Composition, form of production and packaging
The tablets covered with a film shell of white or almost white color, oval, biconcave, labeled "VC2" on one side.
valaciclovir hydrochloride hydrate 611.7 mg,
which corresponds to the content of valacyclovir 500 mg
Excipients: microcrystalline cellulose - 59.6 mg, povidone K30 - 24.5 mg, magnesium stearate - 4.2 mg.
The composition of the film shell: opadrai white Y-5-7068 (hypromellose 3cP - 7.35 mg, giprolose - 6.3 mg, titanium dioxide 4.2 mg, macrogol / PEG 400-2.1 mg, hypromellose 50cP - 1.05 mg) - 21 mg.
10 pieces. - blisters made of PVC / aluminum foil (1) - packs of cardboard.
14 pcs. - blisters of PVC / aluminum foil (3) - packs of cardboard.
The tablets covered with a film cover of white or almost white color, oval, biconcave, with marking "VC3" on one side.
valaciclovir hydrochloride hydrate 1223.4 mg,
which corresponds to the content valaciclovir 1000 mg
Excipients: microcrystalline cellulose - 119.2 mg, povidone K30 - 49 mg, magnesium stearate - 8.4 mg.
The composition of the film shell: opadrai white Y-5-7068 (hypromellose 3cP - 14.7 mg, giprolose - 12.6 mg, titanium dioxide - 8.4 mg, macrogol / PEG 400 - 4.2 mg, hypromellose 50cP - 2.1 mg) - 42 mg.
7 pcs. - blisters made of PVC / aluminum foil (1) - packs of cardboard.
7 pcs. - blisters of PVC / aluminum foil (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
Antiviral drug. In the human body, valacyclovir is rapidly and completely converted into acyclovir and L-valine under the influence of valacyclovirhydrolase.
Acyclovir in vitro possesses specific inhibitory activity against the viruses Herpes simplex types 1 and 2, Varicella zoster and Epstein-Barr, cytomegalovirus (CMV) and human herpesvirus type 6. Acyclovir inhibits the synthesis of viral DNA immediately after phosphorylation and conversion into active form of acyclovir triphosphate . The first stage of phosphorylation occurs with the participation of virus-specific enzymes. For viruses Herpes simplex, Varicella zoster and Epstein-Barr, such an enzyme is viral thymidine kinase, which is present in virus-infected cells. Partial selectivity of phosphorylation persists in CMV and is mediated through the product of the phosphotransferase UL 97 gene. Activation of acyclovir with a specific viral enzyme to a great extent explains its selectivity.
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 the nucleoside, is inserted into the viral DNA, which leads to an obligate (complete) chain rupture, discontinuation of DNA synthesis and, consequently, to blocking the replication of the virus.
In patients with preserved immunity, Herpes simplex and Varicella zoster viruses with a low sensitivity to valacyclovir are extremely rare (less than 0.1%), but can sometimes be found in patients with severe impairment of immunity, for example, with bone marrow transplant, in chemotherapy for malignant neoplasms and those infected with HIV.
Resistance is caused by a deficiency of thymidine kinase of the virus, which leads to excessive spread of the virus in the host organism. Sometimes a decrease in sensitivity to acyclovir is due to the appearance of strains of the virus with a violation of the structure of the viral thymidine kinase or DNA polymerase. The virulence of these varieties of the virus resembles that of its wild strain.
Valaciclovir and acyclovir have similar pharmacokinetic parameters after oral administration.
After ingestion, valacyclovir is absorbed well from the digestive tract, quickly and almost completely converted to acyclovir and L-valine. This transformation is catalyzed by the enzyme valacyclovirhydrolase, isolated from the human liver.
After a single dose of 0.25-2 g valacyclovir C max atciclovir in healthy volunteers with normal renal function averages 10-37 Ојmol / l (2.2-8.3 Ојg / ml), and the median time to achieve this concentration is 1-2 hours.
When taking valaciclovir in a dose of 1 g, the bioavailability of acyclovir is 54% and does not depend on the intake of food.
C max valacyclovir in plasma is only 4% of the concentration of acyclovir and is achieved on average 30-100 min after taking the drug; After 3 hours, the C max level remains the same or decreases.
