Valtrex, 500 mg

Active substance: 

Valacicpovir hydrochloride 556 mg (equivalent to 500 mg of valacicpovir).

Excipients: 

Microcrystalline cellulose; 
Crospovidone; 
Povidone K 90;
Magnesium stearate; 
Colloidal anhydrous silicon; 
White dye concentrate;
Carnauba wax;
Ink for printing; 
Brilliant Blue 5312 (FT 203).

      Pharmacodynamics

      In the human body, valaciclovir is rapidly and completely converted to acyclovir, under the influence of the enzyme valacicpovirhydrolase. Acyclovir has in vitro specific inhibitory activity against herpes simplex viruses (HSV) type 1 and type 2, zoster varicella virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and type 6 human herpes virus . Acyclovir inhibits the synthesis of viral DNA immediately after phosphorylation and transformation into an active form of acyclovir triphosphate.

The first stage of phosphorylation requires the activity of virus-specific enzymes. For HSV, VZV, and EBV, this enzyme is viral thymidine kinase, which is present in virus-infected cells. Partial selectivity of phosphorylation is preserved in cytomegalovirus and is mediated through the product of the phosphotransferase gene UL 97. Activation of acyclovir by a specific viral enzyme to a large extent explains its selectivity.

      The process of acyclovir phosphorylation (conversion from mono-to triphosphate) is completed by cell kinases. Acyclovir triphosphate competitively inhibits viral DNA polymerase and, being a nucleoside analogue, integrates into viral DNA, which leads to obligate breaking of the chain, termination of DNA synthesis and, consequently, to block virus replication.

      HSV and VZV with reduced sensitivity to valacicpovir are extremely rare in patients with preserved immunity, but can sometimes be found in patients with severely impaired immunity, for example, bone marrow transplant, those receiving chemotherapy for malignant neoplasms, and HIV-infected people.

Resistance is usually due to a deficiency of thymidine kinase, which leads to an 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 resembles that of its wild strain.

       Pharmacokinetics

       General information: after oral administration, valaciclovir is well absorbed from the gastrointestinal tract, quickly and almost completely turning into acyclovir and valine. This conversion is catalyzed by the enzyme valacicpovirhydralase isolated from the human liver. After a single dose of valacicpovir in a dose of 250-2000 mg, the average peak plasma concentration of acyclovir in healthy volunteers with normal renal function is 10-37 μmol (2.2-8.3 μg / ml), and the median time to reach this concentration is 1-2 hours. When taking valacicpovir in a dose of 1000 mg, the bioavailability of acyclovir is 54% and does not depend on food intake.

The peak plasma concentration of valacicpovir is only 4% of the concentration of acyclovir, the median time to reach it is 30-100 minutes after taking the dose, after 3 hours the peak concentration level remains the same or decreases. Valaciclovir and acyclovir have similar pharmacokinetic parameters after oral administration.

The degree of binding of valacicpovir to plasma proteins is very low (only 15%). In patients with normal renal function, the half-life of acyclovir from plasma after taking valacyclovir is about 3 hours, and in patients with end-stage renal failure, the average half-life is about 14 hours. Valacyclovir is excreted in the urine mainly in the form of acyclovir (more than 80% of the dose) and the metabolite of acyclovir 9-carboxymethoxymethylguanine, less than 1% of the drug is eliminated unchanged.

      Patient characteristics: the pharmacokinetics of valaciclovir and acyclovir are not significantly impaired in patients infected with PGi and VZ viruses.

      In late pregnancy, the steady daily indicator “area under the curve” (area under the plasma concentration / time ratio curve) after taking 1000 mg of valaciclovir was approximately 2 times greater than that when taking acyclovir at a dose of 1200 mg per day. Taking Valtrex at a dose of 1000 mg or 2000 mg does not violate the disposition and pharmacokinetic parameters of valaciclovir in HIV-infected patients compared with healthy individuals.

       In organ transplant recipients receiving 2000 mg of valaciclovir 4 times a day, the peak concentration of acyclovir is equal to or greater than that of healthy volunteers receiving the same dose of the drug, and their daily area under the curve is significantly higher.

• Treatment of herpes zoster (shingles). Valtrex accelerates the disappearance of pain, reduces its duration and the percentage of patients with pain caused by shingles, including acute and postherpetic neuralgia.
• Treatment of infections of the skin and mucous membranes caused by HSV, including newly diagnosed and recurrent genital herpes.
• Treatment of labial herpes (lip fever).
• Valtrex is able to prevent the formation of lesions if taken when the first symptoms of herpes simplex recur.
• Prevention (suppression) of relapses of infections of the skin and mucous membranes caused by HSV, including genital herpes.
• Valtrex can reduce the infection of a healthy partner with genital herpes if it is taken as suppressive therapy in combination with safe sex.
• Prevention of cytomegalovirus (CMV) infection resulting from organ transplantation. The prophylactic administration of Valtrex for CMV infection weakens the severity of the acute transplant rejection reaction (in patients with kidney transplants), opportunistic infections, and other herpes virus infections (HSV, VZV).

