In humans, valacyclovir is rapidly and completely converted to acyclovir, under the influence of valatsikpovirgidrolazy enzyme. Acyclovir has in vitro specific inhibitory activity against herpes simplex virus (HSV) 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpesvirus type 6 . Acyclovir inhibits viral DNA synthesis and the phosphorylation immediately after conversion into the active acyclovir triphosphate form.
The first stage of phosphorylation requires the activity of a virus-specific enzyme. For HSV, VZV, EBV and so the enzyme is a viral thymidine kinase, which is present in infected cells by a virus. Partial selectivity in phosphorylation stored and cytomegalovirus mediated through phosphotransferase gene product of UL 97. Activation of acyclovir specific viral enzyme to a great extent explains its selectivity.
Acyclovir phosphorylation process (conversion of a mono- triphosphate) is completed by cellular kinases. Acyclovir triphosphate competitively inhibits viral DNA polymerase, and being a nucleoside analogue, it is incorporated into the viral DNA, which leads to rupture obligate chain termination of DNA synthesis and therefore to block viral replication.
In patients with immunocompetent HSV and VZV with reduced sensitivity to valatsikpoviru are extremely rare, but can sometimes be found in patients with severe immune disorders, eg, bone marrow transplant patients receiving chemotherapy for malignant tumors and in HIV-infected patients.
Resistance is usually due to a thymidine kinase deficiency, which leads to an excessive spread of the virus in the host organism. Sometimes reduction of sensitivity to acyclovir due to the appearance of virus strains with impaired viral thymidine kinase or DNA polymerase structure. The virulence of the virus species resembles that of his wild strain.
General: After oral administration valaciclovir is well absorbed from the gastrointestinal tract and rapidly and almost completely transformed into aciclovir and valine. This conversion is catalyzed by the enzyme valatsikpovirgidralazoy isolated from human liver. After receiving a single dose in valatsikpovira 250-2000 mg mean peak concentration of acyclovir in plasma in healthy volunteers with normal renal function is 10-37 micromol (2,2- 8.3 ug / ml), and the median time to achieve this concentration 1-2 hours. When receiving valatsikpovira at a dose of 1000 mg of acyclovir bioavailability is 54% and is independent of food intake.
Valatsikpovira peak concentration in the plasma of only 4% of the concentration of acyclovir, the median time to achieve it – 30 – 100 minutes postdose through 3 hours Level peak concentration is retained unchanged or reduced. Valaciclovir and acyclovir have similar pharmacokinetic parameters after oral administration.
Valatsikpovira degree of binding to plasma proteins is very low (only 15%). In patients with normal renal function, the half-life of acyclovir in plasma after ingestion of valaciclovir is about 3 hours, and in patients with end-stage renal failure average half-life of about 14 hours. Valaciclovir is excreted primarily in the urine as acyclovir (more than 80% of the dose) and metabolite 9-karboksimetoksimetilguanina acyclovir, is eliminated in unmodified form at least 1% of the formulation.
Characteristics of patients: the pharmacokinetics of valaciclovir and aciclovir are largely not impaired in patients infected with viruses PIP OT
In late pregnancy steady daily indicator “area under curve” (curve area ratio under the plasma concentration / time) after receiving 1000 mg valaciclovir was greater than about 2 times, than that when taking acyclovir at a dose of 1200 mg per day. Admission Valtrex 1000 mg or 2000 mg does not violate the disposition and pharmacokinetic parameters of valaciclovir in HIV-infected patients compared to healthy individuals.
In organ transplant recipients receiving valaciclovir 2000 mg four times a day, peak acyclovir concentrations equal to or greater than that in healthy volunteers receiving the same dose of drug, and the daily parameters “area under curve” have much higher.
The active ingredient is:
Valatsikpovira hydrochloride 556 mg (equivalent to 500 mg valatsikpovira).
Povidone K 90;
Colloidal anhydrous silica;
Concentrate white coloring;
Brilliant blue 5312 (FT 203).
