Civalgan pills 450mg, 60pcs

Composition

1 film-coated tablet contains:

Composition of the tablet core:

Active ingredient: valganciclovir hydrochloride-496.30 mg, corresponds to valganciclovir-450.00 mg.

Excipients: povidone-28.80 mg; tartaric acid-21.60 mg; mannitol-144.50 mg; crospovidone-14.40 mg; sodium stearyl fumarate-14.40 mg.

Composition of the tablet shell: polyvinyl alcohol-9.20 mg; titanium dioxide-5.58 mg; macrogol 3350-4.65 mg; talc – 3.40 mg; iron oxide yellow dye-0.08 mg; iron oxide red dye-0.08 mg; iron oxide black dye-0.01 mg

Pharmacological action

Pharmacotherapeutic group: Antiviral agent

ATX Code: J05AB14

Pharmacological properties

Pharmacodynamics

Mechanism of action

Valganciclovir is an L-valyl ester (prodrug) of ganciclovir, which is rapidly converted to ganciclovir after oral use by intestinal and hepatic esterases. Ganciclovir is a synthetic analog of 2′ – deoxyguanosine that inhibits the replication of herpes viruses in vitro and in vivo. Human viruses that are sensitive to ganciclovir include cytomegalovirus (CMV), herpes simplex viruses 1 and 2, human herpes virus types 6,7 and 8, Epstein-Barr virus, chickenpox virus and hepatitis B virus.

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

The virostatic activity of ganciclovir is due to the suppression of viral DNA synthesis by the following mechanisms: (1) competitive inhibition of deoxyguanosine triphosphate incorporation into DNA by viral DNA polymerase; (2) incorporation of ganciclovir triphosphate into viral DNA, which leads to the cessation of elongation or very limited elongation of viral DNA. According to in vitro studies, the typical inhibitory concentration that suppresses CMV replication by 50% (IC50) is in the range of

0.08 mmol/L (0.02 mcg/ml) to 14 mmol/L (3.5 mcg/ml).

The clinical antiviral effect of valganciclovir was shown to reduce CMV excretion from the body of patients with acquired immunodeficiency syndrome (AIDS) and newly diagnosed CMV retinitis from the initial indicator of 46% to 7% after 4 weeks of treatment with valganciclovir.

Efficiency

Adults

Treatment of CMV retinitis

Clinical studies were conducted in patients with AIDS and

CMV retinitis. Valganciclovir demonstrated similar clinical efficacy in the induction therapy of CMV retinitis compared to intravenous ganciclovir.

The use of valganciclovir allows you to get the same systemic effect of ganciclovir as when using the recommended intravenous doses of ganciclovir, effective in the treatment of CMV retinitis. It was shown that the area under the concentration-time curve (AUC) of ganciclovir correlates with the time interval before the progression of CMV retinitis.

Prevention of CMV infection

, the incidence of CMV disease (CMV syndrome + invasive tissue infection) during the first 6 months after transplantation of the heart, liver, kidneys, patients with a high risk of CMV infection (CMV-positive donor (D+)/CMV-negative recipient(R-) (D+/R-)) It was 12.1% in the group of patients receiving valganciclovir (900 mg per day) and 15.2% in the group of patients receiving ganciclovir orally (1000 mg 3 times a day) from 10 to 100 days after transplantation. Most of the cases occurred after the withdrawal of preventive therapy (after the 100th day of the post-transplant period). At the same time, cases of CMV infection in the valganciclovir treatment group appeared later than in the ganciclovir treatment group. The incidence of acute graft rejection in the first 6 months was 29.7% in the valganciclovir-treated group and 36% in the ganciclovir-treated group.

Increasing the duration of 900 mg valganciclovir up

to 200 days after kidney transplantation in patients at high risk of CMV infection (D+/R -) was associated with greater effectiveness in preventing CMV infection in the first 12 months after transplantation compared to taking 900 mg valganciclovir up to 100 days after transplantation.

The transplant survival rate at 12 months was 98.2% in the group of patients treated with valganciclovir before day 100, and 98.1% in the group of patients treated with valganciclovir before day 200. The incidence of acute graft rejection confirmed by biopsy in the first 12 months was 17.2% in the group of patients treated with valganciclovir before day 100, and 11.0% in the group of patients treated with valganciclovir before day 200.