Teratogenicity: Valaciclovir does not have teratogenic effects in rats and rabbits. Valacyclovir is almost completely metabolized with the formation of acyclovir. Subcutaneous administration of acyclovir in conventional teratogenicity tests did not cause teratogenic effects in rats and rabbits. In additional studies in rats, fetal development disorders were detected with subcutaneous administration of the drug in doses that caused an increase in the plasma concentration of acyclovir to 100 μg / ml and toxic effects in the mother's body.

      Fertility: when taken orally, valaciclovir did not cause fertility impairment in male or female rats.

      Pregnancy: there are insufficient data on the use of Valtrex during pregnancy. Valtrex should be used during pregnancy only if the potential benefit exceeds the potential risk. Data on pregnancy outcomes in women taking Valtrex or Zovirax (acyclovir is an active metabolite of valacyclovir) did not show an increase in the number of birth defects in their children compared to the general population. Since the register includes a small number of women who took valaciclovir during pregnancy, no reliable and definite conclusions about the safety of valaciclovir during pregnancy can be made.

     Lactation: Acyclovir, the main metabolite of valaciclovir, is excreted in breast milk. After the administration of valaciclovir in a dose of 500 mg by mouth, the maximum concentration of acyclovir (Cmax) in breast milk was 0.5-2.3 times (on average 1.4 times) higher than the corresponding concentration of acyclovir in the mother's plasma. The ratio of the AUC of acyclovir in breast milk to the mother plasma Acyclovir AUC ranged from 1.4 to 2.6 (average value 2.2).

The mean concentration of acyclovir in breast milk was 2.24 μg / ml (9.95 μgM). When the mother takes 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 from blood plasma. Valacyclovir unchanged was not detected in maternal plasma, breast milk, or urine.

     Valtrex should be prescribed with caution to lactating women. However, iv administration of Zovirax at a dose of 30 mg / kg / day is used in newborns to treat diseases caused by the herpes simplex virus.

Valtrex is contraindicated in patients with hypersensitivity to valacicpovir, acicpovir and any auxiliary ingredient that is part of the drug Valtrex.

Use with caution in clinically severe forms of HIV infection.

Adverse reactions are listed below in accordance with the classification of major systems and organs and the frequency of occurrence.
Used frequency indicators:

Very often: ≥ 1 in 10
Often: ≥ 1 in 100 or <1 in 10;
Infrequently: ≥ 1 in 1000 or <1 in 100
Rarely: ≥ 1 in 10000 or <1 in 1000
Very rarely: <1 in 10000.

Disorders of the nervous system
Often: headache.

Gastrointestinal Disorders
Often: nausea.
Post-Marketing Research Data

Disorders of the blood and lymphatic system
Very rarely: leukopenia, thrombocytopenia. Leukopenia was mainly observed in patients with reduced immunity.

Immune system disorders
Very rare: anaphylaxis.

Mental disorders and disorders of the nervous system
Rarely: dizziness, confusion, hallucinations, decreased mental ability.
Very rarely: agitation, tremor, ataxia, dysarthria, psychotic symptoms, cramps, encephalopathy, coma.

The symptoms listed above are reversible and are usually observed in patients with impaired renal function or against the background of other predisposing conditions. In patients with a transplanted organ receiving high doses (8 g per day) of Valtrex for the prevention of CMV infection, neurological reactions develop more often than when taking lower doses.

Disorders of the respiratory, chest and mediastinal organs
Infrequently: dyspnea

Gastrointestinal disorders
Rarely: abdominal discomfort, vomiting, diarrhea

Violations of the liver and bile ducts
Very rarely: reversible violations of the functional liver tests, which are sometimes regarded as manifestations of hepatitis.

Disorders from the skin and subcutaneous tissue
Infrequently: rashes, including photosensitivity.
Rarely: itching.
Very rare: urticaria, angioedema.

Disorders from the kidneys and urinary tract
Rarely: impaired renal function. Very rarely: acute renal failure, renal colic. (Renal colic may be associated with impaired renal function.).

Others: In patients with severely impaired immunity, especially in patients with advanced stages of AIDS who receive 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). Similar complications were noted in patients with the same diseases, but not receiving valaciclovir.

Clinically significant interactions have not been established. Acyclovir is eliminated in the urine mainly unchanged, actively secreting into the renal tubule. After the appointment of 1g. Valtrex cimetidine and probenecid, blocking tubular secretion, increase the AUC of acyclovir and reduce its renal clearance.

However, this dose of Valtrex does not require any correction due to the wide therapeutic index of acyclovir. Caution must be exercised in case of simultaneous use of Valtrex in higher doses (4 g per day) and drugs that compete with acyclovir for the elimination route, since there is a potential threat of an increase in plasma levels of one or both drugs or their metabolites.

An increase in AUC of acyclovir and an inactive metabolite of mycophenolate mofetil, an immunosuppressive drug used in transplantation, was noted with the simultaneous use of these drugs.

Caution must also be exercised (observe changes in kidney function) when Valtrex is combined in higher doses (4 g per day or more) with drugs that affect other kidney functions (e.g., cyclosporine, tacrolimus).

