Valtsit

General characteristics. Structure:

Active ingredient: 450 mg of a valgantsiklovir (in the form of a valgantsiklovir of a hydrochloride – 496.3 mg).

Excipients: K30 povidone, кросповидон, cellulose microcrystallic, stearic acid.

Cover: (gipromelloza of 2910 - 3 joint ventures, gipromelloza of 2910 - 6 joint ventures, titanium dioxide (E171), macrogoal 400, dye ferrous oxide red (E172), polysorbate 80); use of the ready mix Opadry Pink 15B24005 is allowed.

Pharmacological properties:

Pharmacodynamics. Action mechanism. Valgantsiklovir represents L-valilovy the ether (pro-medicine) of a gantsiklovir which after intake is quickly turning in ганцикловир under the influence of intestinal and hepatic esterases. Gantsiklovir - a synthetic analog 2 deoxyguanosines which suppresses replication of viruses herpes group of in vitro and in vivo. To the viruses of the person sensitive to a gantsiklovir, carry a cytomegalovirus (TsMV), viruses of a herpes simplex 1 and 2, a virus of herpes of the person of types 6, 7 and 8, Epstein-Barre's virus, a virus of chicken pox and a virus of hepatitis B.

In TsMV-infitsirovannykh cells under the influence of a virus protein kinase of UL97 ганцикловир it is phosphorylated with formation of a gantsiklovirmonofosfat in the beginning. Further phosphorylation happens under the influence of cellular kinases to formation of a gantsiklovirtrifosfat who then is exposed to slow intracellular metabolism. After disappearance of a gantsiklovir the period of intracellular semi-removal of a gantsiklovirtrifosfat in the cells infected with TsMV makes 18 hours of extracellular liquid; in the cells infected with a herpes simplex virus - 6-24 hours. As phosphorylation of a gantsiklovir more depends on action of a virus kinase, it occurs preferential in the infected cells.

Virostatichesky activity of a gantsiklovir is caused by suppression of synthesis of virus DNA by means of the following mechanisms: (1) competitive inhibition of embedding of a dezoksiguanozintrifosfat in DNA under the influence of a virus DNA polymerase; (2) inclusion of a gantsiklovirtrifosfat in virus DNA that leads to the termination of lengthening or very limited lengthening of virus DNA. According to the researches in vitro, the typical inhibiting concentration which suppresses replication of TsMV for 50% (IC50) is in the range from 0.08 µmol/l (0.02 mkg/ml) to 14 µmol/l (3.5 mkg/ml).

The clinical antiviral effect of the drug Valtsit® was proved by reduction of allocation of TsMV from an organism of patients with acquired immunodeficiency syndrome (AIDS) and for the first time the revealed TsMV-retinitis from an initial indicator of 46% to 7% in 4 weeks of treatment by the drug Valtsit®.

Efficiency. Adults. Treatment of the TsMV-retinitis. Clinical trials were conducted at patients with AIDS and the TsMV-retinitis. The drug Valtsit® showed identical clinical performance in induction therapy of the TsMV-retinitis in comparison with an intravenous gantsiklovir.

Use of the drug Valtsit® allows to receive the same system influence of a gantsiklovir, as when using of the recommended intravenous doses of a gantsiklovir, effective at treatment of the TsMV-retinitis. It is shown that the area under a curve "concentration time" (AUC) of a gantsiklovir correlates with a period before progressing of the TsMV-retinitis.

Prevention of the TsMV-infection. Frequency of development of the TsMV-disease (the TsMV-syndrome + an invasive infection of fabrics) within the first 6 months after transplantation of heart, a liver, a kidney at patients with high risk of the TsMV-infection (TsMV-pozitivny the donor (D+) / ЦМВ-негативный the recipient (R-) (D+/R-) made 12.1% in group of the patients receiving the drug Valtsit® (900 mg a day), and 15.2% in group of the patients receiving ганцикловир in (1000 mg 3 times a day) from 10 to 100 day after transplantation. The most part of cases fell on the period after cancellation of preventive therapy (after the 100th day of the post-transplant period). At the same time cases of development of the TsMV-infection in group of treatment valgantsikloviry appeared later, than in group of treatment gantsikloviry. Frequency of acute graft rejection in the first 6 months made 29.7% in group of the patients receiving валганцикловир and 36% in group of the patients receiving ганцикловир.

Increase in duration of reception of 900 mg of the drug Valtsit® till 200th day after transplantation of kidneys at patients with high risk of the TsMV-infection (D+/R-) was followed by bigger efficiency of prevention of the TsMV-infection in the first 12 months after transplantation in comparison with reception of 900 mg of the drug Valtsit® till 100th day after transplantation.

Frequency of survival of a transplant in 12 months made 98.2% in group of the patients receiving the drug Valtsit® till 100th day and 98.1% in group of the patients receiving the drug Valtsit® till 200th day. Frequency of the acute graft rejection confirmed with a biopsy in the first 12 months made 17.2% in group of the patients receiving валганцикловир till 100th day and 11.0% in group of the patients receiving валганцикловир till 200th day.

