Expiration date: 01/2025

The form of the release of the film-coated tablets 450 mg - 60 pcs with instructions for use in the up

Keep away from children

Dosage form

Oval biconvex tablets covered with a film coating from pink to light pink color. The cross section shows a white or almost white core.

Instruction manual

In order to avoid overdose, it is necessary to strictly follow the recommendations for dosing.

Standard dosage regimen

The drug Valganciclovir should be taken orally during meals. Valganciclovir is rapidly and largely metabolized to form ganciclovir. The bioavailability of ganciclovir when taking the drug Valganciclovir is 10 times higher than when taking ganciclovir orally. therefore, it is necessary to strictly adhere to the dosage regimen of Valganciclovir described below.

CMV retinitis therapy

Adults

Induction therapy of CMV retinitis

In patients with active CMV retinitis, the recommended dose of Valganciclovir is 900 mg (2 tablets of 450 mg) 2 times a day for 21 days. Prolonged induction therapy increases the risk of myelotoxicity.

Maintenance therapy of CMV retinitis

After a course of induction therapy or in patients with inactive CMV retinitis, the recommended dose is 900 mg (2 tablets of 450 mg) 1 time per day. If the course of retinitis worsens, the course of induction therapy can be repeated. The duration of maintenance therapy is determined individually.

Prevention of CMV infection after solid organ transplantation

Adults

Patients who have undergone kidney transplantation, therapy with Valganciclovir should be started within the first 10 days after surgery at a dose of 900 mg (2 tablets of 450 mg) 1 time per day. Therapy is continued until the 200th day of the post-transplant period.

Patients who have undergone transplantation of other solid organs, therapy with Valganciclovir should be started within the first 10 days after surgery at a dose of 900 mg (2 tablets of 450 mg) 1 time per day. Therapy is continued until the 100th day of the post-transplant period.

Special instructions for dosing

Children's patients CMV-retinitis therapy

The use of Valganciclovir in children under 18 years of age for the purpose of CMV retinitis therapy is contraindicated. since the efficacy and safety of valganciclovir in this age group for this indication has not been established.

Prevention of CMV infection after solid organ transplantation

The dosage regimen in children aged 16 to 18 years does not differ from the dosage regimen in adults (see the section "Prevention of CMV infection after solid organ transplantation"). Valganciclovir tablets are contraindicated in children and adolescents under 16 years of age in order to prevent CMV infection after transplantation of solid organs, since the efficacy and safety of valganciclovir in this age group has not been established.

Elderly patients

Efficacy and safety have not been established.

Clinical studies have not been conducted in patients over 65 years of age. Since renal clearance decreases with age, valganciclovir should be prescribed to elderly patients strictly taking into account the indicators of renal function.

Patients undergoing hemodialysis

In patients undergoing hemodialysis (CC less than 10 ml / min), there are no recommendations for dosing valganciclovir. In such patients, the use of valganciclovir is contraindicated.

Patients with hepatic insufficiency

Efficacy and safety have not been established.

Patients with severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia

Patients treated with valganciclovir (and ganciclovir) had cases of severe neutropenia, anemia, thrombocytopenia, bone marrow depression and aplastic anemia. Treatment should not be started if the APN is less than 500 cells in 1 ml or the number of platelets is less than 25,000 cells in 1 ml, as well as if the hemoglobin concentration is below 80 g / l.

Composition

Per 1 tablet

Active substance: valganciclovir hydrochloride - 496,360 mg; in terms of valganciclovir - 450,000 mg.

Excipients: microcrystalline cellulose (MCC-101) - 86,100 mg; crospovidone - 25,600 mg; povidone-K25 - 25,600 mg; magnesium stearate - 6,400 mg.

Shell composition: opadray II 85F240012 Pink - 16,000 mg, including: polyvinyl alcohol - 6,400 mg; macrogol 3350 - 3,232 mg; red iron oxide dye - 0.064 mg; yellow iron oxide dye - 0.035 mg; talc - 2,368 mg; titanium dioxide - 3,901 mg.

