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

Treatment of CMV retinitis in adult patients with AIDS.

Prevention of CMV infection after solid organ transplantation in adults and children over 16 years of age at risk.

Pharmacological effect

Pharmacotherapeutic group: Antiviral agent

ATX code: J05AB14

Pharmacological properties

Pharmacodynamics

Mechanism of action

Valganciclovir is the L-valyl ester (prodrug) of ganciclovir, which, after oral administration, is rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2′-deoxyguanosine, which suppresses the 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 virus types 6, 7 and 8, Epstein-Barr virus, varicella zoster virus and hepatitis B virus.

In CMV-infected cells, ganciclovir is first phosphorylated by the viral protein kinase UL97 to form ganciclovir monophosphate. Further phosphorylation occurs by cellular kinases to form 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 CMV-infected cells is 18 hours; in cells infected with herpes simplex virus – 6-24 hours. Since ganciclovir phosphorylation is largely dependent on the action of viral kinase, it occurs predominantly in infected cells.

The virostatic activity of ganciclovir is due to the suppression of viral DNA synthesis through the following mechanisms: (1) competitive inhibition of the incorporation of deoxyguanosine triphosphate into DNA under the action of viral DNA polymerase; (2) incorporation of ganciclovir triphosphate into viral DNA, resulting in no or very limited elongation of viral DNA. According to in vitro studies, the typical inhibitory concentration that inhibits 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 the release of CMV from the body of patients with acquired immunodeficiency syndrome (AIDS) and newly diagnosed CMV retinitis from an initial rate of 46% to 7% after 4 weeks of treatment with valganciclovir.

Efficiency

Adults

Treatment of CMV retinitis

Clinical studies have been conducted in patients with AIDS and

CMV retinitis. Valganciclovir has demonstrated equal clinical efficacy in the induction therapy of CMV retinitis compared with intravenous ganciclovir.

The use of valganciclovir provides the same systemic exposure to 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, kidney transplantation in patients with a high risk of CMV infection (CMV-positive donor (D+)/CMV-negative recipient (R-) (D+/R-)) 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 in the period after discontinuation of preventive therapy (after the 100th day of the post-transplant period). Moreover, 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 group of patients receiving valganciclovir and 36% in the group of patients receiving ganciclovir.

Increasing the duration of valganciclovir 900 mg to

Day 200 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 with valganciclovir 900 mg before day 100 after transplantation.

The graft survival rate at 12 months was 98.2% in the group of patients receiving valganciclovir before day 100 and 98.1% in the group of patients receiving valganciclovir before day 200. The incidence of biopsy-proven acute graft rejection in the first 12 months was 17.2% in the group of patients receiving valganciclovir before day 100 and 11.0% in the group of patients receiving valganciclovir before day 200.

Viral resistance

With long-term use of valganciclovir, viruses that are resistant to ganciclovir may appear. This may be due to either selection of mutations in the viral kinase gene (UL97), responsible for monophosphorylation of ganciclovir, or in the viral DNA polymerase gene (UL54). Mutations in the UL97 gene occur earlier and are more common compared to mutations in the UL54 gene. A virus that has only a mutation in the UL97 gene is resistant only to ganciclovir; Moreover, the most common substitution type mutations associated with the emergence of resistance are M460V/I, H520Q, C592G, A594V, L595S, C603W. A virus with mutations in the UL54 gene may be cross-resistant to other antiviral drugs with a similar mechanism of action, and vice versa. The development of cross-resistance to cidofovir in most cases is 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 mutations 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 treatment with valganciclovir, respectively,

2.2%, 6.5%, 12.8% and 15.3% of leukocytes have UL97 mutations.

Prevention of CMV infection in patients after solid organ transplantation

Genotyping of CMV in polymorphonuclear leukocytes showed:

absence of mutations conferring resistance to ganciclovir in samples obtained on day 100 (end of valganciclovir prophylaxis) 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 mutations in samples obtained from patients randomized to valganciclovir with suspected CMV infection 6 months after transplantation, and the presence of mutations in patients receiving oral ganciclovir in 6.9%.