Viral resistance

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

Adults

Treatment of CMV retinitis

Genotyping of CMV in polymorphonuclear leukocytes showed that after 3,6,12, and 18 months of valganciclovir treatment

, UL97 mutations were detected in 2.2%,6.5%,12.8%, and 15.3% of leukocytes, respectively.

Prevention of CMV infection in patients after solid organ transplantation

Genotyping of CMV in polymorphonuclear leukocytes showed:

the absence of mutations causing resistance to ganciclovir, in samples obtained at 100-th day (the end of the preventive reception of valganciclovir) in patients of group valganciclovir, and the presence of mutations in samples obtained from patients treated with oral ganciclovir (1.9 per cent);

lack of mutations that lead to resistance, in samples obtained from patients randomized to the group of valganciclovir with suspected CMV infection 6 months after transplantation, and the presence of mutations in patients receiving oral ganciclovir,6.9%.

Among patients who received valganciclovir before day 100 and day 200 of the post-transplant period, mutations in the replacement type were generally more common during preventive therapy than after it was completed (5/12 [42%] compared to 4/58 [7%]).

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

Preclinical safety data sheet

The carcinogenicity of ganciclovir has been proven in mouse studies. Valganciclovir, like ganciclovir, is a potential carcinogen.

Valganciclovir and ganciclovir had mutagenic effects in mouse lymphoma cells and clastogenic effects in mammalian cells.

Given the rapid and complete conversion of the drug to ganciclovir, no additional reproductive toxicity studies have been conducted with valganciclovir. The same warning about possible reproductive toxicity applies to both drugs (see the section “Special instructions”). In animals, ganciclovir disrupts fertility and has a teratogenic effect. Based on animal experiments in which systemic exposure to ganciclovir at concentrations below therapeutic levels caused aspermia, it is highly likely that ganciclovir and valganciclovir may inhibit spermatogenesis in humans.

Data obtained in

an ex vivo human placenta model indicate that ganciclovir passes through the placenta, most likely by simple transfer. In the concentration range from 1 to

10 mg/ml, the drug was unsaturated and passed through the placenta by passive diffusion.

Pharmacokinetics

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

The parameters that determine the exposure of ganciclovir after taking valganciclovir are bioavailability and renal function. The bioavailability of ganciclovir was similar in all patients treated with valganciclovir. The systemic exposure of ganciclovir to heart, kidney, and liver transplant recipients was similar to that after oral valganciclovir use in accordance with the dosage regimen depending on renal function.

Suction

Valganciclovir is a prodrug of ganciclovir, is well absorbed in the gastrointestinal tract, in the intestinal wall and is rapidly metabolized in the liver to form ganciclovir. The absolute bioavailability of ganciclovir after taking valganciclovir is about 60%. Systemic exposure to valganciclovir is low and short-lived. The area under the concentration-time curve (AUC24) and maximum concentration (Cmax) are approximately 1% and 3% of those of ganciclovir, respectively.

The proportional dependence of the AUC of ganciclovir on the dose after taking valganciclovir in doses from 450 to 2625 mg is indicated only for the case of taking the drug after a meal. If valganciclovir is taken with a meal at the recommended dose of 900 mg, both the average AUC24 (approximately 30%) and the average Cmax (approximately 14%) of ganciclovir increase. Therefore, valganciclovir is recommended to be taken with a meal (see section “Dosage and use”).

Distribution.

Due to the rapid metabolism of valganciclovir to ganciclovir, the binding of valganciclovir to plasma proteins was not determined. The binding of ganciclovir to plasma proteins at drug concentrations from 0.5 to 51 mcg/ml is 1-2%. The steady-state volume of distribution of ganciclovir after intravenous use was

0.680 ± 0.161 l / kg.

Metabolism

Valganciclovir is rapidly hydrolyzed to form ganciclovir, and no other metabolites have been identified. After a single oral dose of 1000 mg of radiolabeled ganciclovir, the radioactivity index of none of the metabolites in feces or urine did not exceed

1-2%.

