Valtsikon

General characteristics. Structure:

Active ingredient: 556 mg of a valatsiklovir of a hydrochloride (in terms of валацикловир 500 mg).

Excipients: cellulose microcrystallic, hypro rod (hydroxypropyl cellulose), кросповидон, magnesium stearate.

Film cover: [a gipromelloza – 10,50 mg, a hypro rod (hydroxypropyl cellulose) – 4,07 mg, talc – 4,12 mg, titanium dioxide – 2,31 mg] or [dry mix for a film covering – white, containing a gipromelloza (50%), hydroxypropyl cellulose (19,4%), talc (19,6%), titanium dioxide (11%)].

Pharmacological properties:

Pharmacodynamics. Valatsiklovir – nukleozidny inhibitor of a DNA polymerase of viruses of herpes. Blocks synthesis of virus DNA and replication of viruses. In a human body валацикловир completely turns into an acyclovir and L-valine. The acyclovir of in vitro has the specific inhibiting activity concerning the herpes simplex viruses (HSV) of 1,2 types (Herpes simplex of 1,2 types), a virus of chicken pox and the surrounding herpes (VZV – a virus a varitsella-zoster, Varicella zoster), a cytomegalovirus (TsMV), the Epstein-Burra's virus (EBV) and a virus of herpes of the person 6 types. The acyclovir inhibits synthesis of virus DNA right after phosphorylation and transformation into an active form ацикловиртрифосфат. The first stage of phosphorylation occurs with the participation of virusospetsifichesky enzymes. For the VPG, VZV and VEB viruses such enzyme is the virus thymidinekinase which is present at the cells affected with a virus. Partial selectivity of phosphorylation remains at a cytomegalovirus and is mediated through a product of a gene of UL 97 phosphotransferase. Activation of an acyclovir specific virus enzyme substantially explains its selectivity.

Process of phosphorylation of an acyclovir (transformation from mono - in triphosphate) comes to the end with cellular kinases. Atsiklovirtrifosfat competitively inhibits a virus DNA polymerase and, being a nucleoside analog, is built in virus DNA that leads to an obligate rupture of a chain, the termination of synthesis of DNA and, therefore, to blocking of replication of a virus.

With the kept immunity the VPG and VZV viruses with a hyposensitivity to a valatsiklovir occur at patients extremely seldom (less than 0,1%), but can be sometimes found in patients with heavy disturbances of immunity, for example, with a marrow transplant, at receiving chemotherapy concerning malignant new growths and at HIV-positive people.

Resistance is caused by deficit of a thymidinekinase of a virus that leads to excessive spread of a virus in the owner's organism. Sometimes decrease in sensitivity to an acyclovir is caused by emergence of virus strains with disturbance of structure of a virus thymidinekinase or DNA polymerase. Virulence of these kinds of a virus reminds that at its wild strain.

Pharmacokinetics. Absorption. After intake валацикловир it is well absorbed from digestive tract, quickly and almost completely turns into an acyclovir and valine. This transformation is catalyzed by liver enzyme – valatsiklovirgidrolazy.

After a single dose of 250-2000 mg of a valatsiklovir average maximum concentration (Cmax) of an acyclovir in a blood plasma at healthy volunteers with normal function of kidneys averages 10-37 µmol/l (2,2-8,3 mkg/ml), and the average time of achievement of the maximum concentration of 1-2 h. At reception of a valatsiklovir in a dose from 1000 mg bioavailability of an acyclovir makes 54% and does not depend on meal. Cmax of a valatsiklovir in a blood plasma makes only 4% of concentration of an acyclovir and is reached on average in 30-100 min. after administration of drug; in 3 h the Cmax level remains the same or decreases. Valatsik-lovir and an acyclovir have similar pharmacokinetic parameters after intake.

