Zivalgan, 450 mg 60 pcs

Pharmacotherapeutic group: Antiviral drug

ATX code: J05AB14

Pharmacological properties

Pharmacodynamics

Mechanism of action

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

In CMV-infected cells, under the action of the viral protein kinase UL97, ganciclovir is first 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 ganciclovirtriphosphate in CMV-infected cells is 18 hours; in herpes simplex virus-infected cells it is 6-24 hours. Since phosphorylation of ganciclovir depends to a greater extent on the action of viral kinase, it occurs predominantly in infected cells.

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

0.08 µmol/L (0.02 µg/ml) to 14 µmol/L (3.5 µg/ml).

The clinical antiviral effect of valganciclovir was proven by a decrease in CMV excretion from patients with acquired immunodeficiency syndrome (AIDS) and newly diagnosed CMV retinitis from a baseline of 46% to 7% after 4 weeks of valganciclovir treatment.

Efficacy

Adults

The treatment of CMV retinitis

Clinical studies have been conducted in patients with AIDS and

CMV retinitis. Valganciclovir demonstrated equal clinical efficacy in induction therapy for CMV retinitis compared to intravenous ganciclovir.

The use of valganciclovir produces the same systemic effects of ganciclovir as the recommended intravenous doses of ganciclovir effective in the treatment of CMV retinitis. The area under the concentration-time curve (AUC) of ganciclovir has been shown to correlate with the time to progression of CMV retinitis.

Prevention of CMV infection

The incidence of CMV disease (CMV syndrome + invasive tissue infection) during the first 6 months after heart, liver, and kidney transplantation in patients at high risk for CMV infection (CMV-positive donor (D+)/CMV-negative recipient(R-) (D+/R-)) was 121 % in the group of patients treated with valganciclovir (900 mg daily) and 15.2 % in the group of patients treated with oral ganciclovir (1000 mg 3 times daily) from day 10 to 100 after transplantation. Most of the cases occurred in the period after withdrawal of prophylactic therapy (after the 100th day of the post-transplant period). The incidence of CMV infection in the valganciclovir treatment group occurred later than in the ganciclovir treatment group. Frequency of acute graft rejection in the first 6 months was 29.7% in the valganciclovir-treated group and 36% in the ganciclovir-treated group.

The increase in the duration of administration of 900 mg of valganciclovir to

The 200th day after renal transplantation in patients at high risk for CMV infection (D+/R-) was associated with greater efficacy in preventing CMV infection in the first 12 months after transplantation compared with administration of 900 mg of valganciclovir before the 100th day after transplantation.

The 12-month graft survival rate was 98.2% in the group of patients receiving valganciclovir until day 100 and 98.1% in the group of patients receiving valganciclovir until day 200. The incidence of acute graft rejection confirmed by biopsy in the first 12 months was 17.2% in the group of patients who received valganciclovir up to day 100 and 11.0% in the group of patients who received valganciclovir up to day 200.

Viral resistance

Viruses resistant to ganciclovir may emerge with long-term administration of valganciclovir. This may be due to either selective mutations of the viral kinase gene (UL97), which is responsible for monophosphorylation of ganciclovir, or the viral DNA polymerase gene (UL54). Mutations of the UL97 gene occur earlier and are more common than mutations of the UL54 gene. A virus with only the UL97 gene mutation is only resistant to ganciclovir, with the most common substitution type mutations associated with the emergence of resistance being M460V/I, H520Q, C592G, A594V, L595S, 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 is mostly caused by substitution mutations in the exonuclease domains and region V of the viral DNA polymerase. The development of cross-resistance to foscarnet is caused by substitution type mutations within or between regions II (codons 696-742) and III (codons 805-845) of the viral DNA polymerase.

Adults

The 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.

