VALVIR PILLS 500MG

Dosage form

: film coated tablets

Composition

1 tablet, film coated, contains:
active substance: Valaciclovir hydrochloride hydrate 611.70 mg or 1223.40 mg, corresponding to 500 mg or 1000 mg of valaciclovir;
Excipients: microcrystalline cellulose 59.60 / 119.20 mg, povidon-K30 24.50 / 49.00 mg, Magnesium stearate 4.20 / 8.40 mg;
film coating: Opadry white Y-5-7068 (hypromellose SsR 7.35 / 14.7 mg, hyprolosis 6.3 / 12.6 mg, titanium dioxide 4.2 / 8.4 mg, macrogol / PEG 400 2.1 / 4, 2 mg, hypromellose 50cP 1.05 / 2.1 mg) - 21/42 mg.

Tablets 500 mg: oval biconvex pills of white or almost white color with VC2 marking on one side.
1000 mg tablets: oval biconvex pills of white or almost white color with VC3 marking on one side.

: antiviral agent

Pharmacology

Pharmacodynamics
Antiviral drug. In humans, valacyclovir is rapidly and completely converted to Acyclovir and L-valine under the influence of valacyclovir hydrolase. In vitro acyclovir has a specific inhibitory activity against Herpes simplex types 1 and 2, Varicella zoster and Epstein-Barr viruses, 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 the viruses Herpes simplex, Varicella zoster and Epstein-Barr, this enzyme is viral thymidine kinase, which is present in virus-infected cells. Partial selectivity of phosphorylation is retained in CMV and is mediated through the UL 97 phosphotransferase gene product. Activation of acyclovir with a specific viral enzyme explains its selectivity to a great extent.
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 an analogue of a nucleoside, integrates into viral DNA, which leads to an obligate (complete) breaking of the chain, termination of DNA synthesis and, therefore, blocking viral replication.
Herpes simplex and Varicella zoster viruses with reduced sensitivity to valacyclovir are extremely rare (less than 0.1%) in patients with immunity, but can sometimes be found in patients with severe immunity disorders, such as a bone marrow transplant, in those who receive Chemotherapy for malignant neoplasms and those infected with human immunodeficiency virus (HIV).
Resistance is caused by a deficiency in the thymidine kinase of the virus, which leads to an excessive spread of the virus in the host. Sometimes the 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 virus resembles that of its wild strain.
Pharmacokinetics
Valacyclovir and acyclovir have similar pharmacokinetic parameters after oral administration.
Suction
After oral administration, valaciclovir is well absorbed from the gastrointestinal tract (GIT), quickly and almost completely converted into acyclovir and L-valine. This transformation is catalyzed by the enzyme valaciclovirhydrolase, isolated from human liver.
After a single dose of 0.25-2 g of valaciclovir, the maximum plasma concentration (Cmax) acyclovir in healthy volunteers with normal renal function averages 10–37 μmol / l (2.2–8.3 mcg / ml), and the median time to reach this concentration is 1–2 h.
When taking valacyclovir in a dose of 1 g acyclovir bioavailability is 54% and does not depend on food intake.
WITHmax Valaciclovir in plasma is only 4% of the concentration of acyclovir and is achieved on average 30-100 minutes after taking the drug; after 3 h level Cmax stays the same or decreases.
Distribution
The degree of binding of acyclovir with 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 secret of the vagina, cerebrospinal fluid, and herpetic vesicle fluid.
Removal
In patients with normal renal function, the half-life (T1/2) acyclovir after a single dose and repeated use is approximately 3 hours. Valaciclovir is excreted in the urine, mainly as acyclovir (more than 80% of the dose) and its 9-carboxymethoxymethylguanine metabolite, less than 1% of the drug is excreted unchanged.
Pharmacokinetics in special clinical situations
In patients with end-stage renal failure T1/2 acyclovir is approximately 14 h.
The pharmacokinetics of acyclovir is largely not impaired in patients infected with the Herpes simplex and Varicella zoster viruses, as well as in elderly patients and patients with cirrhosis of the liver.
In patients with severe impaired renal function Cmax acyclovir is approximately twice as much compared with healthy patients and T1/2 Acyclovir is increased 5 times. Aciclovir, the main metabolite of valacyclovir, is excreted in breast milk. After administration of valacyclovir orally at a dose of 500 mg Cmax acyclovir in breast milk 0.5-2.3 times (on average 1.4 times) exceeded its corresponding concentrations in the mother's plasma. The ratio of the area under the concentration-time curve (AUC) of acyclovir in breast milk to the AUC of acyclovir in the mother's plasma was 1.4-2.6 (average 2.2). The average concentration of acyclovir in breast milk is 2.24 mcg / ml. When appointing the mother of valaciclovir at a dose of 500 mg, 2 times a day, the child will be exposed to the same effect of acyclovir as when taken orally at a dose of about 0.61 mg / kg / day. T1/2 breast milk acyclovir is the same as blood plasma. Valaciclovir in unchanged form is not detected in the plasma of the mother, breast milk or urine of the child.
In late pregnancy, the steady daily AUC after taking 1 g of valaciclovir was more than 2 times greater than that when taking acyclovir at a dose of 1.2 g per day. During pregnancy, the pharmacokinetic characteristics of valaciclovir do not change.
Taking valacyclovir at a dose of 1 g and 2 g does not disturb the distribution and pharmacokinetic parameters of valacyclovir in HIV-infected patients compared with healthy individuals.
In recipients of organ transplants receiving valaciclovir at a dose of 2 g 4 times a day, Cmax Acyclovir is equal to or greater than that of healthy volunteers receiving the same dose of the drug, and their daily AUC values ​​are much higher.

