Valvir - instructions for use, dose, side effects, contraindications

film coating: Drop off white Y-5-7068 (hypromellose ZSR 7.35 / 14.7 mg, giprolose 6.3 / 12.6 mg, titanium dioxide 4.2 / 8.4 mg, macrogol / PEG 400 2.1 / 4.2 mg, hypromellose 50cP 1.05 / 2.1 mg) - 21/42 mg.

Description:

Tablets 500 mg: oval, biconvex tablets white or almost white, labeled VC2 on the one hand.

Tablets 1000 mg: oval, biconvex tablets white or almost white, labeled VC3 on the one hand.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.B.11 Valaciclovir

J.05.A.B Nucleosides and nucleotides

Pharmacodynamics:

Antiviral drug. In the human body valaciclovir quickly and completely turns into acyclovir and Lvaline under the influence of valacyclovirhydrolase.

Acyclovir in vitro has a specific inhibitory activity against viruses Herpes simplex types 1 and 2, Varicella zoster and Epstein-Barr, cytomegalovirus (CMV) and human herpes virus type 6. Acyclovir inhibits the synthesis of viral deoxyribonucleic acid (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 the obligate (complete) rupture of the chain, the cessation of DNA synthesis and, therefore, the blocking of viral replication.

In patients with preserved immunity, viruses Herpes simplex and Varicella zoster with a decreased sensitivity to valacyclovir are extremely rare (less than 0.1%), but can sometimes be found in patients with severe immunity disorders, for example, with bone marrow transplant, in chemotherapy for malignant neoplasms and in those infected with the human immunodeficiency virus (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.

Pharmacokinetics:

Valaciclovir and acyclovir have similar pharmacokinetic parameters after oral administration.

Suction

After oral administration valaciclovir well absorbed from the gastrointestinal tract (GIT), quickly and almost completely turns into acyclovir and L-valine. it the conversion is catalyzed by the enzyme valacyclovirhydrolase, isolated from the liver rights.

After a single dose of 0.25-2 g valacyclovir, the maximum concentration in the blood plasma (FROM_max) of acyclovir in healthy volunteers with normal kidney function averages 10-37 μmol / L (2.2-8.3 μg / ml), and the median time to achieve this concentration 1-2 h.

When taking valaciclovir in a dose of 1 g, the bioavailability of acyclovir is 54% and does not depend on the intake of food.

FROM_maxvalacyclovir in plasma is only 4% of the concentration of acyclovir and is achieved on average 30-100 minutes after taking the drug; after 3 h level C_m_Ohremains the same or decreases.

Distribution

The degree of binding of acyclovir to plasma proteins is very low - about 15%. Acyclovir quickly distributed to the tissues of the body, especially the liver, kidneys, muscles, lungs.

It also penetrates the secret of the vagina, cerebrospinal fluid and the liquid of herpetic vesicles.

Excretion

In patients with normal renal function, the elimination half-life T_1/2Acyclovir after a single dose and re-use is approximately 3 hours. Valaciclovir is excreted in the urine, mainly in the form of acyclovir (more than 80% of the dose) and its metabolite 9-carboxymethoxymethylguanine, in unchanged form is derived less 1% of the preparation.

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 is largely unaffected in patients infected with viruses Herpes simplex and Varicella zoster, as well as in elderly patients and patients with cirrhosis of the liver.

In patients with severe renal dysfunction C_m_Oh acyclovir is approximately twice as large as in healthy patients and T_1/2 Acyclovir is increased 5 times.

Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After valaciclovir was administered orally at a dose of 500 mg C_m_Oh Acyclovir in breast milk in 0,5-2,3 times (on average, 1,4 times) exceeded 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 (2.2 on average). The average concentration of acyclovir in breast milk is 2.24 μg / ml. When the mother of valacyclovir is given a dose of 500 mg twice a day, the child will undergo the same effects of acyclovir as if taking it inside at a dose of about 0.61 mg / kg / day. T_1/2 Acyclovir from breast milk is the same as from plasma blood. Valaciclovir in unmodified form is not determined in the plasma of the mother, breast milk or urine of the child.