Preventing CMV infection in patients after solid organ transplantation

CMV genotyping in polymorphonuclear leukocytes showed:

The absence of ganciclovir resistance-causing mutations in samples obtained at day 100 (end of prophylactic valganciclovir administration) in patients in the valganciclovir group and the presence of mutations in samples obtained from patients taking oral ganciclovir (1.9%);

The absence of resistance-causing mutations in samples obtained from patients randomized to the valganciclovir group with suspected CMV infection 6 months after transplantation and the presence of mutations in patients receiving oral ganciclovir in 6.9%.

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

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

Preclinical safety data

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

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

In view of the rapid and complete conversion of the drug to ganciclovir, no additional reproductive toxicity studies have been performed with valganciclovir. The same warning about possible reproductive toxicity applies to both drugs (see “Special Indications”). In animals, ganciclovir impairs fertility and has teratogenic effects. Given experiments on animals in which systemic exposure to ganciclovir in concentrations below therapeutic levels caused aspermia, it is very likely that ganciclovir and valganciclovir may inhibit spermatogenesis in humans.

The data obtained in a human placenta model

ex vivo show that ganciclovir penetrates the placenta, most likely by simple transfer. In the concentration range from 1 to

10 mg/ml, the transition of the drug through the placenta was unsaturated and 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 determining exposure to ganciclovir after valganciclovir administration are bioavailability and renal function. The bioavailability of ganciclovir was similar in all patients receiving valganciclovir. Systemic exposure of ganciclovir for heart, kidney and liver transplant recipients was similar to that after oral administration of valganciclovir according to the dosing regimen depending on renal function.

Intestation

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. Absolute bioavailability of ganciclovir after valganciclovir administration is about 60%. Systemic exposure of valganciclovir is low and of short duration. The area under the curve “concentration-time” (AUC24) and maximum concentration (Cmax) are approximately 1% and 3% of those of ganciclovir, respectively.

The proportional dose-response AUC of ganciclovir after doses of valganciclovir between 450 and 2625 mg has been shown only when the drug is taken after meals. If valganciclovir is taken with meals at the recommended dose of 900 mg, both the average AUC24 (by approximately 30%) and the average Cmax (by approximately 14%) of ganciclovir increase. Consequently, it is recommended that valganciclovir be taken with food (see section “Dosage and administration”).

Distribution.

Due to the rapid metabolism of valganciclovir to ganciclovir, the binding of valganciclovir to plasma proteins was not determined. Binding of ganciclovir with blood plasma proteins at pre¬drug concentrations from 0.5 to 51 mcg/ml is 1-2%. Equilibrium volume of distribution of ganciclovir after intravenous administration was 0.680 ± 0.161 l/kg.

Metabolism

Valganciclovir is rapidly hydrolyzed to form ganciclovir, no other metabolites were identified. After a single oral administration of 1000 mg of radioactive isotope-labeled ganciclovir, the radioactivity of none of the metabolites in the feces or urine exceeded

1-2%.

The main route of excretion of valganciclovir, like that of ganciclovir, is glomerular filtration and active tubular secretion. Renal clearance accounts for 81.5 ± 22% of systemic clearance of ganciclovir.

Pharmacokinetics in special patient groups

Patients with renal impairment

Impaired renal function resulted in decreased clearance of ganciclovir formed from valganciclovir, with a corresponding increase in terminal elimination half-life. Consequently, patients with impaired renal function require dose adjustments (see subsection “Dosage Guidelines” of section “Dosage and administration” and section “Precautions”).

Patients with hepatic insufficiency

The pharmacokinetics of valganciclovir-derived ganciclovir were studied in patients with a stable functioning liver transplant in an open-label, 4-part cross-over study design. Absolute bioavailability of ganciclovir formed from valganciclovir (at a single dose of 900 mg after meal) was approximately 60%, which is consistent with that in other patient groups. The AUC0-24 of ganciclovir was comparable to that after intravenous administration of ganciclovir at a dose of 5 mg/kg in patients who underwent liver transplantation.

Indications

Active ingredient

Composition

1 film-coated tablet contains:

Composition of the core of the tablet:

The active ingredient: valganciclovir hydrochloride – 496.30 mg, corresponding to valganciclovir – 450.00 mg.