Genital Herpes, Herpes Zoster, Cytomegalovirus
- Treatment of herpes zoster (shingles). Valtrex accelerates the disappearance of pain, reduces the duration and percentage of patients with pain caused by herpes zoster, including acute and post-herpetic neuralgia.
- Treatment of infections of the skin and mucous membranes caused by HSV, including first identified and recurrent genital herpes.
- Treatment of herpes labialis (lip fever).
- Valtrex is able to prevent the formation of lesions, if taken at the first symptoms of recurrent herpes simplex.
- Prevention (suppression) of recurrences of skin infections and mucous membranes caused by HSV, including genital herpes.
- Valtrex can reduce infection with genital herpes healthy partner, when taken as suppressive therapy in combination with safer sex.
- prophylaxis of cytomegalovirus (CMV) infections occurring in organ transplantation. Prophylactic Valtrex CMV infection weakens the severity of acute graft rejection reaction (in kidney transplant patients), opportunistic infections and other infections of herpesvirus (HSV, VZV).
Valtrex is contraindicated in patients with known hypersensitivity to valatsikpoviru, atsikpoviru and any auxiliary ingredient, a part of Valtrex.
It should be used with caution in symptomatic forms of HIV.
Adverse reactions listed below according to the classification of the main systems and organs and occurrence frequency.
Used frequency indicators:
Very often: ≥ 1 in 10
Frequently: ≥ 100 1 or < 1 to 10;
Infrequently: ≥ 1 in 1000 or < 1 100
Rarely: ≥ 1 in 10,000, or < 1 1000
Very seldom: < 1 in 10,000.
Disorders of the nervous system
Violations by the gastrointestinal tract
These post-marketing studies
Disorders of the blood and lymphatic system
Very rare: leucopenia, thrombocytopenia. Basically, leukopenia was observed in patients with reduced immunity.
Disorders of immune system
Very rare: anaphylaxis.
Mental disorders and disorders of the nervous system
Rare: dizziness, confusion, hallucinations, mental decline
Very rare: agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma.
The above symptoms are reversible and usually seen in patients with impaired renal function or in the background of other predisposing conditions. Patients with organ transplant receiving high dose (8 g daily) Valtrex for preventing CMV infection often develop neurological reactions than when lower doses.
Violations by breathing, chest and mediastinum
Violations by the gastrointestinal tract
Rare: abdominal discomfort, vomiting, diarrhea
Violations of the liver and biliary tract
Very rare: reversible disturbances of liver function tests, which are sometimes regarded as manifestations of hepatitis.
Violations of the skin and subcutaneous tissue
Uncommon: rash, including photosensitivity
Very rare: urticaria, angioneurotic edema.
Violations by the kidneys and urinary tract
Rare: pochek.Ochen dysfunction rare: acute renal failure, renal colic. (Renal colic may be associated with renal impairment.).
Others: In patients with severely impaired immune system, particularly in patients with advanced stages of AIDS receiving high doses of valaciclovir (8 g daily) for a long period of time, there have been cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination). These complications have been observed in patients with the same disease but not receiving valacyclovir.
How to accept, acceptance rate and dosage
Treatment of herpes zoster
Valtrex administered in a dose of 1000 mg 3 times daily for 7 days.
Treatment of infections caused by HSV Adults Valtrex administered in a dose of 500 mg 2 times a day.
In the case of relapse, treatment should continue for 3 or 5 days. In more severe cases, the primary treatment should be started as early as possible, and its duration should be increased from 5 to 10 days. In recurrent HSV is considered the ideal appointment of Valtrex in the prodromal period or immediately upon appearance of the first symptoms of the disease.
In a alternative for the treatment of herpes labialis (lip fever) effectively assignment Valtrex dose of 2 g twice for 1 day. The second dose is to be taken after about 12 hours (but not earlier than 6 hours) after the first dose. By using such dosing regimen duration of treatment should not exceed 1 day as it was shown to provide no additional clinical benefit. Therapy should be initiated with the appearance of the earliest symptoms of fever lip (ie, tingling, itching, burning).
Prevention (suppression) of recurrences of infections caused by HSV Adults
In patients with preserved immune Valtrex is appointed at a dose of 500 mg once a day.