Deduction

The main route of elimination of valganciclovir, as well as ganciclovir, is glomerular filtration and active tubular secretion. Renal clearance accounts for 81.5 ± 22% of the systemic clearance of ganciclovir.

Pharmacokinetics in special patient groups

Patients with renal insufficiency

Impaired renal function resulted in a decrease in the clearance of valganciclovir-derived ganciclovir, with a corresponding increase in the terminal half-life. Therefore, patients with impaired renal function need to adjust the dose (see the section ” Special instructions for dosage “of the section” Dosage and use “and the section”Special instructions”).

Patients with hepatic insufficiency

The pharmacokinetics of valganciclovir-derived ganciclovir were studied in patients with a stable functioning liver transplant in an open-label study with a 4-component cross-sectional design. The absolute bioavailability of ganciclovir derived from valganciclovir (with a single dose of 900 mg after a meal) was approximately 60%, which coincides with the indicator in other groups of patients. The AUC0-24 of ganciclovir was comparable to that after intravenous use of ganciclovir at a dose of 5 mg / kg to liver transplant patients.

Indications

Treatment of CMV retinitis in adult patients with AIDS. Prevention of CMV infection after solid organ transplantation in high-risk adults and children over 16 years of age.

Use during pregnancy and lactation

Additional reproductive toxicity studies with valganciclovir were not conducted due to the rapid and complete conversion of valganciclovir to ganciclovir. Ganciclovir interferes with fertility and has a teratogenic effect in animals (see the section “Preclinical safety data” in the section “Pharmacological properties”). Women of childbearing age should be advised to use reliable methods of contraception during treatment with valganciclovir, while men should be advised to use a barrier method of contraception during treatment and at least 90 days after its end (see the section “Preclinical safety data” in the section “Pharmacological properties”). The safety of using valganciclovir during pregnancy in humans has not been established. During pregnancy, the use of valganciclo-vir should be avoided, except in cases where the potential positive effect of treatment on the mother justifies the possible risk to the fetus. Studies on the effects of valganciclovir and ganciclovir on peri-and postnatal development have not been conducted, and the possibility of ganciclovir excretion in breast milk and the development of serious adverse reactions in an children cannot be excluded. If it is necessary to use the drug during lactation, it is necessary to stop breastfeeding.

Contraindications

Hypersensitivity to valganciclovir, ganciclovir or any of the components of the drug. Due to the similar chemical structure of acyclovir, valacyclovir and valganciclovir, cross-sensitivity reactions to these drugs are possible.

The absolute neutrophil count is less than 500 cells per 1 µl, the platelet count is less than 25,000 cells per 1 µl, or the hemoglobin concentration is less than 80 g / l (see section “Special instructions”).

Creatinine clearance is less than 10 ml / min.

Children under 16 years of age (prevention of CMV infection after solid organ transplantation in adults and children over 16 years of age at risk).

Children under 18 years of age (treatment of CMV retinitis in adult patients with AIDS).

Breast-feeding period.

With caution

Elderly age (efficacy and safety have not been established).

Side effects

Data from clinical trials

Valganciclovir is a prodrug of ganciclovir that rapidly converts to ganciclovir after oral use, so all known adverse effects associated with taking ganciclovir are expected for valganciclovir. All adverse events reported in clinical trials have previously been observed with ganciclovir.

Adults

Treatment of CMV retinitis in patients with AIDS

The safety profiles of valganciclovir and ganciclovir when administered intravenously for 28 days were the same. The most common adverse events were diarrhea, neutropenia, and fever. Oral valganciclovir – treated patients were more likely to have oral mucosal candidiasis, headache and weakness, and intravenous ganciclovir-treated patients were more likely to have nausea and injection site adverse events (phlebitis and thrombophlebitis) (see table 1).

Table 1. Proportion of patients with selected adverse events that occurred during the randomized phase of the study.

The following table (see table 2) presents adverse events (regardless of their severity and drug-related status) with a frequency of ≥ 5%, obtained in clinical trials on the use of valganciclovir either in patients with CMV retinitis or in patients after solid organ transplantation.

The most common adverse reactions, regardless of severity, but, according to the researchers, related to taking the drug (long-term, probable or possible relationship) in patients with CMV retinitis were: neutropenia, anemia, diarrhea and nausea.