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

Particle coating composition: 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.

How to take, the dosage

The dosing recommendations must be strictly followed to avoid overdose.

The standard dosing regimen

Valganciclovir should be taken orally with meals (see “Absorption” and “Pharmacokinetics in Special Patient Groups” under “Pharmacological properties”).

Valganciclovir is rapidly and largely metabolized to form ganciclovir. Bioavailability of ganciclovir in case of taking valganciclovir tablets is 10 times higher than in case of oral administration of ganciclovir (see sections “Cautions” and “Overdose”).

Therapy for CMV retinitis

Adults

Induction therapy for CMV retinitis

. In patients with active CMV retinitis, the recommended dose of valganciclovir is 900 mg (2 450 mg tablets) twice daily for 21 days. Prolonged induction therapy increases the risk of myelotoxicity (see section “Cautions”).

Supportive therapy for CMV retinitis

After a course of induction therapy or in patients with inactive CMV retinitis, the recommended dose is 900 mg (2 450 mg tablets) once daily. If the course of retinitis worsens, the course of induction therapy may be repeated (see subsection “CMV retinitis induction therapy” of section “Dosage and administration”).

Prevention of CMV infection after solid organ transplantation

Adults

Patients who have had a kidney transplant should start therapy with valganciclovir within the first 10 days after surgery at a dose of 900 mg (2 tablets of 450 mg) once daily and continue therapy until day 200 of the post-transplant period.

Patients who have had transplants of other solid organs should start valganciclovir within the first 10 days after surgery at a dose of 900 mg (2 450 mg tablets) once daily and continue until day 100 of the post-transplant period.

Patients with renal impairment

Careful monitoring of serum creatinine concentration or creatinine clearance is necessary. Dose adjustments in adult patients are made depending on creatinine clearance as shown in the table below (see subsection “Pharmacokinetics in Special Patient Groups” of the section “Pharmacological properties” and section “Cautions”).

The creatinine clearance is calculated according to the serum creatinine concentration using the following formula:

(140 – age [years]) × (body weight [kg])

for men = ————————

(72) × (0.011 × serum creatinine concentration [μmol/L])

for women = 0.85 × index for men

Creatinine clearance (ml/min)

Dose for induction therapy

Dose for maintenance therapy/prevention

≥ 60

900 mg 2 times daily

900 mg 1 time daily

40-59

450 mg 2 times a day

450 mg 1 time per day

25-39

450 mg once 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 impairment

Efficacy and safety have not been established.

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

Patients with severe leukopenia, neutropenia, anemia, thrombocytopenia, or pancytopenia. Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow suppression, and aplastic anemia have been reported in patients treated with valganciclovir (and ganciclovir). The treatment should not be started if the absolute number of neutrophils is less than 500 cells per 1 µl or the number of thrombocytes is less than 25000 cells per 1 µl, or if hemoglobin is lower than 80 g/l. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia it is recommended to administer hematopoietic growth factors and/or discontinue the drug (see sections “Special indications” and “Side effects”).

Patients in the elderly

Efficacy and safety have not been established.

Patients of Childhood

Therapy of CMV retinitis

Valganciclovir is contraindicated in children under 18 years of age for therapy 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 dosing regimen in children from 16 to 18 years of age does not differ from that in adults (see subsection “Prevention of CMV infection after solid organ transplantation” in section “Dosage and administration”). Valganciclovir is contraindicated in children and adolescents under 16 to prevent CMV infection after transplantation of solid organs, because efficacy and safety of valganciclovir use in this age group has not been established.

Special Instructions

Mutagenic, teratogenic, aspermatogenic, and carcinogenic effects of ganciclovir have been identified in animal experiments. Valganciclovir should be considered a potential teratogen and carcinogen for humans, the use of which can cause birth defects and cancer (see subsection “Rules for handling the drug” of section “Specific information”). In addition, it is likely that valganciclovir may temporarily or irreversibly inhibit spermatogenesis (see sections “Side effects”, “Use in pregnancy and lactation”, subsection “Preclinical safety data” of section “Pharmacological properties”).