In late pregnancy, a steady daily rate AUC after taking 1 g valacyclovir was more approximately in 2 times than that with acyclovir at a dose of 1.2 g per day.

In pregnancy, the pharmacokinetic characteristics of valaciclovir do not change.

Taking valaciclovir in a dose of 1 g and 2 g does not violatedistribution and pharmacokinetic parameters of valacyclovir in HIV-infected patients compared with healthy individuals.

In transplant recipients of organs receiving valaciclovir in a dose of 2 g 4 times a day, FROM_m_Oh Acyclovir is equal to or greater than that of healthy volunteers receiving the same dose of the drug, and the daily AUC values are significantly higher.

Indications:

- 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, development of opportunistic infections and other viral infections caused by viruses Herpes simplex and Varicella zoster) in adults and children over 12 years of age.

Contraindications:Hypersensitivity to valacyclovir, acyclovir and other components of the drug, clinically expressed forms of HIV infection with a CD4 + lymphocyte content of less than 100 / μl, bone marrow transplantation, kidney transplantation, children's age (up to 12 years with CMV, up to 18 years for other indications) .

Carefully:

In patients with renal insufficiency; patients with clinically expressed forms of HIV infection; while taking nephrotoxic medicines at the same time.

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.

Dosing and Administration:

Inside. Adults.

Shingles Herpes - 1000 mg 3 times a day for 7 days.

Herpes simplex - 500 mg twice a 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 therapy labial herpes effective use of the drug in a dose of 2 g 2 times during 1 day: the second dose should be taken approximately 12 h (but not earlier than 6 h) after the first dose (do not use this dosing regimen more than 1 day, as, 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 once a day; with very frequent relapses (10 or more per year) - 250 mg twice a day; for adult patients with immunodeficiency - 500 mg 2 times a day. The duration of the course is 4-12 months.

Prevention of infection, 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 a regular sexual life; with irregular sexualcontacts Valvir should be taken 3 days before the proposed sexual contact (data on the prevention of infection in other populations of patients are absent).

Prevention of cytomegalovirus infection: Adults and teenagers over 12 years of age - 2 g 4 times a day (as soon as possible, after transplantation). The duration of the course is 90 days, but in patients at high risk, treatment may be longer.

The dose of Valvir should be reduced in patients with a significant decrease in renal function (see the table).

Table. Valvir dosing regimens for different therapeutic indications depending on the creatinine clearance

Therapeutic indications		Creatinine clearance (CK), ml / min	Dosing regimen
Shingles		15-30	1 g 2 times a day
Shingles		less than 15	1 g once a day
Herpes simplex		less than 15	500 mg once a day
Labial herpes		29-49	1 g 2 times for 1 day
		15-30	500 mg 2 times for 1 day
		less than 15	500 mg once a day
Plain herpes	Patients with preserved immunity	less than 15	250 mg once a day.
Plain herpes	patients with reduced immunity	less than 15	500 mg once a day
Reduced infection with genital herpes		less than 15	250 mg once a day
Cytomegalovirus infection		75 and more	2 g 4 times a day
		50-74	1.5 g 4 times a day
		25-49	1.5 g 3 times a day
		10-24	1.5 g 2 times a day
		less than 10 or hemodialysis	1.5 g once a 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 violation of kidney function.It is necessary to maintain an adequate water-electrolyte balance.

Side effects:

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 - ≥ 1/10000 or <1/1000; very rarely - <1/10000.

Co sides of the digestive system: often - nausea; rarely - discomfort in the abdomen, including 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.

Mental disorders and disorders of the nervous system: 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, convulsions, 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 high doses of valaciclovir (8 g / day) for the prevention of CMV infection, neurologic reactions develop more often than with lower doses.

On the part of the respiratory and mediastinal organs: 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: Patients with severely impaired immune system, particularly the Nazis with an advanced stage of syndrome acquired immune deficiency receiving high doses of valaciclovir (8 g / day) for a long time, the cases of renal failure was observed, 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 sense organs: impaired vision.