Among patients receiving valganciclovir before post-transplant day 100 and day 200, substitution mutations were overall more common during prophylaxis than after completion of prophylaxis (5/12 [42%] vs. 4/58 [7%]).

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

Preclinical safety data

Ganciclovir has been shown to be carcinogenic in studies in mice. Valganciclovir, like ganciclovir, is a potential carcinogen.

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

Given the rapid and complete conversion of the drug to ganciclovir, additional reproductive toxicity studies have not been conducted with valganciclovir. Both drugs carry the same warning about possible reproductive toxicity (see section “Special Instructions”). In animals, ganciclovir impairs fertility and has a teratogenic effect. Given animal studies in which systemic exposure to subtherapeutic concentrations of ganciclovir caused aspermia, it is likely that ganciclovir and valganciclovir may inhibit spermatogenesis in humans.

Data from the human placenta model

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

At 10 mg/ml, the passage of the drug through the placenta was unsaturated and occurred through 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.

Parameters that determine ganciclovir exposure after administration of valganciclovir are bioavailability and renal function. The bioavailability of ganciclovir was similar in all patients receiving valganciclovir. Systemic exposure to ganciclovir in heart, kidney, and liver transplant recipients was similar to that following oral valganciclovir following dosing regimens based on renal function.

Suction

Valganciclovir is a prodrug of ganciclovir, is well absorbed from 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 of valganciclovir is low and short-term. 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 dose after administration of valganciclovir in doses from 450 to 2625 mg is shown only when taking the drug after meals. When valganciclovir is taken with food at the recommended dose of 900 mg, both the mean AUC24 (by approximately 30%) and the mean Cmax (by approximately 14%) of ganciclovir increase. Therefore, valganciclovir is recommended to 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. 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 administration was

0.680 ± 0.161 l/kg.

Metabolism

Valganciclovir is rapidly hydrolyzed to form ganciclovir; no other metabolites have been identified. After a single oral dose of 1000 mg of radiolabeled ganciclovir, the radioactivity of any of the metabolites in the feces or urine did not exceed

1-2%.

Removal

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

Pharmacokinetics in special groups of patients

Patients with renal failure

Impaired renal function resulted in decreased clearance of ganciclovir derived from valganciclovir, with a corresponding increase in terminal half-life. Therefore, patients with impaired renal function require dose adjustment (see the subsection “Special instructions for dosing” of the section “Dosage and Administration” and the section “Special instructions”).

Patients with liver failure

The pharmacokinetics of ganciclovir, derived from valganciclovir, were studied in patients with stable liver transplantation in an open-label study with a 4-arm crossover design. The absolute bioavailability of ganciclovir derived from valganciclovir (with a single dose of 900 mg after food) was approximately 60%, which is the same as 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 undergoing liver transplantation.

Special instructions

In a place protected from light, at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Active ingredient

By prescription

Composition

1 film-coated tablet contains:

Tablet core composition:

Active substance: 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; 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; red iron oxide dye – 0.08 mg; iron dye black oxide – 0.01 mg.

Pregnancy

Additional reproductive toxicity studies have not been conducted with valganciclovir due to the rapid and complete conversion of valganciclovir to ganciclovir. Ganciclovir impairs fertility and has a teratogenic effect in animals (see subsection “Preclinical safety data” in the section “Pharmacological properties”).

During treatment with valganciclovir, women of childbearing age should be advised to use reliable methods of contraception; men are recommended to use a barrier method of contraception during treatment and for at least 90 days after its completion (see the subsection “Non-clinical safety data” of the section “Pharmacological properties”).

The safety of valganciclovir during pregnancy in humans has not been established. During pregnancy, the use of valganciclovir should be avoided unless the potential benefit of treatment for the mother justifies the possible risk to the fetus.

Studies of the effect of valganciclovir and ganciclovir on peri- and postnatal development have not been conducted, and the possibility of ganciclovir being excreted in breast milk and the development of serious adverse reactions in the infant cannot be ruled out. If it is necessary to use the drug during lactation, breastfeeding must be stopped.