Distribution. Communication with proteins of a valatsiklovir – 13-18%, an acyclovir – 9-33%. The acyclovir is well distributed in fabrics and liquids of an organism, including a brain, kidneys, lungs, a liver, watery moisture, the lacrimal liquid, intestines, muscles, a spleen, a uterus, a mucous membrane and a secret of a vagina, sperm, amniotic liquid, cerebrospinal fluid (50% of concentration in plasma), liquid of herpetic bubbles. The highest concentration are created in kidneys, a liver and intestines. Gets through a placenta and into breast milk.

Removal. Valatsiklovir is brought with urine, mainly in the form of an acyclovir (more than 80% of a dose) and its metabolite a 9-karboksimetoksimetilguanin, in not changed look less than 1% of drug are removed. The elimination half-life (T½) of a valatsiklovir makes less than 30 min., an acyclovir – 2,5-3,3 h. At elderly patients (65-83 years) Т½ an acyclovir makes 3,3-3,7 h, and patients with an end-stage of a renal failure have about 14 h.

The pharmacokinetics of a valatsiklovir and acyclovir substantially is not broken at the patients infected with the VPG and VZV viruses.

HIV-positive patients have pharmacokinetic parameters of an acyclovir after intake of a valatsiklovir in a dose of 1000 mg and 2000 mg are comparable to the parameters observed at healthy volunteers.

At recipients of transplants of the bodies receiving валацикловир in a dose of 2000 mg 4 times/days, Cmax of an acyclovir is equal or surpasses that at the healthy volunteers receiving the same dose of drug, and daily indicators of the area under pharmacokinetic curve (AUC) were much higher.

On late durations of gestation the steady daily indicator of the area under a pharmacokinetic curve after reception of 1000 mg of a valatsiklovir was approximately twice more, than that at reception of an acyclovir in a dose of 1200 mg a day.

Indications to use:

Adults:
- treatment of the surrounding herpes (Herpes zoster) (drug promotes stopping of a pain syndrome, reduces its duration and percent of patients with the pains caused by shingles including acute and post-herpetic neuralgia);
- treatment of infections of skin and the mucous membranes caused by the Herpes simplex virus 1,2 types, including for the first time the revealed and recurrent genital herpes (Herpes genitalis), and also labial herpes (Herpes labialis);
- prevention (suppression) of a recurrence of infections of skin and the mucous membranes caused by the Herpes simplex virus 1,2 types including genital herpes;
- prevention of transfer of a virus of genital herpes to the healthy partner at use of drug as suppressive therapy in a combination with safe sex.

Adults and children aged from 12 years are also more senior:
- prevention of a Cytomegaloviral (TsMV) infection, and also reaction of acute graft rejection (at patients with transplants of kidneys), opportunistic infections and other herpesviridae infections (VPG, VZV) after organ transplantation.

Route of administration and doses:

Drug is accepted inside, irrespective of meal, washing down with water.

Treatment of shingles (Herpes zoster). The recommended dose for adults makes 1000 mg of 3 times/days within 7 days.

Treatment of the infections caused by Herpes simplex. For adults the recommended dose for therapy of an episode makes 500 mg of 2 times/days within 5 days. In more hard cases of a debut of a disease it is necessary to begin as soon as possible, and its duration can be increased from 5 to 10 days. In case of a recurrence treatment has to continue 3 or 5 days. At a recurrence of the infections caused by Herpes simplex purpose of a valatsiklovir in a prodromal stage or at once after emergence of the first symptoms of a disease is considered ideal.

As an alternative for treatment of labial herpes purpose of a valatsiklovir in a dose of 2 g 2 times/days is effective. The second dose has to be accepted approximately in 12 h (but not earlier, than in 6 h) after reception of the first dose. When using such mode of dosing duration of treatment makes 1 days.

Therapy has to be begun at emergence of the earliest symptoms of labial herpes (i.e. tingling, an itch, burning).