Virus resistance. At long reception of a valgantsiklovir the viruses steady against a gantsiklovir can develop. It can be caused or selection of mutations of a gene of a virus kinase (UL97) which is responsible for monophosphorylation of a gantsiklovir, or gene of a virus DNA polymerase (UL54). Mutations of a gene of UL97 arise in earlier terms and meet more often in comparison with UL54 gene mutation. The virus having only UL97 gene mutation is steady only against a gantsiklovir; at the same time the most often found mutations as replacement associated with stability emergence are M460V/I, H520Q, C592G, A594V, L595S, C603W. The virus with mutations of a gene of UL54 can have cross resistance to other antiviral drugs with the similar mechanism of action and vice versa. Development of cross resistance to a tsidofovir is in most cases caused by mutations as replacement in ekzonukleazny domains and the region of the V virus DNA polymerase. Development of cross resistance to a foskarnet is caused by mutations as replacement within regions of II (a codon 696-742) and III (a codon 805-845) a virus DNA polymerase or between them.

Adults. Treatment of the TsMV-retinitis. Genotyping of TsMV in polymorphonuclear leukocytes showed that in 3, 6, 12 and 18 months of treatment valgantsikloviry respectively in 2.2%, 6.5%, 12.8% and 15.3% of leukocytes come to light UL97 mutations.

Prevention of the TsMV-infection at patients after transplantation of solid bodies
Genotyping of TsMV in polymorphonuclear leukocytes showed:
1)     lack of the mutations causing resistance to a gantsiklovir in the samples received for the 100th day (the end of preventive reception of a valgantsiklovir) at patients from group of a valgantsiklovir and existence of mutations in the samples received at the patients accepting ганцикловир orally (1.9%);
2)     lack of the mutations causing resistance in the samples received at patients randomized in group of a valgantsiklovir with the suspected TsMV-infection in 6 months after transplantation, and existence of mutations at the patients receiving ганцикловир orally in 6.9%.

Among the patients receiving валганцикловир till 100th day and till 200th day of the post-transplant period, in general mutations as replacement met during performing preventive therapy more often, than after its end (5/12 [42%] in comparison with 4/58 [7%]).

Virus resistance can be the cause of the insufficient response to therapy and a constant virusovydeleniye during therapy.

Preclinical data on safety. Carcinogenicity of a gantsiklovir is proved in researches on mice. Valgantsiklovir, as well as ганцикловир, is potential carcinogen.

Valgantsiklovir and ганцикловир had mutagen effect in cells of a lymphoma of mice and clastogene effect in cells of mammals.

Considering bystry and full transformation of drug in ганцикловир, additional researches of reproductive toxicity with valgantsikloviry were not conducted. The same warning of possible reproductive toxicity belongs to both drugs (see the section "Special Instructions"). At animals ганцикловир breaks fertility and renders teratogenic effect. Taking into account experiments on animals at whom system influence of a gantsiklovir in concentration is lower than therapeutic caused an aspermia, it is very probable that ганцикловир and валганцикловир can oppress a spermatogenesis at the person.

The data obtained in model with use of a placenta of the person of ex vivo show what ганцикловир gets through a placenta, most likely, by simple transfer. In the range of concentration from 1 to 10 mg/ml transition of drug through a placenta had not saturable character and was carried out by means of passive diffusion.

Pharmacokinetics. Pharmacokinetic characteristics of a valgantsiklovir were studied at HIV - and TsMV-seropolozhitelnykh patients, at patients with AIDS and the TsMV-retinitis and after transplantation of solid bodies.

The parameters defining exposure of a gantsiklovir after reception of a valgantsiklovir are bioavailability and function of kidneys. All patients receiving валганцикловир had a similar bioavailability of a gantsiklovir. System exposure of a gantsiklovir for recipients of a transplant of heart, kidney, liver was similar to that after oral administration of a valgantsiklovir according to the dosing mode depending on function of kidneys.

Absorption. Valgantsiklovir is pro-medicine of a gantsiklovir, is well soaked up in digestive tract, in a wall of intestines and in a liver is quickly metabolized with formation of a gantsiklovir. Absolute bioavailability of a gantsiklovir after reception of a valgantsiklovir makes about 60%. System exposure of a valgantsiklovir low also has short-term character. The area under a curve "concentration time" (AUC24) and the maximum concentration in a blood plasma (Cmax) make about 1% and 3% of those of a gantsiklovir, respectively.

Proportional dependence of AUC of a gantsiklovir on a dose after reception of a valgantsiklovir in doses from 450 to 2625 mg is shown only for a case of administration of drug after food. If валганцикловир accept during food in the recommended dose 900 mg, increase as an average value of AUC24 (approximately for 30%), and an average value of Cmax (approximately for 14%) a gantsiklovira. Therefore, the drug Valtsit® is recommended to be accepted during food (see the section "Route of Administration and Doses").

