Valacyclovir

Pharmacological properties

Valavir is an antiviral drug, acyclovir l-valine ester, which is an analogue of guanine, a purine nucleoside. in the human body, valaciclovir is rapidly and almost completely converted to acyclovir and valine using valacyclovir hydrolase. acyclovir is a specific inhibitor of herpes viruses with in vitro activity against herpes simplex viruses type I and II, varicella zoster virus, cytomegalovirus, Epstein virus-barr and human herpes virus type vi. acyclovir inhibits the synthesis of viral dna immediately after phosphorylation and transformation into an active form of acyclovir triphosphate. at the first stage of phosphorylation, the activity of a virus-specific enzyme is necessary. for herpes simplex virus, varicella zoster virus and Epstein virus, barr is a viral thymidine kinase present only in virus-infected cells. Partial selectivity of phosphorylation is maintained during cytomegalovirus infection and is mediated through the product of the ul97 phosphotransferase gene. activation of acyclovir by a specific viral enzyme largely explains its selectivity.

The process of acyclovir phosphorylation (conversion from mono-to triphosphate) is carried out by cell kinases. Acyclovir triphosphate competitively inhibits viral DNA polymerase and incorporates into viral DNA, which leads to obligate (complete) chain breaking, termination of DNA synthesis, and thus to block virus replication.

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

Extensive monitoring of the clinical isolates of the herpes simplex virus and Varicella zoster virus in patients treated with acyclovir made it possible to find out that in people with normal immunity a virus with reduced sensitivity to acyclovir is extremely rare and appears only in patients with severe immunity disorders, for example, after transplantation organs or in bone marrow recipients during chemotherapy of malignant neoplasms and HIV-infected.

Valacyclovir accelerates the elimination of pain in the treatment of herpes zoster, reduces the duration of the pain syndrome, as well as the number of patients with herpes-associated pain, including acute and postherpetic neuralgia.

Prevention of cytomegalovirus infection with valaciclovir reduces the risk of acute transplant rejection (patients after a kidney transplant), the incidence of opportunistic infections and other infections caused by the herpes virus (herpes simplex virus and Herpes zoster virus).

Pharmacokinetics

Absorption. After oral administration, valaciclovir is well absorbed, quickly and almost completely turns into acyclovir and valine. This transformation, obviously, occurs using the enzyme valaciclovirhydrolase isolated from the human liver. The bioavailability of acyclovir when taking 1 g of valaciclovir is 54% and does not decrease during meals. The pharmacokinetics of valaciclovir is not dose-dependent. The rate and extent of absorption decreases with increasing dose, causing a less proportional increase in C_max within the therapeutic increase in doses and decrease in bioavailability when using the drug in a dose of 500 mg. Average c_max acyclovir is 10–37 μmol (2.2–8.3 μg / ml) after a single dose of 250–2000 mg of valaciclovir in healthy volunteers with normal renal function, and the median time to reach this concentration is 1–2 hours. C_max Valacyclovir in the blood plasma is only 4% of the concentration of acyclovir and occurs on average after 30-100 minutes and after 3 hours it decreases below the measured amount.The pharmacokinetic parameters of valaciclovir and acyclovir after a single and repeated administration are similar.

Distribution. The binding of valaciclovir to plasma proteins is very low - 15%. Penetration in CSF, which is determined by the ratio of CSF / AUC in blood plasma, is approximately 25% for acyclovir and a metabolite of 8-hydroxyacyclovir and 2.5% for a metabolite of 9-carboxymethoxymethylguanine.

Metabolism. Following oral administration, valaciclovir is converted to acyclovir and L-valine by first-pass metabolism in the intestine and / or liver. To a small extent, acyclovir is converted to 9-carboxymethoxymethylguanine metabolites using alcohol dehydrogenase and aldehyde dehydrogenase and to 8-hydroxyacyclovir using aldehyde oxidase. Approximately 88% of the total plasma exposure of the drug belongs to acyclovir, 11% to 9-carboxymethoxymethylguanine and 1% to 8-hydroxyacyclovir. Neither valaciclovir nor acyclovir are metabolized by cytochrome P450 enzymes.

T_½ Acyclovir after a single and multiple administration of valaciclovir to patients with normal renal function is approximately 3 hours. Valacyclovir is excreted in the urine mainly in the form of acyclovir (80% of the dose) and its metabolite 9-carboxymethoxymethylguanine.

In patients with end-stage renal failure T_½ acyclovir is approximately 14 hours

Herpes zoster virus and herpes simplex virus do not significantly change the pharmacokinetics of acyclovir and valacyclovir after oral administration of valacyclovir.

In a study of the pharmacokinetics of valaciclovir and acyclovir in the late stages of pregnancy, the AUC of acyclovir in the plateau phase after applying valacyclovir at a dose of 1000 mg was approximately 2 times higher than after oral administration of acyclovir at a dose of 1200 mg / day.

In patients with HIV infection, the pharmacokinetics of acyclovir after applying a single or multiple dose of 1000 or 2000 mg of valaciclovir did not change compared to those in healthy individuals.