On the part of the organs of hematopoiesis: neutropenia. aplastic anemia, leykoklastichesky vasculitis, thrombotic thrombocytopenic purpura.

From the skin: erythema multiforme.

Laboratory indicators: decline hemoglobin, hypercreatininaemia.

Other: Dysmenorrhea, arthralgia, nasopharyngitis, respiratory tract infections, facial swelling, high blood pressure, tachycardia, fatigue; in children, fever, dehydration, rhinorrhea.

Overdose:

Currently, data on overdose of valacyclovir is not enough.

Symptoms: A single administration of a super-dose of acyclovir up to 20 g, which was partially absorbed from the gastrointestinal tract, was not accompanied by a toxic effect of the drug. With the intake of ultra-high doses of acyclovir for several days, nausea, vomiting, headache, confusion increased; when in / in the introduction - increasing the concentration of serum creatinine, the development of kidney failure, confusion, hallucinations, agitation, convulsions, coma.

Treatment: patients should be under careful medical supervision to identify signs of toxic effects. Hemodialysis significantly enhances the removal of acyclovir from the blood and can be considered a method of choice in managing patients with valacyclovir overdose.

Interaction:

The simultaneous use of valaciclovir with nephrotoxic drugs, including aminoglycosides, organic compounds of platinum, iodinated contrast medium, methotrexate, pentamidine, foscarnet, cyclosporine and tacrolimus should be carried out with caution, especially in patients with impaired renal function,and requires regular monitoring of kidney function.

Clinically significant interaction is not established.

Cimetidine and probenecid after taking 1 g of valaciclovir increase AUC acyclovir, reducing its renal clearance (however, dose adjustment of valacyclovir is not required because of the wide therapeutic index of acyclovir).

Care should be taken in case of simultaneous use of valaciclovir in high doses (4 g / day) and drugs that compete with acyclovir for elimination (the latter is eliminated with urine unchanged as a result of active tubular secretion), since there is a potential threat of an increase in plasma concentration of one or both drugs or their metabolites.

With the simultaneous use of acyclovir with mycophenolate mofetil, there was an increase AUC acyclovir and an inactive metabolite of mycophenolate mofetil.

Special instructions:

Reception of the drug in high doses for a long time under 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, seizures 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.

When violations of liver function in patients with mild or moderate cirrhosis of the liver (synthetic liver function preserved) dose adjustment Valvir 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,therefore, caution should be given to the drug in high doses of this category of patients.

Older patients are not required to adjust the dose, except for cases a significant violation of kidney function. It is necessary to maintain an adequate water-electrolyte balance.

Special studies to study the effects of Valvir in patients with liver transplant were not performed. However, it was shown that preventive the administration of acyclovir in high doses reduces cytomegalovirus infection.

Suppressive therapy with Valvir 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 Valvir, the patient must take measures to ensure safety partner in sexual intercourse.

Use in Pediatrics

The experience of clinical use of the drug in children is absent.

Effect on the ability to drive transp. cf. and fur:

Care should be taken in case of development of adverse reactions affecting the speed of psychomotor reactions.

Form release / dosage:

Film coated tablets, 500 mg and 1000 mg.

Packaging:

Tablets 500 mg: on 10 or 14 tablets in blisters from PVC / Aluminum foil. 1 blister (10 tablets) or 3 blisters (14 tablets each), along with instructions for use in a cardboard box.

Tablets 1000 mg: 7 tablets in PVC blisters / Aluminum foil. For 1 or 4 blisters together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001723

Date of registration:02.07.2012

Expiration Date:02.07.2017

The owner of the registration certificate:Actavis PTS ehf GroupActavis PTS ehf Group Iceland

Manufacturer: & nbsp

ACTAVIS hf. Iceland

Representation: & nbspAktavis, Open Company Aktavis, Open Company

Information update date: & nbsp06.02.2017

Illustrated instructions

Instructions

Valvier (Valvir)