The degree of binding of acyclovir to plasma proteins is very low - about 15%. Acyclovir is rapidly distributed among body tissues, especially in the liver, kidneys, muscles, lungs. It also penetrates the secret of the vagina, cerebrospinal fluid and herpetic vesicle fluid.
In patients with normal renal function T 1/2 acyclovir, after taking a single dose and re-use is approximately 3 hours. Valacyclovir is excreted in the urine, mainly in the form of acyclovir (more than 80% of the dose) and its metabolite 9-carboxymethoxymethylguanine, unchanged less than 1% of the drug is excreted.
Pharmacokinetics in special clinical cases
In patients with terminal stage of renal failure, T 1/2 acyclovir is approximately 14 hours.
The pharmacokinetics of acyclovir are largely unaffected in patients infected with Herpes simplex and Varicella zoster viruses, as well as in elderly patients and patients with cirrhosis.
In patients with severe renal dysfunction, C max of acyclovir is approximately 2 times greater than in healthy patients and T 1/2 acyclovir is 5 times increased.
Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After the administration of valaciclovir inwards at a dose of 500 mg C max of acyclovir in breast milk was 0.5-2.3 times (1.4 times on average) exceeded its corresponding concentrations in the mother's plasma. The ratio of AUC of acyclovir in breast milk to the AUC of acyclovir in the mother's plasma was 1.4-2.6 (2.2 on average). The average concentration of acyclovir in breast milk is 2.24 Ојg / ml. When the mother of valacyclovir is given a dose of 500 mg twice a day, the child will undergo the same effect of acyclovir as if taking it inside at a dose of about 0.61 mg / kg / day. T 1/2acyclovir from breast milk is the same as from plasma. Valacyclovir in unchanged form is not determined in the plasma of the mother, breast milk or urine of the child.
In late pregnancy, a steady daily AUC after receiving 1 g of valaciclovir was more approximately 2-fold than that of acyclovir at a dose of 1.2 g / day. In pregnancy, the pharmacokinetic characteristics of valaciclovir do not change.
The use of valaciclovir in a dose of 1 g and 2 g does not interfere with the distribution and pharmacokinetics of valacyclovir in HIV-infected patients compared to healthy individuals.
In recipients of organ transplants receiving valacyclovir in a dose of 2 g 4 times / day, C max of acyclovir is equal to or greater than that of healthy volunteers receiving the same dose of the drug, and the daily AUC values вЂ‹вЂ‹are significantly higher.
- treatment of herpes zoster;
- treatment and prevention of recurrences 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 taken as a suppressive therapy in combination with safe sex;
- Prevention of cytomegalovirus infection caused by organ transplantation (reduces the severity of acute graft rejection in patients with kidney transplants, the development of opportunistic infections and other viral infections caused by the viruses Herpes simplex and Varicella zoster) in adults and children over 12 years of age.
The drug is administered to adults inside.
With herpes zoster , 1000 mg 3 times a day for 7 days.
With simple herpes - 500 mg 2 times / day. In case of relapse, the course should be 3 or 5 days. At the first episode with a heavy course, the duration of treatment can be increased to 10 days (with relapses, it is ideal to appoint Valvir in the prodromal period or when the first symptoms of the disease, i.e., tingling, itching, burning) occur.
For the treatment of labial herpes, effective administration of the drug at a dose of 2 grams 2 times for 1 day: the second dose should be taken after about 12 hours (but not earlier than 6 hours) after the first dose (do not apply 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 / day; with very frequent relapses (10 and more per year) - 250 mg 2 times / day; for adult patients with immunodeficiency - 500 mg 2 times / day. The duration of the course 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 a year prescribed 500 mg 1 time / day for 1 year or more, every day with regular sexual activity, with irregular sexual intercourse Valvir intake is necessary start 3 days before the alleged sexual contact (data on the prevention of infection in other populations of patients are absent).
Prevention of cytomegalovirus infection: adults and adolescents over 12 years old - 2 grams 4 times / day (as soon as possible, after transplantation). The duration of the course is 90 days, but in patients with high-risk treatment may be longer.