In patients receiving valganciclovir (and ganciclovir) there have been cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, inhibition of bone marrow function and aplastic anemia. The treatment should not be started if the absolute number of neutrophils is less than 500 cells per 1 µl or the number of platelets is less than 25000 cells per 1 µl, and also if hemoglobin is lower than 80 g/l (see subsection “Dosage instructions” of section “Dosage and administration” and section “Side effect”).

In the course of treatment it is recommended to perform regular monitoring of the detailed blood count and platelets. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia it is recommended to prescribe hematopoietic growth factors and/or discontinue the drug (see subsection “Dosage instructions” of “Dosage and administration” and section “Side effects”).

Patients with renal insufficiency may require increased monitoring of gross blood counts, at least every time they visit the transplant clinic. Patients with renal impairment require dose adjustment based on creatinine clearance (see sections “Dosage and administration” and “Pharmacological properties”). In patients with creatinine clearance less than 10 ml/min, the use of valganciclovir is contraindicated.

Long-term induction therapy with valganciclovir increases the risk of myelotoxicity.

Concomitant use of ganciclovir and imipenem/cylastatin has caused seizures in patients. Concomitant use of valganciclovir and imipenem/cilastatin should be avoided in cases where the potential benefits of treatment do not exceed the possible risks (see section “Interaction with other medicinal products”).

Because both zidovudine and ganciclovir can cause neutropenia and anemia, some patients may experience intolerance when taking valganciclovir and zidovudine at full doses at the same time (see section “Interaction with other medicinal products”).

Because of the possible increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be closely monitored for symptoms of toxic effects of didanosine
(see section “Interaction with other medicinal products”).

The use of valganciclovir concomitantly with other drugs with myelosuppressive or nephrotoxic effects (see section “Interaction with other medicinal products”) may increase their toxic effects.

The controlled clinical trial of valganciclovir for prevention of CMV infection did not include patients after lung and intestinal transplantation, so there is limited experience with the drug in these patients.

The bioavailability of ganciclovir from valganciclovir tablets is 10 times greater than that of ganciclovir capsules. Ganciclovir should not be substituted for valganciclovir at a 1:1 ratio. Patients being switched from ganciclovir capsules should be advised of the risk of overdose if they take more valganciclovir tablets than recommended (see sections on Dosage and administration and Overdose).

Treatment instructions

The tablets should not be crushed or crushed. Because valganciclovir is potentially teratogenic and carcinogenic to humans, care should be taken if the tablet breaks. Direct contact of the broken or crushed tablet with skin and mucous membranes should be avoided. In cases of such contact you should rinse the place thoroughly with soap and water, in case of contact with eyes – they should be thoroughly rinsed with sterile water, and if there is no such water – with plain water.

The release of the medication into the environment should be kept to a minimum. The drug should not be disposed of with wastewater or with household waste. If possible, special systems should be used to dispose of medications.

The effect of the drug on the performance of potentially hazardous activities requiring increased concentration and rapid psychomotor reactions

. Treatment with valganciclovir and/or ganciclovir may cause seizures, sedation, dizziness, ataxia and/or confusion, which may adversely affect activities requiring increased concentration, including driving and operating machinery and machines. In this regard, during the treatment with valganciclovir, caution should be exercised when driving vehicles and working with machines and mechanisms. In case of occurrence of the described adverse effects it is necessary to refrain from performing the specified activities.

Treatment instructions

The tablets must not be crushed or crushed. Because valganciclovir is potentially teratogenic and carcinogenic to humans, care should be taken if the tablet breaks. Direct contact of the broken or crushed tablet with skin and mucous membranes should be avoided. In cases of such contact you should rinse the place thoroughly with soap and water, in case of contact with eyes – they should be thoroughly rinsed with sterile water, and if there is no such water – with plain water.