Pharmacotherapeutic group

antiviral agent

Storage temperature

from 2? to 25?

Special conditions

Cross hypersensitivity

Due to the similar chemical structure of ganciclovir, acyclovir and valacyclovir, cross-hypersensitivity reactions to these drugs are possible. Caution should be exercised when prescribing valganciclovir to patients with hypersensitivity to acyclovir, penciclovir or their prodrugs (valacyclovir and famciclovir, respectively) in the anamnesis.

Mutagenicity, teratogenicity, carcinogenicity, fertility and contraception

Mutagenic, teratogenic and carcinogenic effects were revealed in animal experiments, as well as the negative effect of ganciclovir on fertility. Valganciclovir should be considered a potential teratogen and carcinogen for humans, the use of which can cause congenital malformations and cancer. Before starting treatment with the drug, patients should be informed about methods of contraception and possible risks to the fetus. In addition, valganciclovir can temporarily or irreversibly suppress spermatogenesis in humans.

Myelosuppression

Prolonged induction therapy with valganciclovir increases the risk of myelotoxicity. Valganciclovir should be used with caution in patients with hematological cytopenia (including in the presence of hematological cytopenia caused by medications in the anamnesis), as well as in patients receiving radiation therapy.

During treatment, it is recommended to regularly monitor the detailed formula of blood and platelets in all patients.

Patients with severe leukopenia, neutropenia, anemia and / or thrombocytopenia are recommended to use hematopoietic growth factors and / or discontinue taking the drug.

Impaired renal function

Patients with renal insufficiency are recommended to have enhanced monitoring of the expanded blood formula, at least every time they visit a transplant clinic. Patients with renal insufficiency require dose adjustment taking into account the value of CC. Valganciclovir is contraindicated in patients with CC less than 10 ml/min.

Use with other medicines

With the simultaneous use of ganciclovir and imipenem / cilastatin, convulsions were observed in patients. Simultaneous use of valganciclovir and imipenem / cilastatin should be avoided in cases where the potential benefits of treatment do not exceed the possible risk.

Because it's like zidovudine. both ganciclovir and ganciclovir can cause neutropenia and anemia, and some patients may experience intolerance with the simultaneous use of valganciclovir and zidovudine in full doses.

Due to the possible increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be carefully monitored for the appearance of symptoms of the toxic effect of didanosine.

The use of valganciclovir simultaneously with other drugs that have a myelosuppressive or nephrotoxic effect may enhance their toxic effect.

A controlled clinical study of the use of valganciclovir for the prevention of CMV infection did not include patients after lung and intestinal transplantation, therefore, the experience of using the drug in such patients is limited.

The bioavailability of ganciclovir from valganciclovir tablets is 10 times higher than that of ganciclovir capsules. Ganciclovir cannot be replaced with valganciclovir in a ratio of 1:1. Patients who are transferred from ganciclovir capsules. they should be informed about the risk of overdose if they take more tablets of Valganciclovir than recommended.

Rules for handling the drug

Tablets should not be broken or crushed. Since valganciclovir is potentially teratogenic and carcinogenic to humans, care must be taken if the tablet breaks. Direct contact of the broken or crushed tablet with the skin and mucous membranes should be avoided. In cases of such contact, it is necessary to thoroughly wash this place with soap and water, in case of contact with the eyes, they are thoroughly washed with sterile water, and in its absence - with plain water.

The ingress of drugs into the environment should be minimized. Do not dispose of the drug with wastewater or together with household waste.

Influence on the ability to control transp. cf. and fur.:

When treated with valganciclovir and / or ganciclovir, seizures, dizziness and confusion may occur, which may adversely affect activities requiring increased concentration of attention, including driving vehicles and working with machines and mechanisms. In this regard, during treatment with Valganciclovir, care should be taken when driving vehicles and working with machines and mechanisms. If the described adverse events occur, you should refrain from performing these types of activities.

Drug interaction

Drug interaction of valganciclovir

Valganciclovir is a prodrug of ganciclovir, therefore drug interactions characteristic of ganciclovir are expected.