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 number of neutrophils is less than 500 cells in 1 μl, the platelet count is less than 25,000 cells in 1 μl, or the hemoglobin concentration is below 80 g/l (see section “Special instructions”).

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 patients with AIDS).

Breastfeeding period.

With caution

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

Side Effects

Clinical trial data

Valganciclovir is a prodrug of ganciclovir that is rapidly converted to ganciclovir after oral administration, so all known adverse effects associated with ganciclovir are expected for valganciclovir. All adverse events recorded in clinical studies were previously observed during treatment 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 similar. The most common adverse events were diarrhea, neutropenia, and fever. Patients receiving oral valganciclovir were more likely to experience oral candidiasis, headache and weakness, and when treated with intravenous ganciclovir, nausea and adverse events at the injection site (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 receiving valganciclovir N=79

Group of patients receiving intravenous ganciclovir N=79

Diarrhea

16%

10%

Candidiasis of the oral mucosa

11%

6%

Headache

9 %

5%

Weakness

8%

4%

Nausea

8%

14%

Phlebitis and thrombophlebitis

–

6%

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

The most common adverse reactions, regardless of severity, but considered drug-related (remote, probable, or possible) in patients with CMV retinitis were: neutropenia, anemia, diarrhea, and nausea.

Prevention of CMV infection in patients after solid organ transplantation

Table 2 summarizes adverse events (up to 28 days after study completion), regardless of severity or drug-related, with an incidence of ≥ 5% observed in clinical trials in solid organ transplant patients receiving oral valganciclovir or ganciclovir starting within 10 days post-transplant and continuing until post-transplant day 100.

The most common adverse reactions, regardless of severity, but, according to investigators, associated with taking the drug (remote, probable or possible connection) 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) occurring in ≥ 5% of patients with CMV retinitis or solid organ transplantation in clinical trials with valganciclovir or ganciclovir.

Body systems/description of AEs

Patients with CMV retinitis

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

Valganciclovir

(n=370)

Valganciclovir

(n=244)

Oral ganciclovir (n=126)

%

%

%

From the digestive system

Diarrhea

38

30

29

Nausea

25

23

23

Vomit

20

16

14

Stomach ache

13

14

14

Constipation

6

20

20

Pain in the upper abdomen

6

9

6

Dyspepsia

4

12

10

Bloating

2

6

6

Ascites

–

9

6

Liver dysfunction

3

9

11

From the body as a whole

Fever

26

13

14

Fatigue

20

13

15

Swelling of the lower extremities

5

21

16

Pain

3

5

7

Edema

1

11

9

Peripheral edema

1

6

7

Weakness

4

6

6

From the blood and lymphatic system

Neutropenia

24

8

3

Anemia

22

12

15

Thrombocytopenia

5

5

5

Leukopenia

4

14

7

Infectious complications

Candidiasis of the oral mucosa

20

3

3

Pharyngitis/nasopharyngitis

12

4

8

Sinusitis

10

3

–

Upper respiratory tract infections

9

7

7

Flu

9

–

–

Pneumonia

7

4

2

Bronchitis

6

–

1

Pneumocystis pneumonia

6

–

–

Urinary tract infections

5

11

9

From the nervous system

Headache

18

22

27

Insomnia

14

20

16

Peripheral

neuropathy

7

1

1

Paresthesia

6

5

5

Tremor

2

28

25

Dizziness (except vertigo)