Distribution. Thanks to bystry metabolism of a valgantsiklovir in ганцикловир, linkng of a valgantsiklovir with proteins of plasma was not defined. Linkng of a gantsiklovir with proteins of plasma at concentration of drug from 0.5 to 51 mkg/ml makes 1-2%. The equilibrium volume of distribution of a gantsiklovir after intravenous administration made 0.680±0.161 l/kg.

Metabolism. Valgantsiklovir is quickly hydrolyzed with formation of a gantsiklovir, other metabolites is not revealed. After a single dose in 1000 mg marked radioactive isotope of a gantsiklovir the indicator of radioactivity of any of metabolites in Calais or urine did not exceed 1-2%.

Removal. In the main way of removal of a valgantsiklovir, as well as a gantsiklovir, glomerular filtering and active canalicular secretion is. 81.5±22% of system clearance of a gantsiklovir are the share of renal clearance.

Pharmacokinetics at special groups of patients. Patients with a renal failure. The renal failure led to decrease in clearance of the gantsiklovir which is formed of a valgantsiklovir with the corresponding increase in an elimination half-life in a terminal phase. Therefore, patients with a renal failure need dose adjustment (see the subsection "Special Instructions on Dosing" of the section "Route of Administration and Doses" and the section "Special Instructions").

Patients with a liver failure. The pharmacokinetics of the gantsiklovir which is formed of a valgantsiklovir was studied at patients with steadily functioning liver transplant in an open research from the 4th component cross design. Absolute bioavailability of the gantsiklovir which is formed of a valgantsiklovir (at a single dose of drug in a dose of 900 mg after food), made about 60% that matches an indicator at other groups of patients. AUC0-24 of a gantsiklovir was comparable to that after intravenous administration of a gantsiklovir in a dose of 5 mg/kg by the patient who transferred liver transplantation.

Indications to use:

Treatment of the TsMV-retinitis at adult patients with AIDS.

Prevention of the TsMV-infection after transplantation of solid bodies at adults and children is more senior than 16 years from risk group.

Route of administration and doses:

In order to avoid overdose it is necessary to observe recommendations about the dosing mode strictly.

Standard mode of dosing. The drug Valtsit® should be accepted inside during food (see the subsections "Absorption" and "Pharmacokinetics at Special Groups of Patients" of the section "Pharmacological Properties"). Valgantsiklovir is quickly and substantially metabolized with formation of a gantsiklovir. Bioavailability of a gantsiklovir in case of reception of tablets of the drug Valtsit® is 10 times higher, than in case of oral administration of a gantsiklovir (see the sections "Special Instructions" and "Overdose"). 

Therapy of the TsMV-retinitis. Adults. Induction therapy of the TsMV-retinitis. At patients with an active TsMV-retinitis the recommended dose of the drug Valtsit® makes 900 mg (2 tablets on 450 mg) 2 times a day within 21 days. Long induction therapy increases risk of a miyelotoksichnost (see the section "Special Instructions").

Maintenance therapy of the TsMV-retinitis. After carrying out a course of induction therapy or at patients with an inactive TsMV-retinitis the recommended dose makes 900 mg (2 tablets on 450 mg) 1 time a day. If the current of a retinitis worsens, the course of induction therapy can be repeated (see the subsection "Induction Therapy of the TsMV-retinitis" of the section "Route of Administration and Doses").

Prevention of the TsMV-infection after transplantation solid organovvzrosly
The patients who transferred transplantation of a kidney need to begin therapy with the drug Valtsit® during the first 10 days after operation in a dose of 900 mg (2 tablets on 450 mg) 1 time a day and to continue therapy till 200th day of the post-transplant period.

The patients who transferred transplantation of other solid bodies need to begin therapy with the drug Valtsit® during the first 10 days after operation in a dose of 900 mg (2 tablets on 450 mg) 1 time a day and to continue therapy till 100th day of the post-transplant period.

Special instructions on dosing. Patients with a renal failure. It is necessary to carry out careful control of concentration of creatinine in blood serum or clearance of creatinine. Dose adjustment at adult patients is carried out depending on clearance of creatinine as it is shown in the table given below (see the subsection "Pharmacokinetics at Special Groups of Patients" of the section "Pharmacological Properties" and the section "Special Instructions").

