment can be increased to 10 days (in case of relapses, it is ideal to prescribe Valvir in the prodromal period or when the first symptoms of the disease appear, i. e. tingling, itching, burning).

For the treatment of labial herpes, it is effective to prescribe the drug at a dose of 2 g 2 times for 1 day: the second dose should be taken approximately 12 hours (but not earlier than 6 hours) after the first dose (do not use this dosage regimen for more than 1 day, since, as shown, this does not provide additional clinical benefits).

Prevention of relapses of infections caused by the herpes simplex virus: in patients with preserved immunity-500 mg 1 time a day; with very frequent relapses (10 or more per year) – 250 mg 2 times a day; for adult patients with immunodeficiency-500 mg 2 times a day. The course duration is 4-12 months.

Prevention of infection with genital herpes of a healthy partner: infected hete Rozexual adults with preserved immunity and with the number of exacerbations up to 9 per year-500 mg 1 time a day for 1 year or more, every day with regular sexual activity, with irregular sexual contacts, Valvir should be started 3 days before the intended sexual contact (there are no data on the prevention of infection in other patient populations).

Prevention of cytomegalovirus infection: adults and adolescents over 12 years of age – 2 g 4 times a day (as early as possible, after transplantation). The duration of the course is 90 days, but in patients with high risk, treatment may be longer. The dose of Valvir is recommended to be reduced in patients with a significant decrease in renal function.

• Patients undergoing hemodialysis are recommended to use Valvir immediately after the end of the hemodialysis session at the same dose as patients with creatinine clearance less than 15 ml/min.
• Patients undergoing dialysis should be prescribed Valvir after the end of the hemodialysis session.
• It is necessary to frequently determine the CK, especially during periods when kidney function changes rapidly, for example, immediately after transplantation or graft implantation. In this case, the dose of Valvir is adjusted in accordance with the creatinine clearance indicators.
• Impaired liver function: with mild to moderate cirrhosis of the liver (synthetic liver function is preserved), no dose adjustment is required. Pharmacokinetic data in patients with severe cirrhosis of the liver (with impaired synthetic liver function and the presence of shunts between the portal system and the general vascular bed) also do not indicate the need for dose adjustment of Valvir, but the experience of its clinical use in this pathology is limited.
• In the elderly, no dose adjustment is required, except for significant renal impairment. It is necessary to maintain an adequate water-electrolyte balance.

Overdose

Currently, there are insufficient data on valacyclovir overdose.

Symptoms: A single overdose of acyclovir up to 20 g, which was partially absorbed from the gastrointestinal tract, was not accompanied by a toxic effect of the drug. When taking ultrahigh doses of acyclovir orally for several days, nausea, vomiting, headache, confusion developed; when administered intravenously, an increase in serum creatinine concentration, the development of renal failure, confusion, hallucinations, agitation, convulsions, coma.

Treatment: Patients should be closely monitored for signs of toxic effects. Hemodialysis significantly enhances the removal of acyclovir from the blood and can be considered the method of choice in the management of patients with valacyclovir overdose.

Special instructions

Taking the drug in high doses for a long time in 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 fatal outcome. If side effects from the central nervous system occur (including agitation, hallucinations, confusion, delirium, convulsions and encephalopathy), the drug is discontinued.

Patients at risk of dehydration, especially elderly patients, should be adequately hydrated during treatment with Valvir. Patients with renal insufficiency have an increased risk of developing neurological complications. In patients with impaired liver function in patients with mild or moderate cirrhosis of the liver (synthetic liver function is preserved), no dose adjustment of Valvir is required. The pharmacokinetic study in patients with severe cirrhosis of the liver (with impaired synthetic liver function and the presence of shunts between the portal system and the general vascular bed) also did not receive data indicating the need to adjust the dosage regimen; however, the clinical experience of using Valvir in this category of patients is organic. There are no data on the use of Valvir in high doses (4 g/day or more) in patients with liver diseases, so caution should be exercised when prescribing the drug in high doses to this category of patients.

Elderly patients do not need to adjust the dose, except in cases of significant renal impairment. It is necessary to maintain an adequate water-electrolyte balance.

No specific studies have been conducted to investigate the effects of Valvir in patients undergoing liver transplantation. However, high-dose prophylactic use of acyclovir has been shown to reduce cytomegalovirus infection. Suppressive therapy with Valvir reduces the risk of transmission of genital herpes, but does not completely eliminate it and does not lead to a complete cure. During therapy with Valvir, the patient should take measures to ensure the safety of the partner during sexual contact.

Use in pediatrics

There is no experience of clinical use of the drug in children.

Influence on the ability to drive a car and/or other mechanisms

Caution should be exercised in the event of adverse reactions affecting the rate of psychomotor reactions.

Form of production

Film-coated tablets

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

2 years

Active ingredient

Valacyclovir

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults

Indications

Cytomegalovirus infection, Herpes