Prevention (suppression) of a recurrence of the infections caused by Herpes simplex. At adult patients with the kept immunity the recommended dose makes 500 mg of 1 times/days. At patients with an immunodeficiency the recommended dose makes 500 mg of 2 times/days.

Prevention of transfer of genital herpes to the healthy partner. To the infected immunocompetent persons with a recurrence no more than 9 times a year the recommended dose of a valatsiklovir makes 500 mg of 1 times/days within a year and more than an every day.

Data on prevention of infection in other populations of patients are absent.

Prevention of a Cytomegaloviral infection after transplantation. The recommended dose for adults and teenagers at the age of 12 years is also more senior makes 2 g 4 times/days, is appointed as soon as possible after transplantation.

The dose should be reduced depending on KK. Duration of treatment makes 90 days, but at patients with high risk the course of treatment can be prolonged.

Patients with a renal failure. Treatment of shingles and the infections caused by Herpes simplex, prevention (suppression) of a recurrence of the infection caused by VPG, prevention of transfer of genital herpes to the healthy partner

The dose of a valatsiklovir is recommended to be reduced at patients with considerable depression of function of kidneys (see the dosing mode in table 1). At such patients it is necessary to support adequate hydration.

There is no experience of use of a valatsiklovir for children with KK values less than 50 ml/min. / 1.73 sq.m.

Indications	KK, ml/min.	Dose of a valatsiklovir
Herpes zoster	15-30	1 g 2 times/days
	less than 15	1 g 1 times/days
Treatment of the infection caused by the Herpes simplex virus (according to the scheme of 500 mg of 2 times/days)	less than 15	500 mg of 1 times/days
Treatment of labial herpes (according to the scheme of 2 g 2 times/days within one days)	31-49	1 g twice within one day
	15-30	500 mg twice within one day
	less than 15	500 mg once
Prevention (suppression) of a recurrence of the infections caused by VPG:
patients with normal immunity	less than 15	250 mg of 1 times/days
patients with reduced immunity	less than 15	500 mg of 1 times/days
decrease in risk of transfer of genital herpes	less than 15	250 mg of 1 times/days

The patients who are on a hemodialysis are recommended to apply валацикловир right after the end of a session of a hemodialysis in the same dose as to patients with KK less than 15 ml/min.

Prevention of a Cytomegaloviral infection after transplantation. The mode of purpose of a valatsiklovir at patients with a renal failure has to be set according to table 2.

Table 2

KK, ml/min.	Dose of a valatsiklovir
≥75	2 g 4 times/days
from 50 to <75	1.5 of 4 times/days
from 25 to <50	1.5 of 3 times/days
from 10 to <25	1.5 of 2 times/days
<10 or dialysis *	1.5 of 1 times/days

* At the patients who are on a hemodialysis валацикловир it is necessary to appoint after the end of a session of a hemodialysis.

It is necessary to define often KK, especially when function of kidneys quickly changes, for example, right after transplantation or engraftment of a transplant, at the same time the dose of a valatsiklovir is adjusted according to KK indicators.

Patients with an abnormal liver function. About an abnormal liver function of easy and moderate severity at safe synthetic function of dose adjustment of a valatsiklovir it is not required from adult patients.

Pharmacokinetic data at adult patients with heavy abnormal liver functions (dekompensirovanny cirrhosis), with disturbance of synthetic function of a liver and existence of a porto-caval anastomosis also do not confirm need to adjust a dose of a valatsiklovir, however clinical experience at this pathology is limited.

Children aged up to 12 years. There are no data on use of the drug Valtsikon® for children.

Patients of advanced age. Dose adjustment is not required except for a considerable renal failure. It is necessary to support adequate water and electrolytic balance.

Features of use:

Patients with risk have dehydrations, especially at patients of advanced age, during treatment it is necessary to provide adequate completion of liquid.

As the acyclovir is removed by kidneys, the dose of drug of Valtsikon has to be adjusted depending on extent of disturbance of renal function. At patients with a renal failure the increased risk of development of neurologic complications is noted, such patients need to provide careful observation. As a rule, these reactions have reversible character and disappear after drug withdrawal.