The clearance of creatinine is calculated depending on concentration of creatinine in blood serum on the following formula:

                              (140 - age of [years]) x (body weight [kg])
for men = ------------------------------------------------------------------------------------
                         (72) x (0.011 x concentration of creatinine in blood serum [µmol/l])

for women = 0.85 x an indicator for men

Clearance of creatinine (ml/min.)
 Dose for induction therapy
 Dose for the supporting therapy/prevention
 
³60
 900 mg 2 times a day
 900 mg of 1 times a day
 
40-59
 450 mg 2 times a day
 450 mg of 1 times a day
 
25-39
 450 mg of 1 times a day
 To 450 mg there are each 2 days
 
10-24
 To 450 mg there are each 2 days
 450 mg 2 times a week
 
<10
 it is not recommended
 it is not recommended

Patients with a liver failure. Efficiency and safety are not established. Patients with a heavy leukopenia, a neutropenia, anemia, thrombocytopenia or a pancytopenia. At the patients receiving the drug Valtsit® (and ганцикловир), cases of a heavy leukopenia, a neutropenia, anemia, thrombocytopenia, a pancytopenia, oppression of marrow and aplastic anemia were noted. Treatment should not be begun if the absolute number of neutrophils is less than 500 cells in 1 мкл or number of thrombocytes less than 25000 cells in 1 мкл and also if hemoglobin is lower than 80 g/l. Patients with a heavy leukopenia, a neutropenia, anemia and/or thrombocytopenia are recommended to appoint hemopoietic growth factors and/or to interrupt administration of drug (see the sections "Special Instructions" and "Side effect").

Patients of advanced age. Efficiency and safety are not established.

Patients of children's age. Therapy of the TsMV-retinitis. It is not recommended to apply drug Valtsit® tablets at children up to 18 years for the purpose of therapy of the TsMV-retinitis as efficiency and safety of use of the drug Valtsit® for this age group is not established.

Prevention of the TsMV-infection after transplantation solid organovrezhy dosing at children aged from 16 to 18 years does not differ from the dosing mode at adults (see the subsection "Prevention of the TsMV-infection after Transplantation of Solid Bodies" of the section "Route of Administration and Doses"). Tablets of the drug Valtsit® are not recommended to apply at children and teenagers up to 16 years for the purpose of prevention of the TsMV-infection after transplantation of solid bodies as efficiency and safety of use of the drug Valtsit® for this age group is not established.

Features of use:

Additional researches of reproductive toxicity with valgantsikloviry were not conducted because of bystry and full transformation of a valgantsiklovir in ганцикловир. Gantsiklovir breaks fertility and has teratogenic effect at animals (see the subsection "Preclinical Data on Safety" of the section "Pharmacological Properties").

During treatment by the drug Valtsit® women of childbearing age should recommend to use reliable methods of contraception, men are recommended to use a barrier method of contraception during treatment and not less than 90 days after its termination (see the subsection "Preclinical Data on Safety" of the section "Pharmacological Properties" and the section "Special Instructions").

Safety of use of the drug Valtsit® at pregnancy at the person is not established. At pregnancy of purpose of the drug Valtsit® it is necessary to avoid, except for cases when the potential positive effect of treatment for mother justifies possible risk for a fruit.

Researches of influence of a valgantsiklovir and gantsiklovir on peri-and post-natal development was not carried out, at the same time it is impossible to exclude a possibility of allocation of a gantsiklovir with breast milk and development of serious side reactions in the baby. Thus, the decision on drug withdrawal or on the termination of breastfeeding should be accepted on the basis of assessment of potential positive effect of treatment for the nursing mother and risk for the baby.

In experiments on animals mutagen, teratogenic, aspermatogenny and cancerogenic action of a gantsiklovir was revealed. The drug Valtsit® should be considered potential teratogen and carcinogen for the person whose use can cause inborn malformations and cancer (see the subsection "Rules of the Treatment of Drug" of the section "Special Instructions"). Besides, it is probable that the drug Valtsit® can temporarily or it is irreversible to suppress a spermatogenesis (see the sections "Side Effect", "Use at Pregnancy and during Breastfeeding", the subsection "Preclinical Data on Safety" of the section "Pharmacological Properties").

At the patients receiving the drug Valtsit® (and ганцикловир), cases of a heavy leukopenia, a neutropenia, anemia, thrombocytopenia, a pancytopenia, oppression of function of marrow and aplastic anemia were noted. Treatment should not be begun if the absolute number of neutrophils is less than 500 cells in 1 мкл or number of thrombocytes less than 25000 cells in 1 мкл and also if hemoglobin is lower than 80 g/l (see the subsection "Special Instructions on Dosing" of the section "Route of Administration and Doses" and the section "Side effect").  

During treatment it is regularly recommended to carry out control of the developed blood count and thrombocytes. Patients with a heavy leukopenia, a neutropenia, anemia and/or thrombocytopenia are recommended to appoint hemopoietic growth factors and/or to interrupt administration of drug.

Long induction therapy by the drug Valtsit® increases risk of a miyelotoksichnost.

At simultaneous use of a gantsiklovir and imipenema/tsilastatin for patients spasms were noted. It is necessary to avoid simultaneous use of a valgantsiklovir and an imipenema/tsilastatin in cases if potential advantages of treatment do not exceed possible risk.