Prevention of CMV infection in patients after solid organ transplantation

Table 2 shows adverse events (up to 28 days after completion of the study) regardless of their severity and their association with the drug, with a frequency of ≥ 5%, obtained in clinical studies in patients after solid organ transplantation who received valganciclovir or ganciclovir orally, starting taking the drugs within 10 days after transplantation and continuing to take them until the 100th day of the post-transplant period.

The most common adverse reactions, regardless of severity, but, according to researchers, related to taking the drug (long-term, probable or possible relationship) in patients after solid organ transplantation who received treatment before the 100th day of the post-transplant period: leukopenia, diarrhea, nausea, neutropenia; in patients who underwent kidney transplantation and received treatment before the 200th day of the post-transplant period: leukopenia, neutropenia, anemia and diarrhea.

Table 2. Proportion of patients with adverse events (AES) that occurred in ≥ 5% of patients with CMV retinitis or after solid organ transplantation in clinical trials with valganciclovir or ganciclovir.

The following are serious adverse events that occurred with a frequency of less than 5% in three clinical trials and are not listed above.

From the blood and lymphatic system: pancytopenia, bone marrow suppression, aplastic anemia, febrile neutropenia; potentially life-threatening bleeding associated with the development of thrombocytopenia.

From the genitourinary system: reduced creatinine clearance.

From the central and peripheral nervous system: convulsions, psychotic disorders, hallucinations, confusion, agitation.

From the body as a whole: hypersensitivity reactions to qualganciclovir.

Severe neutropenia (absolute neutrophil count less than 500 in 1 µl) is more common in patients with CMV retinitis (16%) than in patients receiving valganciclovir (5%) or oral ganciclovir (3%) after solid organ transplantation before the 100th day of the post-transplant period or in patients receiving valganciclovir(10%) before the 200th day of the post-transplant period. Patients receiving both valganciclovir and ganciclovir orally after solid organ transplantation before day 100 or day 200 of the post-transplant period showed a more significant increase in serum creatinine concentrations compared to patients with CMV retinitis. Impaired renal function is characteristic of patients who have undergone organ transplantation.

The overall safety profile of valganciclovir does not change with an increase in the period of prophylactic use to 200 days in patients after a kidney transplant at risk. Patients receiving valganciclovir before day 200 of the posttransplantation period, compared with patients receiving valganciclovir before day 100 of the posttransplantation period, there is a slight increase in the incidence of leukopenia. The incidence of neutropenia, anemia, and thrombocytopenia is similar in patients treated before day 100 and day 200 of the post-transplant period.

Table 3. Changes in laboratory parameters reported when taking valganciclovir in adults.

Experience with ganciclovir

Since valganciclovir is rapidly metabolized to form ganciclovir, the following are the adverse events noted during treatment with ganciclovir and not mentioned above.

From the digestive system: cholangitis, dysphagia, belching, esophagitis, fecal incontinence, flatulence, gastritis, gastrointestinal disorders, gastrointestinal bleeding, ulcerative stomatitis, pancreatitis, glossitis, hepatitis, jaundice.

From the body as a whole: asthenia; bacterial, fungal and viral infections; malaise; mucositis; photosensitization reaction; tremor; sepsis.

Skin and subcutaneous fat disorders: alopecia, dry skin, sweating, urticaria.

From the central and peripheral nervous system: sleep disorders, amnesia, anxiety, ataxia, coma, dry mouth, emotional disorders, hyperkinetic syndrome, hypertonus, decreased libido, myoclonic twitching, nervousness, drowsiness, intellectual disorders.

Musculoskeletal system disorders: bone and muscle pain, myasthenic syndrome.

From the genitourinary system: hematuria, impotence, frequent urination.

Endocrine system disorders: diabetes mellitus.

From the laboratory parameters: increased activity of alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase in the blood, decreased blood glucose concentration, hypoproteinemia.

From the sensory organs: amblyopia, blindness, ear pain, hemorrhage in the eye, pain in the eyeballs, deafness, glaucoma, impaired taste perception, tinnitus, visual impairment, changes in the vitreous body.