Imipenem/cilastatin: pharmacodynamic interaction cannot be excluded between these drugs

Convulsions were observed with the simultaneous use of ganciclovir and imipenem /cilastatin. Simultaneous use of valganciclovir and imipenem / cilastatin should be avoided in cases where the potential benefits of treatment do not exceed the possible risk.

Potential drug interactions

An increase in the toxic effect of ganciclovir / valganciclovir is possible when used simultaneously with other drugs that have a myelosuppressive or nephrotoxic effect. Such drugs include nucleoside analogues (zidovudine. didanosine. stavudine), immunosuppressants (cyclosporine, tacrolimus, mycophenolate mofetil), anticancer drugs (doxorubicin, vinblastine, vincristine, hydroxyurea), anti-infective drugs (trimethoprim/sulfonamide, dapsone, amphotericin B, flucytosine, pentamidine). These drugs can be used simultaneously with valganciclovir only if the expected benefit from the treatment exceeds the possible risk.

Zidovudine: with simultaneous use with ganciclovir, pharmacodynamic interaction is possible. Since both zidovudine and ganciclovir can cause neutropenia and anemia, some patients may experience intolerance while taking valganciclovir and zidovudine in full doses.

Didanosine: a persistent increase in the concentration of didanosine in plasma was detected when administered with ganciclovir intravenously. With intravenous administration of ganciclovir at doses of 5-10 mg / kg / day, the AUC of didanosine increased by 38-67%. which confirms the pharmacokinetic interaction of didanosine and ganciclovir with simultaneous use. There was no significant effect on ganciclovir concentrations. However, patients should be carefully monitored for symptoms of the toxic effect of didanosine (for example, pancreatitis) when using valganciclovir.

Probenecid: simultaneous oral administration of probenecid resulted in a statistically significant decrease in renal clearance of ganciclovir (20%) and an increase in the duration of its action (40%). This is explained by the mechanism of interaction - competition for tubular renal excretion. Patients taking probenecid and valganciclovir at the same time should be closely monitored due to the possible toxic effects of ganciclovir.

Pharmacodynamics

The mechanism of action.

Valganciclovir is an L-valyl ether (prodrug) of ganciclovir, which, after ingestion, rapidly turns into ganciclovir under the action of intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine. which suppresses the reproduction of herpes group viruses in vitro and in vivo. Human viruses sensitive to ganciclovir include cytomegalovirus (CMV), Herpes simplex types 1 and 2, human herpes virus types 6. 7 and 8 (HHV-6. HHV-7, HHV-8), Epstein-Barr virus (EBV), Varicella zoster virus and hepatitis B virus.

In CMV-infected cells, under the action of the viral protein kinase UL97, ganciclovir is initially phosphorylated to form ganciclovir monophosphate. Further phosphorylation occurs under the action of cellular kinases with the formation of ganciclovir triphosphate, which then undergoes slow intracellular metabolism. After the disappearance of ganciclovir from the extracellular fluid, the intracellular half-life of ganciclovir triphosphate in cells infected with CMV is 18 hours, respectively; in cells infected with Herpes simplex - 6-24 hours. Since the phosphorylation of ganciclovir largely depends on the action of viral kinase, it occurs mainly in infected cells.

The virostatic activity of ganciclovir is due to the suppression of the synthesis of viral deoxyribonucleic acid (DNA) by the following mechanisms:

• competitive inhibition of the incorporation of deoxyguanosine triphosphate into DNA under the action of viral DNA polymerase;
• the inclusion of ganciclovir triphosphate in viral DNA, leading to the termination of elongation or very limited elongation of viral DNA. According to an in vitro study, the typical inhibitory concentration, which suppresses CMV replication by 50% (IC50), ranges from 0.08 mmol/l (0.02 mg/ml) to 0.14 mmol/l (3.5 mg/ml).

The clinical antiviral effect of valganciclovir was proved by a decrease in the release of CMV from the body of patients with acquired immunodeficiency syndrome (AIDS) and newly diagnosed CMV retinitis from an initial indicator of 46% to 7% after 4 weeks of treatment with valganciclovir.