In organ transplant recipients treated with valaciclovir at a dose of 2000 mg 4 times a day, C_max acyclovir equaled or exceeded that of healthy volunteers who received the drug in the same dose, and the daily AUC was significantly higher.

Indications

• Treatment for herpes zoster (herpes zoster); treatment for infections of the skin and mucous membrane caused by the herpes simplex virus, including primary and recurrent genital herpes; treatment for labial herpes (labial fever); preventive treatment (suppression) for relapses of skin and mucous membrane infections caused by the herpes simplex virus, including genital herpes; reducing the risk of transmitting the genital herpes virus to a healthy partner when using valavir as suppressive therapy subject to safe sex rules; prevention of cytomegalovirus infection and diseases after organ transplantation.

Application

Treatment for herpes zoster: adults - 1000 mg (2 tablets) of valavir 3 times a day for 7 days.

Herpes Simplex Infections Treatment

Patients with normal immunity (adults): 500 mg (1 tablet) of the drug 2 times a day.

For recurrent cases, treatment should last 3 or 5 days. In the initial course of the disease, which may be more severe, treatment should be extended from 5 to 10 days. Therapy should be started as soon as possible. For recurrent forms of infections caused by the herpes simplex virus, it would be ideal to use the drug in the prodromal period or immediately after the onset of the first symptoms. Valavir can prevent the development of lesions in relapses of infections caused by the herpes simplex virus, provided that treatment is started immediately after the first symptoms of the disease appear.

An effective dose of Valavir is 2000 mg (4 tablets) 2 times a day for 1 day for the treatment of labial herpes (lip fever).The second dose should be applied approximately 12 hours (not earlier than 6 hours) after the first dose. With this dosing regimen, the duration of treatment should be no more than 1 day, since it is proved that longer use does not increase the clinical effectiveness of therapy. Treatment should begin when the first early symptoms of labial herpes appear (tingling sensation, itching, or burning in the lips).

Preventive treatment (suppression) of recurrence of infection caused by the herpes simplex virus:

• patients with normal immunity (adults) - 500 mg (1 tablet) of the drug 1 time per day;
• patients with immunodeficiency (adults) - a dose of 500 mg (1 tablet) 2 times a day.

Reducing the transmission of genital herpes virus. Adults with normal immunity heterosexuals who have ≤9 exacerbations per year, should administer Valavir to an infected partner at a dose of 500 mg once a day.

There is no evidence of a decrease in the transmission of genital herpes virus in other patient populations.

Prevention of cytomegalovirus infection and disease. Adults and children over the age of 12 years: appoint Valavir in a dose of 2000 mg (4 tablets) 4 times a day as soon as possible after transplantation. In renal failure, the dose is reduced (see Dosage for impaired renal function). The duration of treatment is usually 90 days, but can be increased for patients with a high degree of risk.

Dosage for impaired renal function. Caution is advised to administer valaciclovir to patients with impaired renal function. Be sure to maintain an adequate level of hydration.

* Use in the presence of tablets of the drug in a dose of 250 mg.

Patients who are on intermittent hemodialysis are recommended to use Valavir in the same doses as patients with creatinine clearance of 15 ml / min. Doses must be prescribed after hemodialysis.

Creatinine clearance must be constantly monitored, especially during periods when kidney function can change rapidly, for example immediately after transplantation. Accordingly, the dose of Valavir should be changed.

Dosage for impaired liver function. There is no need to change the dose for patients with mild or moderate degree of cirrhosis (the synthesizing function of the liver is preserved). Pharmacokinetics in the late stages of cirrhosis (with impaired liver synthesizing function and the presence of portal block signs) indicate that there is no need to change the dose, but clinical experience is limited.

On the use of the drug in higher doses (≥4000 mg / day) (see SPECIAL INSTRUCTIONS).

Elderly patients. The dose of Valavir requires correction in order to avoid possible impaired renal function (see Dosage for impaired renal function).

It is necessary to maintain an adequate level of body hydration.

Contraindications

Valavir is contraindicated in patients with hypersensitivity to valaciclovir, acyclovir, or to any component of the drug.

Side effects

Among the more serious adverse reactions were reports of thrombotic thrombocytopenic purpura / hemolytic uremic syndrome, diabetes and neurological disorders.

From the nervous system: headache.

From the digestive tract: nausea.

On the part of the blood and lymphatic system: leukopenia (mainly observed in patients with immunodeficiency), thrombocytopenia.

From the immune system: anaphylactic reactions.

From the nervous system and mental disorders: dizziness, confusion, hallucinations, decreased mental ability, agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma. The above symptoms in most cases are reversible and are noted mainly in patients with renal failure or with other addiction factors (see SPECIAL INSTRUCTIONS). In patients after organ transplantation, receiving valaciclovir for the prevention of cytomegalovirus infection in high doses (8 g / day), neurological reactions occur more often than in patients receiving the drug in lower doses.

From the respiratory system and chest organs, mediastinum: shortness of breath.

From the digestive tract: abdominal discomfort, vomiting, diarrhea.

From the hepatobiliary system: a reversible increase in the level of functional liver samples. This is periodically described as hepatitis.

On the part of the skin and subcutaneous tissues: rash, including photosensitization, itching,