The effect of the drug on the performance of potentially hazardous activities requiring increased concentration and rapid psychomotor reactions

. Treatment with valganciclovir and/or ganciclovir may cause seizures, sedation, dizziness, ataxia and/or confusion, which may adversely affect activities requiring increased concentration, including driving and operating machinery and machines. In this regard, during the treatment with valganciclovir, caution should be exercised when driving vehicles and working with machines and mechanisms. In case of appearance of dangerous adverse events, it is necessary to refrain from performing the specified activities.

Synopsis

Contraindications

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

The absolute number of neutrophils is less than 500 cells per 1 µl, the number of platelets is less than 25000 cells per 1 µl, or the concentration of hemoglobin is less than 80 g/l (see section “Special Precautions”).

Creatinine clearance 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 AIDS patients).

The period of breastfeeding.

With caution

Elderly age (efficacy and safety not established).

Side effects

Clinical Study Data

Valganciclovir is a prodrug of ganciclovir that converts quickly to ganciclovir after oral administration, so all known adverse effects associated with ganciclovir administration are to be expected for valganciclovir. All adverse events reported in clinical studies have previously been observed with treatment with ganciclovir.

Adults

The treatment of CMV retinitis in AIDS patients

The safety profiles of valganciclovir and ganciclovir when administered intravenously for 28 days were similar. The most frequent adverse events were diarrhea, neutropenia and fever. Oral valganciclovir patients were more likely to have oral candidiasis, headache, and weakness, while intravenous valganciclovir therapy was associated with 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.

Adverse event

Group of patients who received valganciclovir N=79

Group of patients who received ganciclovir intravenously N=79

Diarrhea

16%

10%

Mucosal candidiasis

11%

6%

Headache

9%

5%

Weakness

8 %

4%

Nausea

8 %

14%

Phlebitis and thrombophlebitis

–

6%

The following table (see Table 2) shows the adverse events.

The following table (see Table 2) presents adverse events (regardless of their severity and relationship to the drug) with an incidence of ≥5% from clinical trials of valganciclovir either in patients with CMV retinitis or in patients after solid organ transplantation.

The most common adverse reactions, regardless of severity but judged by investigators to be associated with drug administration (remote, probable or possible association) in patients with CMV retinitis were: neutropenia, anemia, diarrhea and nausea.

Prevention of CMV infection in patients after solid organ transplantation

Prevention of CMV infection in patients after solid organ transplantation. Table 2 presents adverse events (up to 28 days after study completion), regardless of severity or association with drug administration, with an incidence of ≥ 5% in clinical trials in patients after solid organ transplantation who received valganciclovir or ganciclovir orally, starting within 10 days after transplantation and continuing until day 100 of the post-transplant period.

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

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

Body systems/description of NIH

Patients with CMV retinitis

Patients after solid organ transplantation who received treatment before day 100 of the post-transplant period

Overdose

In one adult patient a bone marrow suppression (medullary aplasia) with lethal outcome occurred when valganciclovir was used for several days in doses at least 10 times higher than recommended with regard to renal function impairment (decreased creatinine clearance).

It is possible that overdose of valganciclovir may lead to increased nephrotoxicity (see sections “Special Precautions” and “Administration and Dose”).

Valganciclovir plasma concentrations in patients with overdose can be reduced by hemodialysis and hydration.

Ganciclovir overdose with intravenous administration

Because valganciclovir is rapidly and largely converted to ganciclovir, the adverse events seen in ganciclovir overdose may also be expected in valganciclovir overdose.

In clinical trials and post-marketing use of the drug, there have been cases of intravenous ganciclovir overdose described. Some of these were without adverse events. Most patients, however, experienced one or more of the following adverse events:

Hematotoxicity: pancytopenia, suppression of bone marrow function, medullary aplasia, leukopenia, neutropenia, granulocytopenia;

Hepatotoxicity: hepatitis, liver function impairment;

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, seizures.

Pregnancy use