Viral resistance.

With prolonged use of valganciclovir, viruses resistant to ganciclovir may appear. This may be due to either the selection of mutations of the viral kinase gene (UL97) responsible for the monophosphorylation of ganciclovir, or the viral DNA polymerase gene (UL54). Mutations of the UL97 gene occur at an earlier time and are more common compared to the mutation of the UL54 gene. A virus with only a mutation of the UL97 gene is resistant only to ganciclovir; at the same time, the most common mutations by type of substitution associated with the emergence of resistance are M460V/I, H520Q, C592G, A594V, L595S, C603W. A virus with UL54 gene mutations may have cross-resistance to other antiviral drugs with a similar mechanism of action, and vice versa. The development of cross-resistance to ganciclovir and cidofovir in most cases is due to mutations of the type of substitution in the exonuclease domains in region V of the viral DNA polymerase. The development of cross-resistance to foscarnet is caused by mutations of the type of substitution within region II (codon 696-742) and III (codon 805-845) of the viral DNA polymerase or between them.

Adults

Treatment of CMV retinitis.

Genotyping of CMV in polymorphonuclear leukocytes showed that after 3, 6, 12 and 18 months of treatment with valganciclovir, respectively, UL97 mutations were detected in 2.2%, 6.5%, 12.8% and 15.3% of leukocytes.

Prevention of CMV infection in patients after transplantation of solid organs. Genotyping of CMV in polymorphonuclear leukocytes showed:

• the absence of mutations causing resistance to ganciclovir, in samples obtained on 100 day (end of preventive reception of valganciclovir) in patients receiving valganciclovir, and the presence of mutations in samples obtained from patients receiving ganciclovir inside (1.9 percent).
• the absence of mutations causing resistance, in samples obtained from patients with suspected CMV infection, the host valganciclovir, 6 months after transplantation, and the presence of mutations in patients receiving ganciclovir inside (6.9%).

Among patients treated with valganciclovir before the 100th day and up to the 200th day of the posttransplantation period, in general, mutations by the type of replacement were more common during the period of preventive therapy than after its completion (5/12 [42%] compared with 4/58 [7%].

Viral resistance may be the cause of insufficient response to therapy and constant viral release during therapy.

Pharmacokinetics

The pharmacokinetic characteristics of valganciclovir were studied in HIV- and CMV-seropositive patients, in patients with AIDS and CMV-retinitis, as well as after solid organ transplantation.

Bioavailability and renal function determine the exposure of ganciclovir after taking valganciclovir. The bioavailability of ganciclovir was similar in all patients receiving valganciclovir. The systemic exposure of ganciclovir for heart, kidney, and liver transplant recipients was similar to that after oral administration of valganciclovir in accordance with the dosage regimen depending on kidney function. The proportional dependence of the area under the pharmacokinetic curve "concentration-time" (AUC) of ganciclovir on the dose after taking from 450 to 2625 mg of valganciclovir was observed only in the case of taking the drug after meals.

Suction

Valganciclovir is a prodrug of ganciclovir, it is well absorbed in the gastrointestinal tract, in the intestinal wall and in the liver, it is rapidly metabolized to form ganciclovir. The bioavailability of ganciclovir after oral administration of valganciclovir is about 60%. The systemic exposure of valganciclovir is low and has a short-term character. AUC0-24 and the maximum plasma concentration (Cmax) are approximately 1% and 3% of those of ganciclovir, respectively.

If valganciclovir is taken during a meal at the recommended dose of 900 mg, both the average AUC0-24 (by about 30%) and the average Cmax (by about 14%) of ganciclovir increase. Therefore, valganciclovir is recommended to be taken with meals.

Distribution

Due to the fact that valganciclovir is rapidly metabolized into ganciclovir. binding of valganciclovir to plasma proteins was not determined. The equilibrium volume of distribution of ganciclovir after intravenous administration was 0.68±0.161 l/kg. The volume of distribution of ganciclovir during intravenous administration correlates with body weight and in the equilibrium state is 0.54-0.87 l / kg. Ganciclovir penetrates into the cerebrospinal fluid. Binding of ganciclovir to plasma proteins at concentrations from 0.5 to 51 mcg/ml is 1-2%.