9

10

6

Depression

9

7

6

From the skin and subcutaneous fat

Dermatitis

18

4

5

Night sweats

7

3

4

Itching

6

7

4

Acne

< 1

4

6

Rash

9

< 1

–

From the respiratory system

Cough

16

6

8

Dyspnea

9

11

10

Productive cough

5

2

2

Nasal discharge

2

4

6

Pleural effusion

< 1

7

8

From the senses

Retinal detachment

13

–

–

Blurred vision

6

1

4

From the musculoskeletal system

Back pain

8

20

15

Arthralgia

6

7

7

Muscle cramps

2

6

11

Pain in the limbs

3

5

7

From the urinary system

Kidney failure

1

7

12

Dysuria

2

7

6

From the immune system

Transplant rejection reaction

–

24

30

Metabolism

Anorexia

5

3

–

Cachexia

5

–

–

Decreased appetite

8

4

5

Dehydration

6

5

6

Weight loss

9

3

3

From the cardiovascular system

Lower blood pressure

1

3

8

Increased blood pressure

3

18

15

Laboratory indicators

Hyperkalemia

< 1

14

14

Hypokalemia

2

8

8

Hypomagnesemia

< 1

8

8

Hyperglycemia

1

6

7

Hypophosphatemia

< 1

9

6

Hypocalcemia

< 1

4

6

Hypercreatininemia

1

10

14

Postoperative complications

Postoperative

complications

1

12

8

Pain in the postoperative period

2

13

7

Infection of a postoperative wound

1

11

6

Increased frequency of need for drainage

–

5

9

Poor postoperative wound healing

< 1

5

6

The following are serious adverse events that occurred at an incidence of less than 5% in three clinical studies and are not listed above.

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

From the genitourinary system: decreased creatinine clearance.

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

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

Severe neutropenia (absolute neutrophil count less than 500 per microliter) is more common in patients with CMV retinitis (16%) than in patients receiving valganciclovir (5%) or oral ganciclovir (3%) after solid organ transplantation before post-transplant day 100 or in patients receiving valganciclovir
(10%) until the 200th day of the post-transplant period. Patients receiving either valganciclovir or ganciclovir orally after solid organ transplantation prior to post-transplant day 100 or day 200 experienced greater increases in serum creatinine concentrations compared with patients with CMV retinitis. Renal dysfunction is common in patients who have undergone organ transplantation.

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

Table 3. Changes in laboratory parameters reported with valganciclovir in adults.

Changes in laboratory parameters

Patients with CMV retinitis

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

Valganciclovir (n=370)

Valganciclovir

(n=244)

Oral ganciclovir (n=126)

%

%

%

Neutropenia (absolute number of neutrophils/µl)

< 500

16

5

3

500 – < 750

17

3

2

750 – < 1000

17

5

2

Anemia (hemoglobin g/l)

< 65

7

1

2

65 – < 80

10

5

7

80 – < 95

14

31

25

Thrombocytopenia (number of platelets/μl)

< 25000

3

0

2

25000 – < 50000

5

1

3

50000 – < 100000

21

18

21

Serum creatinine concentration (mg/dL)

>2.5

2

14

21

>1.5-2.5

11

45

47

Experience with ganciclovir

Because valganciclovir is rapidly metabolized to form ganciclovir, the following are adverse events noted during treatment with ganciclovir and not listed 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; not­disturbed; mucositis; photosensitivity reaction; shiver; sepsis.

From the skin and subcutaneous fat: alopecia, dry skin, sweating, urticaria.

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

From the musculoskeletal system: pain in bones and muscles, myasthenic syndrome.

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

From the endocrine system: diabetes mellitus.

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

From the senses: amblyopia, blindness, ear pain, hemorrhages in the eye, pain in the eyeballs, deafness, glaucoma, taste disturbances, tinnitus, blurred vision, changes in the vitreous body.

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

From the cardiovascular system: arrhythmias, including ventricular, migraine, 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 presents adverse events (developed before
28 days after completion of the study) regardless of their severity and connection with the drug.

The table includes adverse events with frequency of occurrence
≥ 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 post-transplant day 100, and in children after kidney transplantation who started valganciclovir within 10 days after transplantation and continued treatment until day 200 post-transplantation 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 at a higher frequency in children than in adults, such as upper respiratory tract infections, fever, abdominal pain and dysuria, which may reflect characteristics of the pediatric 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 incidence of infections.

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

Table 4. Adverse events occurring with an incidence of ≥ 10% in children after solid organ transplantation.