At patients with the chronic renal failure (CRF) it is recommended to define often clearance of creatinine, especially when function of kidneys quickly changes (in particular, right after transplantation or engraftment of a transplant), at the same time the dose of a valatsiklovir is adjusted according to indicators of clearance of creatinine.

There are no data on use of a valatsiklovir in high doses (4 g or any more in day) at patients with liver diseases therefore high doses of drug Valtsikon to them have to be appointed with care.

Suppressive therapy valatsikloviry reduces risk of transfer of genital herpes, but does not exclude risk of infection and does not lead to full treatment. Therapy by drug Valtsikon is recommended in combination with safe sex.

Administration of drug in high doses at the states which are followed by the expressed immunodeficiency (transplantation of marrow, clinically expressed HIV infection forms, transplantation of a kidney) led for a long time to development of a Werlhof's disease and a gemolitiko-uraemic syndrome, up to a lethal outcome.
At emergence of side effects from the central nervous system (including agitations, hallucinations, confusion of consciousness, nonsense, spasms and encephalopathy) drug is cancelled.

Influence on control of vehicles and mechanisms. There are no data on influence of the valatsiklovir applied in therapeutic doses on ability to control of vehicles and mechanisms. However at assessment of ability of the patient to drive the car or moving mechanisms it is necessary to consider that emergence of side effects from the central nervous system therefore it is necessary to be careful is possible.

Use at pregnancy and during breastfeeding. There are limited data on use of a valatsiklovir at pregnancy. Valatsik-lovir apply only when the potential advantage for mother exceeds possible risk for a fruit.

The registered data on the result of pregnancy at the women accepting валацикловир or an acyclovir (an active metabolite of a valatsiklovir), did not show increase in number of inborn defects at their children in comparison with the general population. As the register included a small amount of the women accepting валацикловир at pregnancy, the authentic and certain conclusions about safety of use of a valatsiklovir at pregnancy cannot be made.

The acyclovir, the main metabolite of a valatsiklovir, is allocated with breast milk. After reception of a valatsiklovir inside in a dose of 500 mg, Cmax of an acyclovir in breast milk by 0,5-2,3 times (on average by 1,4 times) exceeded the corresponding concentration of an acyclovir in a blood plasma of mother. Average value of concentration of an acyclovir in breast milk made 2,24 mkg/ml (9,95 µmol/l). At reception by mother of a valatsiklovir inside in a dose of 500 mg 2 times/days the child will undergo the same influence of an acyclovir, as at reception of an acyclovir inside in a dose about 0,61 mg/kg/days.

Side effects:

From the central nervous system: headache, dizziness, psychotic symptoms, agitation, decrease in mental capacities, ataxy, coma, confusion or oppression of consciousness, dysarthtia, encephalopathy, mania, hallucinations, spasms, tremor. The specified reactions are reversible and are usually observed at patients with a renal failure or against the background of other contributing states. At the patients with a transplanted organ receiving валацикловир in high doses (8 g/days) for prevention of a Cytomegaloviral infection, neurologic reactions develop more often than at reception in lower doses.

From respiratory system: диспноэ.

From the alimentary system: nausea, feeling of discomfort in a stomach, vomiting, diarrhea, reversible disturbances of functional hepatic trials (increase in activity of alaninaminotranspherase, aspartate aminotransferase, an alkaline phosphatase) which sometimes regard as display of hepatitis.

From system of a hemopoiesis: a leukopenia (it is generally noted at patients with reduced immunity), thrombocytopenia, anemia, a trombotichesky Werlhof's disease.

From integuments: mnogoformny erythema, rashes, photosensitization, alopecia.

Allergic reactions: itch, urticaria, Quincke's disease, anaphylaxis.

From an urinary system: pain in a projection of kidneys, renal failures, including an acute renal failure, renal colic. Renal colic can be connected with a renal failure.