Herpes Zoster Treatment

Adults

Valtrex is prescribed at a dose of 1000 mg 3 times a day for 7 days.
Treatment of HSV infections Adults Valtrex is prescribed at a dose of 500 mg 2 times a day.
In case of relapse, treatment should last 3 or 5 days. In more severe primary cases, treatment should be started as early as possible, and its duration should be increased from 5 to 10 days. With recurrence of HSV, the appointment of Valtrex in the prodromal period or immediately after the onset of the first symptoms of the disease is considered ideal.

As an alternative to the treatment of labial herpes (lip fever), the administration of Valtrex in a dose of 2 g twice within 1 day is effective. The second dose should be taken approximately 12 hours (but not earlier than 6 hours) after taking the first dose. When using such a dosage regimen, the duration of treatment should not exceed 1 day, since this, as has been shown, does not provide additional clinical benefits. Therapy should be started when the earliest symptoms of lip fever appear (i.e., tingling, itching, burning).

Prevention (suppression) of relapse of infections caused by HSV Adults
In patients with preserved immunity, Valtrex is prescribed at a dose of 500 mg once a day.
In patients with very frequent relapses (10 or more per year), an additional effect can be achieved with the appointment of Valtrex in a daily dose of 500 mg, divided into 2 doses (250 mg 2 times a day).
For adult patients with immunodeficiencies, the recommended dose of Valtrex is 500 mg 2 times a day. The duration of treatment is 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, Valtrex should be taken 500 mg once a day for a year or more every day with regular sexual activity, with irregular sexual contacts, Valtrex should be started in 3 days before the alleged sexual intercourse.
Data on the prevention of infection in other patient populations do not exist.
Prevention of CMV infection
Doses for adults and adolescents (from 12 years old)
It is recommended to prescribe Valtrex in a dose of 2 g 4 times a day, as soon as possible after transplantation.
The dose should be reduced depending on the clearance of creatinine.
The duration of treatment is 90 days, but in patients at high risk, treatment may be longer.

Doses for renal failure: Treatment of herpes zoster and HSV infections, prevention (suppression) and reduction of infection of a healthy partner: It is recommended to reduce the dose of Valtrex in patients with a significant decrease in renal function (see doses for renal failure in the table).

Therapeutic indications 

Herpes simplex prevention (suppression):
- patients with preserved immunity less than 15 250 mg 1 time per day
- patients with reduced immunity less than 15 500 mg 1 time per day
Reducing infection with genital herpes less than 15 250 mg 1 time per day

It is recommended that patients undergoing hemodialysis use Valtrex immediately after the end of the hemodialysis session in the same dose as patients with creatinine clearance less than 15 ml / min.

CMV prophylaxis: Valtrex administration regimen in patients with impaired renal function should be established in accordance with the data below.
75 and more than 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 3 times a day from 10 to less than 251,
5 g 2 times a day less than 10 or dialysis * 1.5 g once a day.

In patients on hemodialysis , Valtrex should be prescribed after the end of the hemodialysis session.
It is often necessary to determine creatinine clearance, especially during periods when kidney function changes rapidly, for example, immediately after transplantation or graft engraftment, while the dose of Valtrex is adjusted in accordance with creatinine clearance indicators.

Dose of Valtrex in case of impaired liver function
In patients with mild to moderate hepatic cirrhosis (synthetic liver function is preserved), dose adjustment of Valtrex 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 to adjust the dose of Valtrex, however, its clinical experience with this pathology is limited.

Doses in children
There are no data on the use of Valtrex in children.
Doses in the elderly
Dose adjustment is not required, with the exception of significant impairment of renal function. An adequate water-electrolyte balance must be maintained.

Symptoms and signs:

Valtrex overdose data are insufficient. 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. The ingestion of ultra-high doses of acyclovir for several days was associated with gastrointestinal (nausea and vomiting) and neurological symptoms (headache and confusion).

Overdoses with intravenous administration of acyclovir are accompanied by an increase in serum creatinine and the subsequent development of renal failure, with neurological complications including confusion, hallucinations, agitation, convulsions, and coma.

Maintaining:

patients should be closely monitored to detect signs of toxic effects. Hemodialysis significantly enhances the removal of acyclovir from the blood and can be considered the treatment of choice for patients with an overdose of Valtrex.

The degree of hydration: in patients at risk of dehydration, especially in elderly patients, it is necessary to ensure adequate fluid replenishment.

Application for renal failure: the dose of Valtrex should be adjusted depending on the degree of impaired renal function. Patients with renal failure have an increased risk of developing neurological complications.

The use of higher doses of Valtrex for liver failure and liver transplantation: there is no data on the use of Valtrex at higher doses (4 g or more per day) in patients with liver disease, therefore, high doses of Valtrex should be prescribed with caution. Special studies to study the effect of Valtraks during a liver transplant failed. However, it has been shown that prophylactic administration of aceclavir in high doses reduces CMV infection.

Application for genital herpes: suppressive therapy with Valtrex reduces the risk of transmission of genital herpes, but does not completely exclude it and does not lead to a complete cure. Valtrex therapy is recommended in combination with safe sex.

Influence on the ability to drive a car and machinery

No special precautions are required.

coated tablets