Indications and usage

• treatment of herpes zoster;
• treatment and prevention of recurrence of infections of the skin and mucous membranes caused by the herpes simplex virus (including newly diagnosed and recurrent genital herpes);
• treatment of labial herpes;
• reduction of infection with genital herpes of a healthy partner, if it is taken as a suppressive therapy in combination with safe sex;
• prevention of cytomegalovirus infection that occurs during organ transplantation (reduces the severity of the reaction of acute graft rejection in patients with kidney transplants, the development of opportunistic infections and other viral infections caused by Herpes simplex and Varicella zoster viruses) in adults and children over 12 years old.

Contraindications

Hypersensitivity to valacyclovir, acyclovir and other components of the drug, clinically expressed forms of HIV infection with a C04 + 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 reasons) .
With care: liver failure (high doses of the drug), renal failure, pregnancy, lactation.

Use during pregnancy is possible if the expected effect of therapy for the mother outweighs the potential risk to the fetus (information about the use during pregnancy is not enough).
Acyclovir, the main metabolite of valaciclovir, is excreted in breast milk.
With valacyclovir therapy, breastfeeding is possible if the expected effect of therapy for the mother outweighs the potential risk to the baby.

Inside Adults.
Herpes zoster - 1000 mg 3 times a day for 7 days.
Herpes simplex - 500 mg 2 times a day. In case of relapse, the course should be 3 or 5 days. In the first episode with a severe course, the duration of treatment can be extended up to 10 days (with relapses, it is ideal to prescribe Valvir in the prodromal period or when the first symptoms of the disease appear, ie, tingling, itching, burning).
For the treatment of labial herpes, the administration of the drug in a dose of 2 g 2 times within 1 day is effective: the second dose should be taken approximately 12 hours (but not earlier than 6 hours) after the first dose (do not use this dosing regimen for more than 1 day, because as shownthis does not provide additional clinical benefits).
Prevention of recurrence of infections caused by the herpes simplex virus: in patients with preserved immunity - 500 mg 1 time per 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. Course duration - 4-12 months.
Prevention of infection with genital herpes of a healthy partner: infected heterosexual adults with preserved immunity and with the number of exacerbations up to 9 per year - 500 mg once a day for 1 year or more, every day with regular sex life, with irregular sex contacts Valvira intake is necessary start 3 days before the alleged sexual intercourse (data on the prevention of infection in other populations of patients are not available). Prevention of cytomegalovirus infection: adults and adolescents over 12 years old - 2 g 4 times a day (as soon as possible after transplantation). The course duration is 90 days, but in patients with high risk, treatment may be longer. The dose of Valvira is recommended to be reduced in patients with a significant reduction in renal function (see table).

Valvira dosing regimens for various therapeutic indications, depending on creatinine clearance

• Patients on hemodialysis are recommended to use Valvir immediately after the end of the hemodialysis session in the same dose as patients with CC less than 15 ml / min.
• Patients on dialysis should be prescribed Valvir after the end of the hemodialysis session.
• It is often necessary to determine QC, especially during periods when the kidney function changes rapidly, for example, immediately after transplantation or graft engraftment. In this case, the dose of Valvira is adjusted in accordance with the indicators of QA.
• Liver dysfunction: with mild and moderate liver cirrhosis (synthetic function of the liver is maintained), dose adjustment is not 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 Valvira, but experience with its clinical use in this pathology is limited.
• In the elderly, dose adjustment is not required, except for significant impaired renal function.It is necessary to maintain an adequate water-electrolyte balance.

