Valvir pills 1000mg №7

Mechanism of action

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 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 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 of acyclovir in healthy volunteers with normal renal function averages 10-37 mcmol / l (2.2-8.3 mcg / ml), and the median time to reach this concentration is 1-2 hours When taking valacyclovir in a dose of 1 g acyclovir bioavailability is 54% and does not depend on food intake. The maximum concentration of valaciclovir in plasma is only 4% of the concentration of acyclovir and is reached on average 30-100 minutes after taking the drug; after 3 h, the level of maximum concentration remains 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. Inference. In patients with normal renal function, the half-life of acyclovir after a single dose and repeated use is approximately 3 hours. Valacyclovir is excreted in the urine, mainly as acyclovir (more than 80% of the dose) and its 9-carboxymethoxymethylguanine metabolite, less than 1% is excreted in unchanged form. drug. Pharmacokinetics in special clinical situations. In patients with end-stage renal disease, the half-life of acyclovir is approximately 14 hours. The pharmacokinetics of acyclovir are not significantly 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 severely impaired renal function, the maximum concentration of acyclovir is approximately two times greater than in healthy patients and the half-life of acyclovir is increased 5-fold.Acyclovir, the main metabolite of valaciclovir, is excreted in breast milk. After oral administration of valaciclovir at a dose of 500 mg, the maximum concentration of acyclovir in breast milk was 0.5-2.3 times (on average 1.4 times) greater than its corresponding concentration 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. The half-life of acyclovir from breast milk is the same as that from 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, the maximum concentration of acyclovir is equal to or greater than that in healthy volunteers receiving the same dose of the drug, and the 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 the Herpes simplex and Varicella zoster viruses) in adults and children over 12 years of age.

Contraindications

Hypersensitivity to valaciclovir, acyclovir and other components of the drug, clinically expressed forms of HIV infection with CD4 + lymphocyte content less than 100 / μL, bone marrow transplantation, kidney transplantation, children (up to 12 years with CMV, up to 18 years for other reasons).

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 / 10,000 or <1/1000; very rarely - <1/10000.On the part of the digestive tract: often - nausea; rarely, abdominal discomfort, including abdominal pain; vomiting, diarrhea; very rarely reversible impairments of functional hepatic tests, which are sometimes regarded as manifestations of hepatitis. On the part of 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 system and mediastinum: sometimes - dyspnea. From the skin and subcutaneous tissue: sometimes - rash, including manifestations of photosensitivity; rarely - itching. Allergic reactions: very rarely - urticaria, angioedema. On the part of 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 impaired 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. On the part of the skin: erythema multiforme. Laboratory indicators: decrease in hemoglobin, hypercreatininemia. Other: dysmenorrhea, arthralgia, nasopharyngitis, respiratory infections, swelling of the face, high blood pressure, tachycardia, fatigue; in addition, children have fever, dehydration, rhinorrhea.

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 the simultaneous use of valaciclovir in high doses (4 g / day) and drugs,which compete with acyclovir for the elimination pathway (the latter is eliminated with the urine unchanged 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. 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).

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 increased up to 10 days (with relapses, it is ideal to prescribe the drug in the prodromal period or when the first symptoms of the disease appear, ie, pinching, itching, burning). For the treatment of labial herpes, the administration of the drug in a dose of 2 g is effective 2 times within 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 dosing regimen for more than 1 day since, as shown, this 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 sexual activity, with irregular sexual contacts taking the drug 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 the drug is recommended to reduce in patients with a significant reduction in renal function. Dosage regimens for different therapeutic indications, depending on creatinine clearance. Shingles. Creatinine clearance (KK) - 15-30 ml / min, 1 g 2 times a day; creatinine clearance (CC) - less than 15 ml / min, 1 g 1 time per day. Herpes simplex. Creatinine clearance (CC) - less than 15 ml / min, 500 mg, 1 time per day. Labial herpes. Creatinine clearance (CK) - 31-49 ml / min, 1 g 2 times within 1 day; creatinine clearance (CK) - 15-30 ml / min, 500 mg 2 times within 1 day; creatinine clearance (CC) - less than 15 ml / min, 500 mg 1 time per day. Herpes simplex. Patients with preserved immunity. Creatinine clearance (CC) - less than 15 ml / min, 250 mg 1 time per day. Patients with reduced immunity. Creatinine clearance (CC) - less than 15 ml / min, 500 mg 1 time per day. Reduction of infection with genital herpes.Creatinine clearance (CC) - less than 15 ml / min, 250 mg 1 time per day. Cytomegalovirus infection. Creatinine clearance (CC) - 75 ml / min or more, 2 g 4 times a day; creatinine clearance (KK) - 50-74 ml / min, 1.5 g 4 times a day; creatinine clearance (CK) - 25-49 ml / min, 1.5 g 3 times a day; creatinine clearance (CK) - 10-24 ml / min, 1.5 g 2 times a day; creatinine clearance (CK) - less than 10 or hemodialysis, 1.5 g 1 time per day. Patients on dialysis should be prescribed the drug 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 is adjusted in accordance with the indicators of QC. 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 common vascular bed) also do not indicate the need for dose adjustment, 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.

Currently, overdose with valaciclovir is insufficient. Symptoms: a single dose of an 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.

With care: liver failure (high doses of the drug), renal failure, pregnancy, lactation. Use during pregnancy and 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. Taking the drug in high doses for a long time in conditionsaccompanied by severe immunodeficiency (bone marrow transplantation, clinically significant forms of HIV infection, kidney transplantation), led to the development of thrombocytopenic purpura and hemolytic-uremic syndrome, up to a lethal outcome. If the side effects of the central nervous system (including agitation, hallucinations, confusion, delirium, seizures and encephalopathy) occur, the drug is canceled. Patients with the risk of dehydration, especially for elderly patients, during the period of drug treatment must ensure adequate hydration of the body. Patients with renal failure have an increased risk of developing neurological complications. In case of abnormal liver function in patients with mild or moderate liver cirrhosis (the synthetic function of the liver is maintained), dose adjustment 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 this drug is organic. There is no data on the use of the drug 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 in patients with liver transplantation has not been conducted. However, it was shown that prophylactic administration of acyclovir in high doses reduces cytomegalovirus infection. Suppressive drug therapy reduces the risk of transmitting genital herpes, but does not completely exclude it and does not lead to complete cure. During drug 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. Effect on ability to drive a car and / or other mechanisms. Caution should be exercised in case of adverse reactions that affect the speed of psychomotor reactions.

Keep out of the reach of children at a temperature not higher than 30 C.