From the blood and lymphatic system: eosinophilia, leukocytosis, lymphadenopathy, splenomegaly, bleeding.

From the cardiovascular system: arrhythmias, including ventricular arrhythmias, migraines, phlebitis, tachycardia, deep vein thrombophlebitis, vasodilation.

From the respiratory system: congestion in the paranasal sinuses.

Children

Prevention of CMV infection in patients after organ transplantation

Table 4 shows the adverse events that occurred up to 28 days after the end of the study regardless of their severity and connection with taking the drug.

The table includes adverse events with a frequency of≥ 10% reported in clinical studies in children aged 3 weeks to 16 years after solid organ transplantation who started valganciclovir within 10 days after transplantation and continued treatment until day 100 of the post-transplant period, as well as in children after kidney transplantation who started valganciclovir within 10 days after transplantation and continued treatment until day 200 of the post-transplant period.

The overall safety profile of valganciclovir in children does not differ from the safety profile of the drug in adults. Some adverse events were observed in children with a higher frequency than in adults, such as upper respiratory tract infections, fever, abdominal pain and dysuria, which may reflect the characteristics of the child population. In the pediatric population, there was a slight increase in the incidence 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 reactions.

Table 4. Adverse events that occurred with a frequency of ≥ 10% in children after solid organ transplantation.