The dose of Valvir should be reduced in patients with a significant decrease in renal function (see table).
Table. Valvir dosing regimens for various therapeutic indications depending on the CK
Therapeutic indications of CK, ml / min Dosing regimen
Shingles 15-30 1 g 2 times / day
less than 15 1 g 1 time / day
Herpes simplex less than 15 500 mg 1 time / day
Labial herpes 31-49 1 g 2 times for 1 day
15-30 500 mg 2 times for 1 day
less than 15 500 mg 1 time / day
Herpes simplex patients with preserved immunity of less than 15 250 mg 1 time / day
patients with reduced immunity of less than 15 500 mg 1 time / day
Decrease in infection with genital herpes less than 15 250 mg 1 time / day
Cytomegalovirus infection 75 or more 2 g 4 times / day
50-74 1.5 g 4 times / day
25-49 1.5 g 3 times / day
10-24 1.5 g 2 times / day
less than 10 or hemodialysis 1.5 g 1 time / day
Patients on hemodialysis are advised to use Valvir immediately after the end of the hemodialysis session at the same dose as patients with SC 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 engraftment of the graft. In this case, the dose of Valvir is adjusted in accordance with the QA indices.
Dysfunction of the liver : with poorly and moderately expressed liver cirrhosis (the synthetic function of the liver is preserved), correction of the dose of the drug is not required. Pharmacokinetic data in patients with severe liver cirrhosis (with a violation of the synthetic function of the liver and the presence of shunts between the portal system and the common vascular bed) also do not indicate the need for correction of the dose of Valvir, but the experience of its clinical use for this pathology is limited.
In elderly people, dose adjustment is not required, except for a significant impairment of kidney function. It is necessary to maintain an adequate water-electrolyte balance.
The most common adverse reactions with valaciclovir: 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); infrequently (? 1/1000 or <1/100); rarely (? 1/10 000 or <1/1000); very rarely (<1/10 000).
From the digestive system: often - nausea; rarely - discomfort in the abdomen, incl. abdominal pain, vomiting, diarrhea; very rarely - reversible violations of functional liver 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.
From the immune system: very rarely - anaphylaxis.
From the nervous system and psyche: often - headache; rarely agitation, including aggressive behavior; rarely - dizziness, confusion, hallucinations, decreased mental abilities; very rarely - excitation, tremor, ataxia, dysarthria, psychotic symptoms, including mania, depression, seizures, encephalopathy, coma. The listed symptoms are reversible and are usually observed in patients with impaired renal function or against a background of other diseases. In patients with a transplanted organ who receive valaciclovir in high doses (8 g / day) for the prevention of CMV infection, neurologic reactions develop more often than when taken in lower doses.
From the respiratory system: infrequently - dyspnoea.
From the skin and subcutaneous tissue: infrequent - rashes, including photosensitivity manifestations; rarely - itching.
Allergic reactions: very rarely - hives, angioedema.
From the urinary system: infrequently - hematuria (often associated with other disorders of the kidneys); rarely - renal dysfunction; very rarely - acute renal failure, renal colic (may be associated with impaired renal function). Possible precipitation of acyclovir crystals in the lumen of the renal tubules. Adequate drinking regimen should be observed during treatment.
Other: In patients with severe impairment of immunity, especially in patients with advanced stage of acquired immune deficiency syndrome receiving valacyclovir in high doses (8 g / day) for a long time, there were cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination).Similar complications were observed in patients with the same diseases, but not receiving valaciclovir.
It is not possible to determine the incidence of some adverse reactions according to available data.
From the senses: a blurred vision.
On the part of the hematopoiesis: neutropenia, aplastic anemia, leukoplastic vasculitis, thrombotic thrombocytopenic purpura.
From the skin: erythema multiforme.
On the part of laboratory indicators: a decrease in hemoglobin, hypercreatininaemia.
Other: dysmenorrhea, arthralgia, nasopharyngitis, respiratory tract infections, facial edema, increased blood pressure, tachycardia, fatigue; in children, fever, dehydration, rhinorrhea.