As as a zidovudine, and ганцикловир can cause a neutropenia and anemia, at some patients the intolerance at a concomitant use of a valgantsiklovir and a zidovudine in full doses can be noted.

Due to the possible increase in plasma concentration of a didanozin in the presence of a gantsiklovir, it is necessary to observe carefully patients regarding emergence of symptoms of toxic action of a didanozin.  

Use of the drug Valtsit® along with other drugs rendering myelosuppressive or nephrotoxic effect (see the section "Interaction with Other Medicines"), can strengthen their toxic action.

Controlled clinical trial of use of a valgantsiklovir for prevention of the TsMV-infection did not include patients after transplantation of a lung and intestines therefore experience of use of drug for such patients is limited.

Bioavailability of a gantsiklovir from drug Valtsit® tablets by 10 times exceeds that of capsules of a gantsiklovir. Gantsiklovir it is impossible to replace with the drug Valtsit® in the ratio 1:1. Patients who are transferred from capsules of a gantsiklovir should be informed on risk of overdose if they take bigger number of a pill of the drug Valtsit®, than it is recommended (see the sections "Route of Administration and Doses" and "Overdose").

Rules of the treatment of drug. Tablets cannot be broken or made small. As the drug Valtsit® potentially тератогенен is also cancerogenic for the person, it is necessary to be careful if the tablet broke. It is necessary to avoid direct contact of the broken or crushed tablet with skin and mucous membranes. In cases of such contact it is necessary to wash out carefully this place water with soap, at hit in eyes - they are carefully washed out sterile water, and at its absence - simple water.

Hit of medicines to the environment has to be minimized. It is not necessary to utilize drug by means of sewage or together with household waste. It is whenever possible necessary to use special systems for utilization of medicines.

Influence on ability to control of vehicles and work with cars and mechanisms. At treatment by the drug Valtsit® and/or gantsikloviry developing of spasms, sedations, dizzinesses, an ataxy and/or confusion of consciousness is possible that can negatively influence the activity demanding the increased concentration of attention including control of vehicles and work with cars and mechanisms. In this regard during treatment by the drug Valtsit® it is necessary to be careful at control of vehicles and work with cars and mechanisms. At emergence of the described undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

Valgantsiklovir represents pro-medicine of a gantsiklovir which after intake quickly turns in ганцикловир therefore all known undesirable effects connected with reception of a gantsiklovir are expected for the drug Valtsit®. All undesirable phenomena registered in clinical trials of the drug Valtsit® were observed at treatment gantsikloviry earlier.

Adults. Treatment of the TsMV-retinitis at patients with AIDS. Profiles of safety of a valgantsiklovir and a gantsiklovir at intravenous administration within 28 days were identical. Diarrhea, a neutropenia and fever were the most frequent undesirable phenomena. At the patients receiving the drug Valtsit® orally candidiasis of a mucous membrane of an oral cavity, a headache and weakness was more often noted, and at therapy gantsikloviry intravenously – nausea and the undesirable phenomena in the place of an injection (phlebitis and thrombophlebitis) (see table 1).

The undesirable phenomena (regardless of their gravity and communication with administration of drug) with a frequency of emergence of 5% received in clinical trials on use of a valgantsiklovir or for patients with the TsMV-retinitis are presented in the following table (see table 2) or at patients is after transplantation of solid bodies.

The most frequent undesirable reactions regardless of gravity, but, according to researchers, connected with administration of drug (the remote, probable or possible communication) at patients with the TsMV-retinitis were: neutropenia, anemia, diarrhea and nausea.

Prevention of the TsMV-infection at patients after organ transplantation. The undesirable phenomena (up to 28 days after completion of a research) regardless of their gravity and communication with administration of drug, with frequency of emergence of 5% received in clinical trials at patients after transplantation of the solid bodies receiving валганцикловир or ганцикловир orally are presented in table 2, beginning administration of drugs within 10 days after transplantation and continuing reception till 100th day of the post-transplant period.

The most frequent undesirable reactions regardless of gravity, but, according to researchers, connected with administration of drug (the remote, probable or possible communication) at patients after transplantation of the solid bodies receiving treatment till 100th day of the post-transplant period: leukopenia, diarrhea, nausea, neutropenia; at the patients who transferred transplantation of a kidney and receiving treatment till 200th day of the post-transplant period: leukopenia, neutropenia, anemia and diarrhea.
Further the serious undesirable phenomena according to the company connected with administration of drug of Valtsit®, meeting with frequency less than 5% of three clinical trials and not stated above are listed.

From blood and lymphatic system: pancytopenia, oppression of function of marrow, aplastic anemia, febrile neutropenia; potentially life-threatening bleedings connected with development of thrombocytopenia.

From urinogenital system: decrease in clearance of creatinine.

From the central and peripheral nervous system: spasms, psychotic frustration, hallucinations, confusion of consciousness, agitation.

From an organism in general: reactions of hypersensitivity to a valgantsiklovir.