Body systems/ description of AES	Pediatric patients after solid organ transplantation
	Treatment with valganciclovir up to day 100 of the post-transplant period (n=63)			Treatment with valganciclovir before day 200 of the post-transplant period (n=56)
	%			%
Infectious complications
Urinary tract infections	6			34
Urinary tract infections caused by E. coli	–			13
Upper respiratory tract infections	22			34
From the digestive system
Diarrhea			32			32
Constipation			11			5
Nausea			11			9
Abdominal pain			6			18
Vomiting			21			13
Blood and lymphatic system disorders
Leukopenia		2			25
Anemia		14			16
Neutropenia		13			23
From the body as a whole
Interaction Drug interactions of valganciclovir No interactions of valganciclovir with valacyclovir, didanosine, nelfinavir, cyclosporine, omeprazole, and mycophenolate mofetil were detected in the rat model of intestinal permeability in situ. Valganciclovir is converted to ganciclovir, so interactions characteristic of ganciclovir may also occur when taking valganciclovir. Drug interactions of ganciclovir The degree of binding of ganciclovir to plasma proteins is only 1-2%, so reactions associated with protein binding substitution are not expected. Imipenem / cilastatin: Seizures have been reported in patients receiving concomitant use of ganciclovir and imipenem / cilastatin. Concomitant use of valganciclovir and imipenem / cilastatin should be avoided if the potential benefits of treatment do not exceed the possible risk (see section “Special instructions”). Probenecid: concomitant oral use of probenecid resulted in a statistically significant decrease in the 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 carefully monitored for possible toxic effects of ganciclovir. Zidovudine: when co-administered with oral ganciclovir, there was a small but statistically significant increase in the AUC of zidovudine (17%); in addition, there was a statistically insignificant tendency to decrease the concentration of ganciclovir. Since both zidovudine and ganciclovir can cause neutropenia and anemia, some patients may experience intolerance when taking full doses of valganciclovir and zidovudine at the same time (see section “Special instructions”). Didanosine: there was a persistent increase in the concentration of didanosine in plasma when used simultaneously with ganciclovir (both with intravenous and oral use). In the case of oral use of ganciclovir at doses of 3 and 6 g per day, the AUC of didanosine increased by 84-124%, with intravenous use of ganciclovir at doses of 5-10 mg / kg / day, the AUC of didanosine increased by 38-67%. This increase cannot be explained by competitive interaction for renal tubular excretion, since the percentage of didanosine excretion increased. The reasons for this increase may be increased bioavailability or slower metabolism. There was no clinically significant effect on ganciclovir concentrations.However, given the increased plasma concentrations of didanosine in the presence of ganciclovir, patients should be carefully monitored for symptoms of toxic effects of didanosine when using valganciclovir (see the section “Special instructions”). Mycophenolate mofetil: based on the results of a study on a single intravenous dose of ganciclovir and oral use of mycophenolate mofetil, as well as the known effect of impaired renal function on the pharmacokinetics of mycophenolate mofetil and ganciclovir, it can be expected that the simultaneous use of valganciclovir and mycophenolate mofetil, which have a competitive interaction in the process of tubular secretion, will lead to an increase in the concentration of ganciclovir and mycophenolic acid phenolic glucuronide. No significant changes in the pharmacokinetics of mycophenolic acid are expected, so no dose adjustment of mycophenolate mofetil is required. In patients with impaired renal function who are receiving mycophenolate mofetil ivalganciclovir concomitantly, the recommendations for dose adjustment of valganciclovir should be followed and carefully monitored. Zalcitabine: zalcitabine increased the AUCof oral ganciclovir 0-8 by 13%. There were no statistically significant changes in other pharmacokinetic parameters. There were no clinically significant changes in the pharmacokinetics of zalcitabine with concomitant oral use of ganciclovir, despite a slight increase in the elimination rate constant. Stavudine: No statistically significant pharmacokinetic interaction was observed with concomitant oral use of ganciclovir and stavudine. Trimethoprim: trimethoprim significantly reduced the renal clearance of oral ganciclovir by 16.3%, which was also accompanied by a statistically significant decrease in the rate of terminal elimination and a corresponding increase in the half-life by 15%. However, the clinical significance of these changes is unlikely, since AUC0-8 and Cmax did not change. The only statistically significant change in the pharmacokinetic parameters of trimethoprim with simultaneous use of ganciclovir was an increase in the minimum concentration (Withmin) by 12%. However, this is unlikely to be clinically relevant, so no dose adjustment of valganciclovir is required. Cyclosporine: When comparing cyclosporine concentrations before taking the next dose, there was no evidence that ganciclovir altered the pharmacokinetics of cyclosporine. However, after starting ganciclovir, there was a slight increase in the maximum serum creatinine concentration. Other possible drug interactions: since the main route of elimination of ganciclovir is glomerular filtration and active tubular secretion (see section “Elimination” of the section “Pharmacological properties”), the use of valganciclovir simultaneously with antiretroviral drugs that are also eliminated by active tubular secretion (for example, nucleoside reverse transcriptase inhibitors)may affect the concentration of valganciclovir and/or co-administered drugs. Concomitant use of ganciclovir with other drugs that have a myelosuppressive or nephrotoxic effect (for example, dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogues, hydroxycarbamide, and pegylated interferons/ribavirin) may increase their toxic effects. Therefore, these drugs can be used simultaneously with valganciclovir only if the expected benefit of the treatment exceeds the possible risk (see the section “Special instructions”). How to take, course of use and dosage To avoid overdose, it is necessary to strictly follow the recommendations on the dosage regimen. Standard dosage regimen Valganciclovir should be taken orally with a meal (see sections “Absorption” and “Pharmacokinetics in special patient groups” in the section “Pharmacological properties”). Valganciclovir is rapidly and largely metabolized to form ganciclovir. The bioavailability of ganciclovir in the case of taking valganciclovir tablets is 10 times higher than in the case of oral ganciclovir (see the sections “Special instructions” and “Overdose”). 