- hypersensitivity to valaciclovir, acyclovir and other components of the drug;
- clinically expressed forms of HIV infection with a CD4 + lymphocyte content of less than 100 / ОјL;
- bone marrow transplantation;
- kidney transplantation;
- Children's age (up to 12 years with CMV, up to 18 years - according to other indications).
In patients with renal insufficiency; in patients with clinically expressed forms of HIV infection; with the simultaneous administration of nephrotoxic drugs.
PREGNANCY AND LACTATION
Use in pregnancy is possible if the expected effect of therapy for the mother exceeds the potential risk to the fetus (information on use in pregnancy is not enough).
Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. With valacyclovir therapy breastfeeding is possible if the expected effect of therapy for the mother exceeds the potential risk for the child.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution should prescribe the drug for kidney failure
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution should prescribe the drug for liver failure (high doses).
APPLICATION FOR CHILDREN
Contraindicated: children's age (up to 12 years with CMV, up to 18 years - for the rest of the indications).
APPLICATION IN ELDERLY PATIENTS
In elderly people, dose adjustment is not required, except for a significant impairment of kidney function. It is necessary to maintain an adequate water-electrolyte balance.
The use of 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 lethal outcome. When there are side effects from the central nervous system (including agitation, hallucinations, confusion, delusions, convulsions and encephalopathy), the drug is canceled.
Patients with a risk of dehydration, especially elderly patients, during treatment with Valvir should ensure adequate hydration of the body. Patients with renal insufficiency have an increased risk of developing neurological complications.
If liver function is impaired in patients with mild to moderate liver cirrhosis (the synthetic function of the liver is preserved), Valve's 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 common vascular bed), there was also no evidence of a need for correction of the dosing regimen; However, the clinical experience of using Valvir in this category of patients is organic. There is no data on the use of Valvir in high doses (4 g / day or more) in patients with liver disease, so caution should be given to the drug in high doses of this category of patients.
Elderly patients dose adjustment is required, except in cases of significant renal dysfunction. It is necessary to maintain an adequate fluid and electrolyte balance.
Special studies on the effect of the drug in patients Valvira been conducted in liver transplantation. However, it has been shown that prophylactic administration of high doses of acyclovir reduces CMV infection. Suppressive therapy with Valvira reduces the risk of transmission of genital herpes, but does not exclude it completely and does not lead to a complete cure. During therapy with Valvira patient should take measures to ensure the security of the partner during sexual intercourse.
Use in Pediatrics
Clinical experience with the drug in children is missing.
Impact on the ability to drive vehicles and manage mechanisms
Care must be taken in the case of side reactions affecting the speed of psychomotor reactions.
Currently, data on overdose valacyclovir enough.
Symptoms: A single dose of acyclovir in megadoses to 20 g, which partially is absorbed from the gastrointestinal tract, is not accompanied by toxic effects of the drug. If ingestion of acyclovir for several days in the ultra-high doses developed nausea, vomiting, headache, confusion; with a / in the introduction - an increased concentration of serum creatinine, renal failure, confusion, hallucinations, agitation, seizures, coma.
Treatment:patients should be under close medical supervision 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 of valacyclovir.
The simultaneous use of valaciclovir with nephrotoxic drugs, including aminoglycosides, organic
platinum compounds, iodinated contrast agent, methotrexate, pentamidine, foscarnet, cyclosporin and tacrolimus, should be carried out with care, particularly in patients with impaired kidney function and require regular monitoring of renal function.
Clinically significant interaction is not established.
Cimetidine and Probenecid after taking 1 g of valacyclovir increased AUC acyclovir, reducing its renal clearance (however valaciclovir dose adjustment is required due to the wide range of therapeutic acyclovir).
Care must be taken in the case of simultaneous use of valacyclovir in high doses (4 g / day) and drugs that compete with acyclovir for elimination pathway (the latter is eliminated with the urine in an unmodified form as a result of active tubular secretion), since there is a potential threat increase in plasma the concentration of one or both drugs or their metabolites.
With simultaneous use of acyclovir with mycophenolate mofetil AUC increase was observed acyclovir and inactive metabolite of mycophenolate mofetil.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 2 years.