The neutropenia (absolute number of neutrophils less than 500 in 1 мкл) meets at patients with the TsMV-retinitis (16%) more often more often, than at the patients receiving валганцикловир (5%) or peroral ганцикловир (3%) after organ transplantation till 100th day of the post-transplant period or at the patients receiving валганцикловир (10%) till 200th day of the post-transplant period. At the patients receiving both валганцикловир, and ганцикловир orally after organ transplantation till 100th day or the 200th day of the post-transplant period in comparison with patients with the TsMV-retinitis more substantial increase of concentration of creatinine in blood serum is observed. The renal failure is characteristic of the patients who transferred organ transplantation.

The general profile of safety of the drug Valtsit® does not change at increase in the period of preventive use up to 200 days for patients after renal transplantation from risk group. At the patients receiving валганцикловир till 200th day of the post-transplant period, in comparison with patients, receiving валганцикловир till 100 in the afternoon the post-transplant period, some increase in frequency of a leukopenia is observed.

Frequency of development of a neutropenia, anemia and thrombocytopenia is similar at the patients receiving treatment till 100th day and the 200th day of the post-transplant period.

As валганцикловир it is quickly metabolized with formation of a gantsiklovir, the undesirable phenomena noted at treatment gantsikloviry and not mentioned above are included below.

From the alimentary system: cholangitis, dysphagy, eructation, esophagitis, incontience calla, meteorism, gastritis, gastrointestinal frustration, gastrointestinal bleeding, stomacace, pancreatitis, glossitis, hepatitis, jaundice.

From an organism in general: the adynamy, bacterial, fungal and viral infections, an indisposition, mukozit, reaction of a photosensitization, a shiver, sepsis.

From skin and a hypodermic fatty tissue: alopecia, xeroderma, perspiration, small tortoiseshell.

From the central and peripheral nervous system: sleep disorders, amnesia, feeling of alarm, an ataxy, a coma, dryness in a mouth, emotional frustration, a hyperkinetic syndrome, a hyper tone, decrease in a libido, myoclonic twitchings, nervousness, drowsiness, disturbances of intelligence.

From a musculoskeletal system: ostealgia and muscles, myasthenic syndrome.

From urinogenital system: hamaturia, impotence, frequent urination.

From endocrine system: diabetes mellitus.

From laboratory indicators: increase in activity of an alkaline phosphatase, kreatinfosfokinaza, lactate dehydrogenase in blood, decrease in concentration of glucose in blood, a hypoproteinemia.

From sense bodys: an amblyopia, a blindness, ear pains, a hematopsia, pain in eyeglobes, deafness, glaucoma, disturbances of flavoring perception, a sonitus, a vision disorder, changes in a vitreous.

From blood and lymphatic system: eosinophilia, leukocytosis, limfoadenopatiya, splenomegaly, bleedings.

From cardiovascular system: arrhythmias, including ventricular, migraine, phlebitis, tachycardia, thrombophlebitis of deep veins, vazodilatation.

From respiratory system: developments of stagnation in paranasal sinuses.

Children. Prevention of the TsMV-infection at patients after organ transplantation
The undesirable phenomena (which developed till 28 in the afternoon after completion of a research) regardless of their gravity and communication with administration of drug are presented in table 4.

The table included the undesirable phenomena with a frequency of emergence of 10% registered in clinical trials at children aged from 3 weeks up to 16 years after transplantation of the solid bodies which began reception of a valgantsiklovir within 10 days after transplantation and continuing treatment till 100th day of the post-transplant period and also at children is after transplantation of a kidney, begun reception of a valgantsiklovir within 10 days after transplantation and continuing treatment till 200th day of the post-transplant period.

The general profile of safety of the drug Valtsit® at children does not differ from a profile of safety of drug at adults. Some undesirable phenomena were observed at children with a bigger frequency, than adults have, for example, upper respiratory tract infections, fever, abdominal pains and a dysuria that can reflect features of children's population.

In children's population some increase in frequency of a neutropenia was observed, however it did not lead to increase in frequency of infections.

At the children who transferred transplantation of a kidney, increase in the period of preventive use up to 200 days does not lead to increase in frequency of the undesirable phenomena.

The heavy neutropenia was more often observed at the children who transferred a trasplantation of a kidney and receiving валганцикловир till 200th day of the post-transplant period in comparison with the children receiving валганцикловир till 100th day of the post-transplant period and also in comparison with the adults who transferred a trasplantation of a kidney and receiving валганцикловир till 100th and 200th day of the post-transplant period.