Metabolism

Valganciclovir is rapidly hydrolyzed to form ganciclovir; no other metabolites have been identified. Ganciclovir itself is slightly metabolized.

Withdrawal

After oral administration, valganciclovir is rapidly hydrolyzed to ganciclovir. Ganciclovir is removed from the systemic circulation by glomerular filtration and active tubular secretion. With intravenous administration of ganciclovir in patients with normal renal function, more than 90% of non-metabolized ganciclovir was detected in urine within 24 hours. After taking valganciclovir in patients with normal renal function, the concentration of ganciclovir in blood plasma after reaching a peak decreased with a half-life (T1 / 2) from 0.4 hours to 2.0 hours, and the concentration of ganciclovir - after 3.5-4.5 hours.

Pharmacokinetics in special groups of patients

Patients undergoing hemodialysis

Ganciclovir is rapidly excreted during hemodialysis. The data obtained during intermittent hemodialysis in patients receiving valganciclovir determine the estimated clearance of 138 ml/min ± 9.1% and the half-life during dialysis of 3.47 hours. During a 3-hour dialysis session, 55% of the ganciclovir fraction is excreted.

Patients with a stable functioning liver transplant

The pharmacokinetics of ganciclovir formed from valganciclovir were studied in patients with a stably functioning liver transplant in an open study with a 4-component cross-design. Bioavailability of ganciclovir. formed from valganciclovir (with a single dose of valganciclovir at a dose of 900 mg after meals), was approximately 60%. AUC0-24 of ganciclovir was comparable to that after intravenous administration of ganciclovir at a dose of 5 mg/kg to patients undergoing liver transplantation.

Patients with impaired liver function

Pharmacokinetics and population pharmacokinetics have not been studied in patients with impaired liver function receiving ganciclovir.

Patients with cystic fibrosis

During the pharmacokinetic study, it was revealed that cystic fibrosis did not have a statistically significant effect on the overall average systemic exposure of ganciclovir (at a dose of 900 mg per day) in lung transplant recipients (N=31). The exposure of ganciclovir in lung transplant recipients was comparable to that which is effective in the treatment of CMV infection in other solid organ transplant recipients.

Elderly patients

The pharmacokinetics of valganciclovir or ganciclovir have not been studied in patients over 65 years of age. However, considering that valganciclovir is a prodrug of ganciclovir (which is mainly excreted by the kidneys), and also that. as the rate of renal clearance decreases with age, in elderly patients, a decrease in total renal clearance and an elongation of the half-life of ganciclovir can be expected.

Indications

Treatment of CMV retinitis in adult patients with AIDS.

Prevention of CMV infection after transplantation of solid organs in adults and children over 16 years of age from the risk group.

Contraindications

• Hypersensitivity to valganciclovir, ganciclovir or other components of the drug.
• The absolute number of neutrophils (ACN) is less than 500 cells in 1 ml; the number of platelets is less than 25,000 cells in 1 ml; the concentration of hemoglobin is less than 80 g/l.
• Creatinine clearance less than 10 ml/min.
• Children under 16 years of age (prevention of CMV infection after transplantation of solid organs in adults and children over 16 years of age from the risk group).
• Children under 18 years of age (treatment of CMV retinitis in adult patients with AIDS).
• The period of breastfeeding.

With caution:

Elderly patients (safety and efficacy have not been established). Hypersensitivity to acyclovir, penciclovir or their prodrugs (valacyclovir and famciclovir, respectively) in the anamnesis, since due to the similar chemical structure of ganciclovir, acyclovir and valacyclovir, cross-hypersensitivity reactions to these drugs are possible.