The most common adverse reactions with valaciclovir are: headache and nausea, more serious adverse reactions: thrombotic thrombocytopenic purpura / hemolytic uremic syndrome, acute renal failure and neurological disorders.
Undesirable reactions are listed below in accordance with the classification of the main systems and organs and the frequency of occurrence: very often - ≥1 / 10; often - ≥1 / 100 or <1/10; sometimes - ≥1 / 1000 or <1/100; rarely 1/10000 or <1/1000; very rarely - <1 / 10,000. For the digestive tract: often - nausea; rarely, abdominal discomfort, including abdominal pain; vomiting, diarrhea; very rarely - reversible violations of functional hepatic tests, which are sometimes regarded as manifestations of hepatitis.
From the blood and lymphatic system: very rarely - leukopenia (mainly in patients with reduced immunity), thrombocytopenia.
On the part of the immune system: very rarely - anaphylaxis.
Mental and nervous system disorders: often - headache; sometimes agitation, including aggressive behavior; rarely - dizziness, confusion, hallucinations, mental decline; very rarely - excitement, tremor, ataxia, dysarthria; psychotic symptoms, including mania; depression, convulsions, encephalopathy, coma. These symptoms are reversible and are usually observed in patients with impaired renal function or on the background of other diseases.In patients with a transplanted organ, receiving high doses of valaciclovir (8 g / day) for the prevention of CMV infection, neurological reactions develop more often than when receiving lower doses.
On the part of the respiratory and mediastinal organs: sometimes dyspnea.
From the skin and subcutaneous tissue: sometimes - rash, 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: in patients with severe disorders of immunity, especially in patients with advanced stage of acquired immune deficiency syndrome, receiving high doses of valaciclovir (8 g / day) for a long time, there have been cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination). Similar complications were noted in patients with the same diseases, but not receiving valacyclovir.
To establish the frequency of manifestations of some adverse reactions according to the available data is not possible.
From the senses: visual impairment.
From the side of blood-forming organs: neutropenia, aplastic anemia, leukoplastic vasculitis, thrombotic thrombocytopenic purpura.
From the skin: erythema multiforme.
Laboratory values: decrease in hemoglobin, hypercreatininemia.
Other: dysmenorrhea, arthralgia, nasopharyngitis, respiratory infections, swelling of the face, high blood pressure, tachycardia, fatigue; in addition in children - fever, dehydration, rhinorrhea.

Currently, overdose with valaciclovir is insufficient.
Symptoms: A single overdose of acyclovir up to 20 g, which was partially absorbed from the gastrointestinal tract, was not accompanied by the toxic effect of the drug. When administered within a few days of ultra-high doses of acyclovir, nausea, vomiting, headache, confusion developed; with a / in the introduction - an increase in the concentration of serum creatinine, the development of renal failure, confusion, hallucinations, agitation, convulsions, coma.
Treatment: Patients should be carefully monitored for signs of toxic effects. Hemodialysis significantly enhances the removal of acyclovir from the blood and can be considered the method of choice when managing patients with an overdose of valacyclovir.

Clinically significant interactions not established.
Zimetidine and probenecid after taking 1 g of valaciclovir increase the AUC of acyclovir, reducing its renal clearance (however, dose adjustment of valaciclovir is not required due to the wide therapeutic index of acyclovir).
Care must be taken in the case of simultaneous use of valaciclovir in high doses (4 g / day) and drugs that compete with acyclovir for the elimination path (the latter is eliminated with the urine unchanged as a result of active tubular secretion), as there is a potential threat of increase in plasma level of one or both drugs or their metabolites.
With simultaneous use of acyclovir with mycophenolate mofetil, an increase in the AUC of the first and inactive metabolite of the second was noted.
Care must also be taken when combining valaciclovir in high doses (4 g / day and above) with drugs that affect kidney function (for example, cyclosporine, tacrolimus).

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 the side effects of the central nervous system (including agitation, hallucinations, confusion, delirium, seizures and encephalopathy) occur, the drug is canceled.
Patients at risk of dehydration, especially elderly patients, during the period of treatment with the drug Valvir need to ensure adequate hydration of the body.Patients with renal failure have an increased risk of developing neurological complications.
In patients with impaired liver function in patients with mild or moderate liver cirrhosis (the synthetic function of the liver is maintained), dose adjustment of the drug Valvir is not required. In the study of pharmacokinetics in patients with severe cirrhosis of the liver (with a violation of the synthetic function of the liver and the presence of shunts between the portal system and the general vascular bed), there is also no evidence of the need to correct the dosage regimen; however, clinical experience with the use of the drug Valvir in this category of patients is organic. There is no data on the use of the drug Valvir in high doses (4 g / day or more) in patients with liver disease, so you should be careful to prescribe the drug in high doses of this category of patients.
Elderly patients do not require dose adjustment, except in cases of significant impaired renal function. It is necessary to maintain an adequate water-electrolyte balance.
Special studies on the action of the drug Valvir in patients with liver transplantation was not conducted. However, it was shown that prophylactic administration of acyclovir in high doses reduces cytomegalovirus infection. Suppressive therapy with Valvir reduces the risk of transmitting genital herpes, but does not exclude it completely and does not lead to complete cure.During Valvir therapy, the patient must take measures to ensure the safety of the partner during sexual intercourse.
Use in pediatrics
Experience with the clinical use of the drug in children is missing.

Caution should be exercised in case of adverse reactions that affect the speed of psychomotor reactions.

Tablets, film coated 500 mg and 1000 mg.
Tablets 500 mg: 10 or 14 pills in blisters of PVC / Aluminum foil. On 1 blister (on 10 tablets) or on 3 blisters (on 14 tablets) together with the application instruction in a cardboard pack.
1000 mg tablets: 7 pills in PVC blisters / Aluminum foil. On 1 or 4 blisters together with the application instruction in a cardboard pack.

At a temperature not higher than 30 ° C. Keep out of the reach of children!