Body systems/description of AEs

Pediatric patients after solid organ transplantation

Treatment with valganciclovir until the 100th day of the post-transplant period

(n=63)

Treatment with valganciclovir until the 200th day 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

Stomach ache

6

18

Vomit

21

13

From the blood and lymphatic system

Leukopenia

2

25

Anemia

14

16

Interaction

Drug interactions of valganciclovir

Interactions in the in situ model of intestinal permeability in rats
Valganciclovir was not detected with valacyclovir, didanosine, nelfinavir, cyclosporine, omeprazole and mycophenolate mofetil.

Valganciclovir is converted to ganciclovir, so interactions characteristic of ganciclovir may also occur when taken
valganciclovir.

Drug interactions of ganciclovir

The degree of binding of ganciclovir to plasma proteins is only
1-2%, so reactions associated with protein binding displacement are not expected.

Imipenem/cilastatin: Convulsions have been reported in patients with concomitant use of ganciclovir and imipenem/cilastatin. The simultaneous use of valganciclovir and imipenem/cilastatin should be avoided unless the potential benefits of treatment outweigh the possible risks (see section “Special Instructions”).

Probenecid: Concomitant oral administration of probenecid resulted in a statistically significant decrease in the renal clearance of ganciclovir
(20%) and to increase the duration of its action (40%). This is explained by the mechanism of interaction – competition for tubular renal excretion. Patients taking probenecid and valganciclovir concomitantly should be closely monitored due to the potential for ganciclovir toxicity.

Zidovudine: When used concomitantly with oral ganciclovir, a small but statistically significant increase in zidovudine AUC was observed (17%); In addition, there was a statistically insignificant trend toward a decrease in ganciclovir concentrations. Because both zidovudine and ganciclovir can cause neutropenia and anemia, some patients may experience intolerance when taking full doses of valganciclovir and zidovudine concomitantly (see section “Special Instructions”).

Didanosine: A persistent increase in plasma concentrations of didanosine was detected when administered concomitantly with ganciclovir (both intravenously and orally). In the case of oral administration of ganciclovir in doses of 3 and 6 g per day, an increase in didanosine AUC by 84-124% was observed; with intravenous administration of ganciclovir in doses of 5-10 mg/kg/day, didanosine AUC increased by
38-67%. This increase cannot be explained by a 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 increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be carefully monitored for symptoms of didanosine toxicity when using valganciclovir (see section “Special Instructions”).

Mycophenolate mofetil: Based on the results of a study of single intravenous administration of the recommended dose of ganciclovir and oral mycophenolate mofetil, as well as the known effect of renal impairment 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 increased concentrations of ganciclovir and the phenolic glucuronide mycophenolic acid. No significant change in the pharmacokinetics of mycophenolic acid is expected, so no dose adjustment of mycophenolate mofetil is required. In patients with renal impairment who are simultaneously receiving mycophenolate mofetil and
valganciclovir, it is necessary to follow the recommendations for dose adjustment of valganciclovir and conduct careful monitoring.

Zalcitabine: Zalcitabine increased the AUC0-8 of orally administered ganciclovir by 13%. There were no statistically significant changes in other pharmacokinetic parameters. Clinically significant changes in the pharmacokinetics of zalcitabine with simultaneous oral administration of ganciclovir were also not detected, despite a slight increase in the elimination rate constant.

Stavudine: No statistically significant pharmacokinetic interaction was observed with simultaneous oral administration of ganciclovir and stavudine.

Trimethoprim: Trimethoprim statistically significantly reduced the renal clearance of ganciclovir taken orally by 16.3%, which was also accompanied by a statistically significant decrease in the rate of terminal elimination and a corresponding increase in 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 while taking ganciclovir was an increase in the minimum concentration (Cmin) by 12%. However, this is unlikely to be of clinical significance and no dose adjustment of valganciclovir is required.

Cyclosporine: When comparing cyclosporine concentrations before the next dose, there was no evidence that ganciclovir altered the pharmacokinetics of cyclosporine. However, after initiation of ganciclovir, a slight increase in maximum serum creatinine concentration was observed.