Pregnancy and lactation:

Fertility

In the course of studies in animals, the use of ganciclovir caused a violation of fertility. In patients receiving valganciclovir for the prevention of CMV infection for 200 days after kidney transplantation, inhibition of spermatogenesis was noted (compared with the control group not receiving treatment). After about 6 months after discontinuation of therapy, the average sperm density in the treated patients was comparable to that in the control group of patients not receiving therapy. At the same time, normal sperm density was observed in all treated patients with normal sperm density and in 8 out of 13 patients with reduced sperm density at the initial level after discontinuation of treatment. At follow-up in the control group, normal sperm density was observed in all patients with normal sperm density and in 2 out of 4 patients with reduced sperm density at the initial level after discontinuation of treatment.

Contraception in men and women

During treatment and for at least 30 days after the end of treatment with valganciclovir, women with reproductive potential should be advised to use reliable methods of contraception. During treatment and for at least 90 days after its termination, men who have sex are recommended to use a barrier method of contraception, except in cases where there is no risk of pregnancy in a partner.

Pregnancy

The safety of valganciclovir during pregnancy in humans has not been established. However, ganciclovir quickly penetrates through the human placenta. During pregnancy, the appointment of valganciclovir should be avoided, except in cases where the potential positive effect of treatment for the mother justifies the possible risk to the fetus. Additional studies of the reproductive toxicity of valganciclovir have not been conducted due to its rapid and significant conversion to ganciclovir. In animal studies, the use of ganciclovir has been associated with teratogenicity and toxicity to the reproductive system.

The safety of valganciclovir use during labor and delivery has not been studied.

Breastfeeding

Studies of the effect of valganciclovir and ganciclovir on peri- and postnatal development have not been conducted, while it is impossible to exclude the possibility of isolation of ganciclovir with breast milk and the development of serious adverse reactions in an infant. There are no results of studies in humans, but the results of studies in animals show that ganciclovir is excreted in breast milk in rats. If it is necessary to use the drug during lactation, it is necessary to stop breastfeeding.

Overdose

Symptoms

It is possible that an overdose of valganciclovir may lead to an increase in nephrotoxicity.

In the course of clinical studies and post-registration use of valganciclovir, cases of overdose of intravenously administered ganciclovir, including fatal, have been described. Some of them were not accompanied by undesirable phenomena. The majority of patients had one or more of the following adverse events:

• hematological toxicity: myelosuppression, including pancytopenia, bone marrow insufficiency, leukopenia, neutropenia, granulocytopenia:
• hepatotoxicity: hepatitis, impaired liver function;
• nephrotoxicity: increased hematuria in patients with pre-existing renal dysfunction, acute renal failure, increased serum creatinine concentration;
• gastrointestinal toxicity: abdominal pain, diarrhea, vomiting;
• neurotoxicity: generalized tremor, convulsions.

Treatment

It is possible to reduce the concentration of valganciclovir in blood plasma in patients with overdose by hemodialysis and hydration.

Side effects

Valganciclovir is a prodrug of ganciclovir. Valganciclovir is rapidly converted into ganciclovir after oral administration, therefore all known undesirable effects registered with the use of ganciclovir are expected with the use of valganciclovir. All the undesirable effects registered in clinical studies of valganciclovir were previously observed during treatment with ganciclovir. Adverse reactions that occurred when using ganciclovir or valganciclovir are included in Table 3.

The most serious and frequent adverse reactions in patients treated with valganciclovir / ganciclovir. there are disorders on the part of the blood, in particular, neutropenia. anemia and thrombocytopenia.

The overall safety profile of ganciclovir/valganciclovir is comparable in the populations of patients after transplantation and with HIV. The exception is the undesirable reaction "retinal detachment", which was observed only in patients with CMV retinitis. However, there are differences in the frequencies of some adverse reactions.

The use of valganciclovir was associated with an increased risk of diarrhea compared with the use of ganciclovir intravenously. Fever, candidiasis, depression, severe neutropenia (AHN < 500/µl) and skin reactions were more common in patients with AIDS. Impaired kidney and liver function were more often observed in patients after transplantation.