Inborn TsMV-infection. The available limited data demonstrate that the safety profile at use of a valgantsiklovir or gantsiklovir up to 6 months for the purpose of therapy of an inborn TsMV-infection at newborns aged from 2 up to 31 days does not differ from that at adults. At use of a gantsiklovir 3 and 4 degrees (38%) were most often reported about a neutropenia. Only in one case antiviral therapy was cancelled because of development of a neutropenia, in other cases the neutropenia gave in to correction without therapy cancellation. At all newborns increase in the indicators characterizing growth and development (growth, body weight, an average circle of the head) was observed. At use of a valgantsiklovir the neutropenia, anemia, an abnormal liver function and diarrhea were the most frequent undesirable phenomena (it should be noted that the listed undesirable phenomena occurred at the patients who were not receiving drug and with a bigger frequency, than at patients who received drug). The neutropenia and anemia (which are also more often observed at the patients who were not receiving drug) were the only serious undesirable phenomena connected with treatment. It was not observed statistically or clinically significant distinctions between the patients who were receiving and not receiving валганцикловир in the indicators characterizing growth and development (growth, body weight, an average circle of the head).

As валганцикловир it will quickly and substantially be transformed in ганцикловир, the undesirable phenomena observed at use of a gantsiklovir can develop also at treatment by the drug Valtsit®.

The undesirable phenomena described in spontaneous messages during post-marketing use of a gantsiklovir (orally or intravenously), which are not mentioned in one of the above-stated sections for which it is impossible to exclude relationship of cause and effect with drug: an anaphylaxis, decrease in fertility at men.

The undesirable phenomena described at post-marketing use of drug are similar to those which were noted at conduct of clinical trials of the drug Valtsit® and a gantsiklovir.

Interaction with other medicines:

On model of intestinal permeability in situ at rats of interactions of a valgantsiklovir with valatsikloviry, didanoziny, nelfinaviry, cyclosporine, omeprazoly and the mikofenolat mofetily is not revealed.

Valgantsiklovir will be transformed in ганцикловир therefore the interactions characteristic of a gantsiklovir can be expected also at drug Valtsit® use.

Medicinal interactions of a gantsiklovir. Extent of linkng of a gantsiklovir with proteins of plasma makes only 1-2% therefore the reactions connected with substitution of proteinaceous binding are not expected.

Imipenem/tsilastatin: at simultaneous use of a gantsiklovir and imipenema/a tsilastatin at patients spasms were noted. It is necessary to avoid simultaneous use of a valgantsiklovir and an imipenema/tsilastatin in cases if potential advantages of treatment do not exceed possible risk (see the section "Special Instructions").

Probenetsid: concomitant oral administration of a probenetsid led to statistically significant decrease in renal clearance of a gantsiklovir (20%) and to increase in duration of its action (40%). It is explained by the interaction mechanism - the competition for canalicular renal excretion. The patients accepting at the same time пробенецид and the drug Valtsit®, have to be under careful observation because of possible toxic action of a gantsiklovir.

Zidovudine: at simultaneous use with a peroral gantsiklovir small, but statistically significant increase in AUC of a zidovudine (17%) was noted; besides, statistically insignificant tendency to decrease in concentration of a gantsiklovir was noted. As as a zidovudine, and ганцикловир can cause a neutropenia and anemia, at some patients the intolerance at a concomitant use of a valgantsiklovir and a zidovudine in full doses can be noted (see the section "Special Instructions").
Didanozin: permanent increase in concentration of a didanozin in plasma at simultaneous use was revealed with gantsikloviry (both at intravenous, and at a peroral route of administration). In case of oral administration of a gantsiklovir in a dose of 3 and 6 g a day increase in AUC of a didanozin by 84-124% was noted, at intravenous administration of a gantsiklovir in doses of 5-10 mg/kg/days of AUC the didanozina increased by 38-67%. This increase cannot be explained with competitive interaction for renal canalicular excretion as the percent of removal of a didanozin at the same time increased. Increase in bioavailability or delay of metabolism can be the reasons of this increase. Clinically significant influence on concentration of a gantsiklovir was not noted. However, considering increase in plasma concentration of a didanozin in the presence of a gantsiklovir, it is necessary to observe carefully patients regarding emergence of symptoms of toxic action of a didanozin at drug Valtsit® use (see the section "Special Instructions").

Mofetit Mikofenolat: on the basis of results of a research on single intravenous administration of the recommended dose of a gantsiklovir and oral administration of a mikofenolat of a mofetil, and also the known influence of a renal failure on pharmacokinetics of a mikofenolat of a mofetil and gantsiklovir, it is possible to expect that mofetit simultaneous use of a valgantsiklovir and mikofenolat, rendering competitive interaction in the course of canalicular secretion, will lead to increase in concentration of a gantsiklovir and phenolic glucuronide of mikofenolovy acid. Essential change of pharmacokinetics of mikofenolovy acid is not expected therefore it is not required to adjust a dose of a mikofenolat of a mofetil. At patients with a renal failure who at the same time receive a mikofenolat mofetit and валганцикловир, it is necessary to observe recommendations about dose adjustment of a valgantsiklovir and to make careful observation.