From sense bodys: vision disorder.

Laboratory indicators: decrease in a hemoglobin content, giperkreatininemiya.

Others: dysmenorrhea, nasopharyngitis, respiratory infections, increase in arterial pressure, tachycardia, fatigue; at patients with heavy disturbances of immunity, especially at the adult patients with far come stage of HIV infection receiving валацикловир in high doses (8 g/days daily) for a long time, cases of a renal failure, mikroangiopatichesky hemolitic anemia and thrombocytopenia were observed (sometimes in a combination). Similar side reactions were noted at the patients with the same diseases but who are not receiving валацикловир.

Interaction with other medicines:

Cimetidinum and blockers of canalicular secretion reduce effect (reduce speed, but not completeness of transformation into an acyclovir). Correction of the mode of dosing with normal clearance of creatinine is not required from persons.

Nefrotoksichny medicines increase risk of development of renal failures. It is necessary to be careful (to watch change of function of kidneys) at a drug combination Valtsikon in higher doses (4 g a day and more) with drugs which exert impact on other functions of kidneys (for example: cyclosporine, такролимус).

The acyclovir is removed by kidneys, generally in not changed look, by means of active renal secretion. Combined use of medicines with this mechanism of removal can lead to increase in concentration of an acyclovir in a blood plasma.

After purpose of drug Valtsikon in a dose of 1000 mg Cimetidinum and пробенецид which are removed in the same way as валацикловир, increase the size AUC of an acyclovir and thus reduce its renal clearance. In view of a wide therapeutic index of an acyclovir, drug dose adjustment Valtsikon in this case is not required.

It is necessary to be careful in case of simultaneous use of a valatsiklovir in higher doses (4 g a day and above) and medicines which compete with an acyclovir for a way of elimination as there is a potential threat of increase in a blood plasma of level of one or both drugs or their metabolites. Increase in the size AUC of an acyclovir and inactive metabolite of a mikofenolat of a mofetil at simultaneous use of these drugs was noted.

The pharmacokinetics of a valatsiklovir does not change at a concomitant use with digoxin, aluminum / магнийсодержащими antacids, thiazide diuretics.

Contraindications:

Hypersensitivity to the valatsiklovir, an acyclovir and any other component which is a part of drug; HIV infection at the maintenance of CD4+ of lymphocytes less than 100 in 1 мкл; children's age (up to 12 years at prevention of a Cytomegaloviral infection after transplantation, up to 18 years – according to other indications).

With care. A liver/renal failure, advanced age, a hydropenia, a concomitant use of nefrotoksichny medicines, pregnancy, the lactation period, clinically expressed HIV infection forms at patients.

Overdose:

Symptoms: at overdose of a valatsiklovir developing of an acute renal failure and development of neurologic symptoms, including confusion of consciousness, hallucinations, agitation, oppression of consciousness and a coma is possible, also nausea and vomiting are noted. For the prevention of overdose it is necessary to adhere to care at drug use. Many cases of overdose were connected using drug for treatment of patients with a renal failure and patients of advanced age, owing to non-compliance with the mode of dosing (repeatedly received the doses of a valatsiklovir exceeding recommended).

Treatment. Patients are subject to careful observation for timely diagnosis of toxic manifestations. The hemodialysis considerably accelerates removal of an acyclovir from a blood plasma and can be considered as an optimum way of treatment in case of symptomatic overdose.

Storage conditions:

In the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 500 mg. On 5, 10 or 14 tablets in a blister strip packaging from a film of polyvinyl chloride and aluminum foil. On 42, 50 or 60 tablets in bank of polymeric. 2 or 4 blister strip packagings on 5 tablets, 1, 2, 3, 4, 5 or 6 blister strip packagings on 10 tablets or 3 blister strip packagings on 14 tablets, or to one bank together with the application instruction place in a pack from a cardboard.