In patients with very frequent recurrences (10 and over a year) an additional effect can be achieved by assigning Valtrex in a daily dose of 500 mg, divided into two doses (250 mg, 2 times a day).
For adult patients with immunodeficiencies Valtrex recommended dose is 500 mg 2 times a day. The treatment duration of 4-12 months.
Prevention of infection with genital herpes healthy partner.
Infected heterosexual adults with preserved immunity and the number of exacerbations of up to 9 per year, Valtrex should take 500 mg 1 time a day for a year or more each day at a regular sexual life, with no regular sexual intercourse receiving Valtrex should be started 3 the day before the alleged sexual contact.
Information about the prevention of infection in other populations of patients does not exist.
Prevention of CMV disease
Dose for adults and adolescents (from 12 years)
Valtrex is recommended to prescribe a dose of 2 g 4 times a day, as early as possible after transplantation.
The dose should be reduced according to creatinine clearance.
The duration of treatment is 90 days, but in patients with high risk, treatment may be longer.
Doses in renal failure: Treatment of shingles and infections caused by HSV, prevention (suppression) and the reduction of infection of a healthy partner: The dose of Valtrex is recommended to reduce in patients with a significant decrease in renal function (see dosage in renal insufficiency. table).
ml / min
Herpes zoster and ophthalmic
in immunocompetent adults (treatment)
1 g 1 day
at least 15
500 mg 1 time per day
1 g of 2 times per day
more than 50
1 g of 3 times per day
Herpes simplex (treatment)
at least 15
500 mg 1 time per day
Labial herpes (treatment)
1g in 2 hours for 1 day
1 g of 2 times a day
at least 15
500 mg 1 time per day
more than 50
2 g in 2 hours for 1 day
Herpes simplex prevention (suppression):
– Patients with preserved immunity for at least 15 250 mg 1 time per day
– Patients with reduced immunity for at least 15 500 mg 1 time per day
Reduction of genital herpes infection less than 15 250 mg 1 time per day
patients on hemodialysis , recommended Valtrex immediately after hemodialysis in the same dose as patients with a creatinine clearance less than 15 mL / min.
Prevention of CMV: Valtrex destination mode in patients with impaired renal function should be installed in accordance with the data below.
75 and 2 g 4 times a day from 50 to less than 751,
5 g 4 times a day from 25 to less than 501,
5 g of 3 times a day from 10 to less than 251,
5 g of 2-fold in less than 10 hours or dialysis * 1.5 1 g once a day.
In patients on hemodialysis , Valtrex should be administered after hemodialysis.
It is often necessary to determine the creatinine clearance, especially during periods when renal function is changing rapidly, for example, immediately after transplantation or engraftment, the dose Valtrex adjusted in accordance with creatinine clearance rates.
The dose of Valtrex with abnormal liver function
In patients with mild and moderate hepatic cirrhosis (hepatic synthetic function maintained) Valtrex dose adjustment is required. Pharmacokinetic data in patients with severe liver cirrhosis (with impaired liver synthetic function and the presence of shunts between the portal system and general vascular bed) also indicate the need to adjust the dose of Valtrex, however, the experience of its clinical application is limited in this pathology.
The dosage in children
There are no data on the use of Valtrex in children.
The doses in the elderly
Dose adjustment is required, except for a significant renal dysfunction. It is necessary to maintain an adequate fluid and electrolyte Ballance.
At a temperature of not higher than 30 ° C
Clinically significant interactions have not been established. Acyclovir is eliminated in urine mainly unchanged, actively secreting in the renal tubules. Following the appointment of 1g. Valtrex Cimetidine and Probenecid, blocking tubular secretion, increase AUC acyclovir and reduce its renal clearance.
However, the dose of Valtrex does not require any correction due to the wide therapeutic index of aciclovir. Care must be taken in the case of simultaneous application Valtrex at higher doses (4 g daily) and drugs that compete with acyclovir for elimination way since there is a potential threat increase in the plasma level of one or both drugs or their metabolites.