Zaltsitabin: залцитабин raised AUC0-8 of orally accepted gantsiklovir for 13%. Statistically significant changes of other pharmacokinetic parameters were not noted. Clinically significant changes of pharmacokinetics of a zaltsitabin at concomitant oral administration of a gantsiklovir were not also revealed, despite insignificant increase in a constant of speed of elimination.

Stavudin: at concomitant oral administration of a gantsiklovir and stavudin of statistically significant pharmacokinetic interaction it was not noted.

Trimethoprimum: Trimethoprimum statistically significantly reduced renal clearance of the gantsiklovir accepted orally that was followed by also statistically significant reduction in the rate of terminal elimination and the corresponding increase of an elimination half-life for 15% by 16.3%. Nevertheless, the clinical importance of these changes is improbable as AUC0-8 and Cmax at the same time did not change. Increase in the minimum concentration (Cmin) by 12% was the only statistically significant change of pharmacokinetic parameters of Trimethoprimum at a concomitant use of a gantsiklovir. However it is unlikely it has clinical value therefore dose adjustment of a valgantsiklovir is not required.

Cyclosporine: when comparing concentration of cyclosporine before reception of the following dose of data that ганцикловир changed cyclosporine pharmacokinetics it was not received. Nevertheless, after the beginning of use of a gantsiklovir some increase in the maximum concentration of creatinine in blood serum was noted.

Other possible medicinal interactions: as the main way of removal of a gantsiklovir is glomerular filtering and active canalicular secretion (see the subsection "Removal" of the section "Pharmacological Properties"), use of a valgantsiklovir along with anti-retrovirus drugs which are also removed by means of active canalicular secretion (for example, nucleases (t) by idny inhibitors of the return transcriptase), can affect concentration of a valgantsiklovir and/or jointly the used drugs. Use of a gantsiklovir along with other drugs rendering myelosuppressive or nephrotoxic effect (for example, dapsone, pentamidine, flutsitoziny, Vincristinum, vinblastine, adriamycin, Amphotericinum In, analogs of nucleosides, a hydroxycarbamide and pegylated interferonami/ribaviriny), can strengthen their toxic action. Therefore these drugs can be used along with valgantsikloviry only if the expected advantage of the carried-out treatment exceeds possible risk (see the section "Special Instructions").

Contraindications:

Because of a similar chemical structure of an acyclovir, a valatsiklovir and a valgantsiklovir reactions of cross sensitivity to these drugs are possible.

The absolute number of neutrophils less than 500 cells in 1 мкл, number of thrombocytes less than 25000 cells in 1 мкл or concentration of hemoglobin are lower than 80 g/l (see the section "Special Instructions").

Clearance of creatinine less than 10 ml/min.

Children's age up to 16 years (prevention of the TsMV-infection after transplantation of solid bodies at adults and children is more senior than 16 years from risk group).

Children's age up to 18 years (treatment of the TsMV-retinitis at adult patients with AIDS).

With care. Advanced age (safety and efficiency of drug are not established).

Overdose:

One adult patient at use has a valgantsiklovira within several days in doses not less than 10-multiply exceeding recommended taking into account a renal failure (decrease in clearance of creatinine) oppression of marrow (a medullary aplasia) with a lethal outcome developed.

It is possible that the overdose of a valgantsiklovir can lead to increase in nephrotoxicity (see the sections "Special Instructions" and "Route of Administration and Doses").

It is possible to reduce concentration of a valgantsiklovir in plasma at patients with overdose by a hemodialysis and hydration.

Overdose of a gantsiklovir at intravenous administration. As валганцикловир it will quickly and substantially be transformed in ганцикловир, the undesirable phenomena observed at overdose of a gantsiklovir can be expected and at drug Valtsit® overdose.

During clinical trials and post-marketing use of drug cases of overdose of a gantsiklovir at intravenous administration were described. Some of them were not followed by the undesirable phenomena.

At most of patients it was noted one or several of the following undesirable phenomena:
- gematotoksichnost: pancytopenia, oppression of function of marrow, medullary aplasia, leukopenia, neutropenia, granulocytopenia;
- hepatotoxic: hepatitis, abnormal liver function;
nephrotoxicity: strengthening of a hamaturia at patients with already available renal failure, an acute renal failure, increase in concentration of creatinine in blood serum;
- gastrointestinal toxicity: abdominal pains, diarrhea, vomiting;
- neurotoxicity: generalized tremor, spasms.

Storage conditions:

Period of validity 3 years. Not to use after the period of validity specified on packaging.

At a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 60 tablets in a bottle from polyethylene of high pressure with the screwing-up cover from polypropylene opening when pressing. The way of opening of a bottle is given in a cover in the form of the scheme with explanatory texts. The free space in a bottle is filled with cotton wool or other condensing material; the bottle mouth for ensuring control of opening is hermetically corked by aluminum foil with PVC a covering. Each bottle together with the application instruction is placed in a cardboard pack.