Description of individual adverse reactions

Neutropenia

The risk of developing neutropenia cannot be predicted based on the number of neutrophils before treatment is started. The occurrence of neutropenia is typical for the first or second week of induction therapy. The number of neutrophils, as a rule, normalizes within 2-5 days after discontinuation of the drug or dose reduction.

Thrombocytopenia

Patients with an initial low platelet count (<100,000/ml) have an increased risk of developing thrombocytopenia. In patients with iatrogenic suppression of immunity due to immunosuppressant therapy, the risk of developing thrombocytopenia is higher than in patients with AIDS. Severe thrombocytopenia may be accompanied by potentially life-threatening bleeding.

The effect of the duration of therapy / indications for use on the development of adverse reactions

Severe neutropenia (AHN<500/µl) was more often observed in patients with CMV retinitis (16%) treated with valganciclovir, compared with patients after solid organ transplantation treated with valganciclovir or ganciclovir (orally). In patients receiving valganciclovir or ganciclovir (orally) within 100 days after transplantation, the incidence of severe neutropenia was 5% and 3%, respectively. In patients treated with valganciclovir for 200 days after transplantation, the incidence of severe neutropenia was 10%. In patients after solid organ transplantation who received valganciclovir or ganciclovir (orally) for 100 or 200 days, there was a more pronounced increase in serum creatinine concentration compared to patients with CMV retinitis. However, it is important to note that impaired renal function is a characteristic symptom more often observed in patients after solid organ transplantation. The overall safety profile of valganciclovir does not change with the extension of the period of preventive use in patients with a high risk of CMV infection after kidney transplantation up to 200 days.

In patients receiving valganciclovir before the 200th day of the posttransplantation period, compared with patients receiving valganciclovir before the 100th day of the posttransplantation period, there is a slight increase in the frequency of leukopenia.

The rates of neutropenia, anemia, and thrombocytopenia were similar in patients treated before the 100th and 200th days of the posttransplantation period.

Children's patients

The general safety profile of valganciclovir in children does not differ from the safety profile of the drug in adults. In the pediatric population, there was a slight increase in the frequency of neutropenia, but this did not lead to an increase in the frequency of infections.

In children who have undergone kidney transplantation, an increase in the period of preventive use to 200 days does not lead to an increase in the frequency of adverse events.

Congenital CMV infection

Therapy of congenital CMV infection is not an approved indication for the use of valganciclovir. Nevertheless, studies conducted in newborns and young children with congenital CMV infection provide data on the safety profile of valganciclovir in these patient populations. The safety profile of valganciclovir is comparable to the known safety profile of valganciclovir/ganciclovir.

The main manifestation of ganciclovir toxicity is neutropenia (38% of patients had grade 3 and 4 neutropenia, 1 patient needed to cancel therapy). Most of the phenomena were amenable to correction with the simultaneous possibility to continue antiviral therapy. All newborns had an increase in indicators characterizing growth and development (height, body weight, average head circumference). With oral administration of valganciclovir, the most frequent adverse events were neutropenia, anemia, impaired liver function and diarrhea. The listed adverse events were observed more often in patients with 6-week therapy with valganciclovir, compared with patients receiving valganciclovir for 6 months. Serious adverse events associated with treatment were neutropenia and anemia, which were also more often observed with therapy lasting 6 weeks. There were no statistically or clinically significant differences between patients treated with valganciclovir for 6 weeks and for 6 months in indicators characterizing growth and development, such as height, body weight, average head circumference.

Laboratory indicators

When extending the prevention period in adult patients with a high risk of CMV infection after transplantation of solid organs, the frequency of violations of laboratory parameters up to 200 days remained similar.

Severe neutropenia was more frequently observed in children who underwent kidney transplantation and received valganciclovir before the 200th day of the posttransplantation period, compared with children who received valganciclovir before the 100th day of the posttransplantation period, as well as compared with adults who underwent kidney transplantation and received valganciclovir before the 100th and 200th days of the posttransplantation period.

Post-registration application

The adverse events described with the post-registration use of valganciclovir are similar to those observed in clinical studies of valganciclovir and ganciclovir /valganciclovir.