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. Long-term induction therapy increases the risk of myelotoxicity (see section “Special instructions”). CMV-retinitis maintenance therapy After a course of induction therapy or in patients with inactive CMV retinitis, the recommended dose is 900 mg (2 tablets of 450 mg) once a day. If the course of retinitis worsens, the course of induction therapy can be repeated (see the subsection “Induction therapy of CMV retinitis” in the section “Dosage and use”). Prevention of CMV infection after solid organ transplantation Adults Patients who have undergone kidney transplantation should start valganciclovir therapy within the first 10 days after surgery at a dose of 900 mg (2 tablets of 450 mg) once a day and continue therapy until the 200th day of the post-transplant period. Patients who have undergone transplantation of other solid organs should start valganciclovir therapy within the first 10 days after surgery at a dose of 900 mg (2 tablets of 450 mg) once a day and continue therapy until the 100th day of the post-transplant period. Special dosage instructions Patients with renal insufficiency Careful monitoring of serum creatinine concentrations or creatinine clearance should be performed. Dose adjustment in adult patients is carried out depending on creatinine clearance, as shown in the table below (see the section “Pharmacokinetics in special patient groups” in the section “Pharmacological properties” and the section “Special Instructions”). Creatinine clearance is calculated as a function of serum creatinine concentration using the following formula: (140 – age [years]) × (body weight [kg]) for men = ———————— (72) x (0.011 x serum creatinine concentration [mmol / l]) for women = 0.85 × indicator for men Creatinine clearance (ml / min) Dose for induction therapy Maintenance / prevention dose ≥ 60 900 mg 2 times daily 900 mg 1 time daily 40-59 450 mg 2 times daily 450 mg 1 time daily 25-39 450 mg 1 time daily 450 mg every 2 days 10-24 450 mg every 2 days 450 mg 2 times a week < 10 contraindicated contraindicated Patients with hepatic insufficiency Efficacy and safety have not been established. Patients with severe leukopenia, neutropenia, anemia, thrombocytopenia or pancytopenia Cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression, and aplastic anemia have been reported in patients treated with valganciclovir (and ganciclovir). Treatment should not be initiated if the absolute neutrophil count is less than 500 cells per 1 µl or the platelet count is less than 25,000 cells per 1 µl, or if the hemoglobin is below 80 g / l. Patients with severe leukopenia, neutropenia, anemia, and/or thrombocytopenia should be prescribed hematopoietic growth factors and / or discontinue the drug (see sections “Special instructions” and “Side effects”). Elderly patients Efficacy and safety have not been established. Children’s patients CMV retinitis therapy It is contraindicated to use valganciclovir in children under 18 years of age for the treatment of CMV retinitis, since the efficacy and safety of valganciclovir in this age group has not been established. Prevention of CMV infection after solid organ transplantation The dosage regimen for children aged 16-18 years does not differ from the dosage regimen for adults (see the section “Prevention of CMV infection after solid organ transplantation” in the section “Dosage and use”). The use of valganciclovir is contraindicated in children and adolescents under 16 years of age in order to prevent CMV infection after solid organ transplantation, since the efficacy and safety of valganciclovir in this age group has not been established. Overdose One adult patient who was treated with valganciclovir for several days at doses at least 10 times higher than recommended, taking into account impaired renal function (decreased creatinine clearance), developed bone marrow depression (medullary aplasia) with a fatal outcome.  It is possible that an overdose of valganciclovir may lead to an increase in nephrotoxicity (see sections “Special instructions” and “Dosage and use”). Reducing the plasma concentrations of valganciclovir in patients with overdose can be done by hemodialysis and hydration. Overdose of intravenous ganciclovir Since valganciclovir is rapidly and largely converted to ganciclovir, the adverse events observed with an overdose of ganciclovir may also be expected with an overdose of valganciclovir. In clinical studies and post-marketing use of the drug, cases of overdose of ganciclovir with intravenous use have been described. Some of them were not accompanied by adverse events. Most patients experienced one or more of the following adverse events:: the hematologic toxicity: pancytopenia, inhibition of the function of the bone marrow, medullary aplasia, leukopenia, neutropenia, granulocytopenia; hepatotoxicity: hepatitis, abnormal liver function; nephrotoxicity: strengthening of hematuria in patients with existing kidney dysfunction, acute renal failure, the increase in the concentration of creatinine in the blood serum; gastrointestinal toxicity: abdominal pain, diarrhea, vomiting; neurotoxicity: generalized tremor, convulsions. Description Tablets of oval, biconvex shape, covered with a film-coated pink color, with a risk on