Other possible drug interactions: Since the main route of elimination of ganciclovir is glomerular filtration and active tubular secretion (see “Elimination” subsection of the “Pharmacological properties” section), the use of valganciclovir concomitantly with antiretroviral drugs that are also eliminated by active tubular secretion (for example, nucleos(t)ide reverse transcriptase inhibitors) may affect the concentration of valganciclovir and/or together. the drugs used. The use of ganciclovir concomitantly with other drugs that have a myelosuppressive or nephrotoxic effect (for example, dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogues, hydroxyurea and pegylated interferons/ribavirin) may increase their toxic effects. Therefore, these drugs can be used simultaneously with valganciclovir only if the expected benefit from the treatment outweighs the possible risk (see section “Special Instructions”).

Interaction

To avoid overdose, it is necessary to strictly follow the dosage recommendations.

Standard dosage regimen

Valganciclovir should be taken orally with food (see subsections “Absorption” and “Pharmacokinetics in special groups of patients” of the “Pharmacological properties” section).

Valganciclovir is rapidly and extensively metabolized to form ganciclovir. The bioavailability of ganciclovir when taking valganciclovir tablets is 10 times higher than when taking ganciclovir orally (see sections “Special Instructions” 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 tablets of 450 mg) 2 times a day for 21 days. Long-term induction therapy increases the risk of myelotoxicity (see section “Special Instructions”).

Maintenance therapy for 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) once a day. If the course of retinitis worsens, the course of induction therapy can be repeated (see the subsection “Induction therapy for CMV retinitis” in the “Dosage and Administration” section).

Prevention of CMV infection after solid organ transplantation

Adults

Patients who have undergone kidney transplantation should begin therapy with valganciclovir 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 begin therapy with valganciclovir 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 kidney failure

Serum creatinine concentrations or creatinine clearance should be carefully monitored. Dose adjustment in adult patients is carried out depending on creatinine clearance, as shown in the table below (see the subsection “Pharmacokinetics in special groups of patients” of the section “Pharmacological properties” and the section “Special instructions”).

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

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

for men = ————————————————————————

(72) x (0.011 x serum creatinine concentration [µmol/l])

for women = 0.85 × figure for men

Creatinine clearance (ml/min)

Dose for induction therapy

Dose for maintenance/prophylaxis

≥ 60

900 mg 2 times a day

900 mg 1 time per day

40-59

450 mg 2 times a day

450 mg 1 time per day

25-39

450 mg 1 time per day

450 mg every 2 days

10-24

450 mg every 2 days

450 mg 2 times a week

< 10

contraindicated

contraindicated

Patients with liver failure

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 suppression and aplastic anemia have been reported in patients receiving valganciclovir (and ganciclovir). Treatment should not be started if the absolute neutrophil count is less than 500 cells in 1 µl or the platelet count is less than 25,000 cells in 1 µl, as well as if hemoglobin is below 80 g/l. For patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, it is recommended to prescribe hematopoietic growth factors and/or interrupt the drug (see sections “Special Instructions” and “Side Effects”).

Elderly patients

Efficacy and safety have not been established.

Pediatric patients

Therapy for CMV retinitis

The use of valganciclovir in children under 18 years of age for the treatment of CMV retinitis is contraindicated, since the effectiveness 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 to 18 years does not differ from the dosage regimen for adults (see subsection “Prevention of CMV infection after solid organ transplantation” in the “Dosage and Administration” section). The use of valganciclovir is contraindicated in children and adolescents under 16 years of age for the purpose of preventing CMV infection after solid organ transplantation, since the effectiveness and safety of valganciclovir in this age group has not been established.

Overdose

Tablets are oval, biconvex, pink film-coated, scored on one side and embossed “f” on the other. On a cross section, the core is white to white with a yellowish tint.

Storage conditions

2 years.

Do not use the drug after the expiration date.

Shelf life

Valganciclovir

Manufacturer

Izvarino Pharma, Russia