AUC increase was noted acyclovir and inactive metabolite of mycophenolate mofetil, an immunosuppressive drug used in transplantation, while the use of these drugs.
It should also be taken (observe the change of renal function) when combined Valtrex at higher doses (4 g. In a day or more) with drugs that affect the other kidney (e.g., cyclosporine, tacrolimus).
The degree of hydration of the body: in patients at risk of dehydration, especially in elderly patients, it is necessary to provide adequate fluid replacement
Use in renal failure: Valtrex dose should be adjusted according to the degree of renal impairment. Patients with renal impairment are at increased risk of developing neurological complications.
The use of higher doses of Valtrex in hepatic impairment and liver transplantation: no data on the use of Valtrex in higher doses (4g or more per day.) In patients with liver disease, so high doses of Valtrex they should be used with caution. Special studies on the effect of liver transplantation at Valtraksa not provola. However, it has been shown that prophylactic administration of high doses atseklavira reduces CMV infection.
Use in genital herpes: Valtrex suppressive therapy reduces the risk of transmission of genital herpes, but does not exclude it completely and does not lead to a complete cure. Valtrex therapy is recommended in combination with safer sex.
Effects on ability to drive and use machinery
Special precautions are necessary.
Pregnancy and lactation
Teratogenicity: valaciclovir has no teratogenic vozdeystiya in rats and rabbits. Valaciclovir is almost completely metabolised to aciclovir education. Subcutaneous administration of acyclovir in conventional teratogenicity tests did not cause teratogenic effects in rats and rabbits. In additional studies in rats of fetal development were found by subcutaneous administration of the drug in doses which induced an increase in the plasma concentration of acyclovir to 100 .mu.g / mL and the toxic effects in the mother.
Fertility: with oral valacyclovir did not cause disturbances of fertility in male and female rats.
Pregnancy: data on the use of Valtrex in pregnancy is not enough. Valtrex should be used during pregnancy only if the potential benefit outweighs the potential risk. The data records of the outcome of pregnancy in women who took Valtrex or Zovirax (Acyclovir is an active metabolite of valaciclovir), showed no increase in the number of birth defects in their children compared to the general population. Since the register included a small number of women taking valacyclovir during pregnancy, the reliable and specific on the safety of valaciclovir can not be done during pregnancy.
Lactation: acyclovir, the main metabolite of valaciclovir, is excreted in breast milk. After assigning the valaciclovir 500 mg of acyclovir into the maximum concentration (Cmax) in breast milk in 0,5-2,3 times (an average 1.4 times) higher than the corresponding concentration of acyclovir in maternal plasma. The ratio of AUC of acyclovir present in breast milk, to acyclovir AUC maternal plasma ranged from 1.4 to 2.6 (mean 2.2).
The mean value of the concentration of acyclovir in breast milk was 2.24 micrograms / ml (9.95 mkgM). When receiving the mother valaciclovir 500 mg 2 times a day child undergo a similar treatment of acyclovir as when taking it orally at a dose of about 0.61 mg / kg / day. The half-life of acyclovir from breast milk is the same as from the blood plasma. Valacyclovir in unchanged form was not detected in maternal plasma, breast milk, urine, or child.
Valtrex should be used with caution in nursing women. However / in a Zovirax 30 mg / kg / day is used in neonates to treat diseases caused by herpes simplex virus.
Symptoms and signs:
data on overdose of Valtrex are not sufficient. Single administration of an overdose of acyclovir to 20 g, which partially is absorbed from the gastrointestinal tract, is not accompanied by toxic effects of the drug. Ingestion within a few days of ultrahigh doses of acyclovir was associated with gastrointestinal (nausea and vomiting) and neurological symptoms (headache and confusion).
Overdose of intravenous administration of acyclovir accompanied by increased serum creatinine and subsequent development of renal failure, wherein the neurological complications include confusion, hallucinations, agitation, convulsions and coma.
patients should be carefully monitored to detect signs of toxic effects. Hemodialysis significantly enhances the removal of acyclovir from the blood and may be considered the method of choice in the management of patients with an overdose Valtrex.