one side and an embossed “f” on the other. On the cross-section – the core is white to white with a yellowish tinge of color. Special instructions In animal experiments, the mutagenic, teratogenic, aspermatogenic and carcinogenic effects of ganciclovir were revealed. Valganciclovir should be considered a potential teratogen and carcinogen for humans, the use of which can cause congenital malformations and cancer (see the section “Rules for handling the drug” in the section “Special instructions”). In addition, it is likely that valganciclovir may temporarily or permanently inhibit spermatogenesis (see sections “Side effects”, “Use during pregnancy and lactation”, subsection “Preclinical safety data” in the section “Pharmacological properties”). Cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow suppression, and aplastic anemia have been reported in patients receiving valganciclovir (and ganciclovir). Treatment should not be initiated if the absolute neutrophil count is less than 500 cells per 1 µl or the platelet count is less than 25,000 cells per 1 µl, or if the hemoglobin is lower than 80 g / l (see the section ” Special dosage instructions “in the section” Dosage and use “and the section”Side effects”). During treatment, it is recommended to regularly monitor the detailed formula of blood and platelets. Patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia are recommended to be prescribed hematopoietic growth factors and / or discontinue the drug (see the section “Special dosage instructions” of the section “Dosage and use” and the section “Side effects”). Patients with renal insufficiency may require increased monitoring of the detailed blood formula, at least every time they visit a transplant clinic. Patients with renal insufficiency require dose adjustment based on creatinine clearance (see sections “Dosage and use” and “Pharmacological properties”). Valganciclovir is contraindicated in patients with a creatinine clearance of less than 10 ml/min. Long-term induction therapy with valganciclovir increases the risk of myelotoxicity. Seizures have been reported in patients receiving concomitant use of ganciclovir and imipenem / cilastatin. Concomitant use of valganciclovir and imipenem / cilastatin should be avoided if the potential benefits of treatment do not exceed the possible risk (see section “Interactions with other drugs”). Since both zidovudine and ganciclovir can cause neutropenia and anemia, some patients may experience intolerance when taking full doses of valganciclovir and zidovudine at the same time (see the section “Interaction with other drugs”). Due to the possible increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be carefully monitored for symptoms of toxic effects of didanosine(see the section “Interaction with other drugs”). The use of valganciclovir concomitantly with other drugs that have a myelosuppressive or nephrotoxic effect (see the section “Interaction with other drugs”) may increase their toxic effect. A controlled clinical trial using valganciclovir for the prevention of CMV infection did not include patients after lung and bowel transplantation, so 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 should not be substituted for valganciclovir in a ratio of 1: 1. Patients who are transferred from ganciclovir capsules should be informed about the risk of overdose if they take more valganciclovir tablets than recommended (see sections “Dosage and use” and “Overdose”). Rules for handling the drug Tablets should not be broken or crushed. Since valganciclovir is potentially teratogenic and carcinogenic to humans, care should be taken if the tablet breaks. Avoid direct contact of the broken or crushed tablet with the skin and mucous membranes. 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 the absence of it – with plain water. The release of medicinal products into the environment should be kept to a minimum. Do not dispose of the product using waste water or together with household waste. If possible, it is necessary to use special systems for disposing of medicines. Effect of the drug on the performance of potentially dangerous activities that require increased concentration and speed of psychomotor reactions When treated with valganciclovir and/or ganciclovir, seizures, sedation, dizziness, ataxia and/or confusion may occur, which may adversely affect activities that require increased concentration, including driving a vehicle and working with machines and mechanisms. In this regard, during treatment with valganciclovir, care should be taken when driving a vehicle and working with machines and mechanisms. If the described adverse events occur, you should refrain from performing these types of activities. Rules for handling the drug Tablets should not be broken or crushed. Since valganciclovir is potentially teratogenic and carcinogenic to humans, care should be taken if the tablet breaks. Avoid direct contact of the broken or crushed tablet with the skin and mucous membranes. 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 the absence of it – with plain water. Effect of the drug on the performance of potentially dangerous activities that require increased concentration and speed of psychomotor reactions When treated with valganciclovir and/or ganciclovir, seizures, sedation, dizziness, ataxia and/or confusion may occur, which may adversely affect activities that require increased concentration, including driving a vehicle and working with machines and mechanisms. In this regard, during treatment with valganciclovir, care should be taken when driving a vehicle and working with machines and mechanisms. If dangerous adverse events occur, you should refrain from performing these activities. Storage conditions Keep out of the reach of children in a dark place, at a temperature not exceeding 25 °C. Shelf life is 2 years. Do not use the product after the expiration date. Active ingredient Valganciclovir Conditions of release from pharmacies By prescription Dosage form Tablets Buy Civalgan pills 450mg, 60pcs on our website! 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