Tsivilgan - instructions for use, doses, side effects, contraindications

Composition of the tablet shell: polyvinyl alcohol 9.20 mg; titanium dioxide - 5.58 mg; macrogol 3350 - 4.65 mg; talc - 3.40 mg; ferric oxide yellow oxide - 0.08 mg; ferric oxide red oxide - 0.08 mg; dye iron oxide black - 0,01 mg.

Description:

The tablets are oval, biconcave, covered with a film membrane of pink color, with a risk on one side and embossed "f" another. On the cross section - the core is white to white with a yellowish hue of color.

Pharmacotherapeutic group:antiviral agent

ATX: & nbsp

J.05.A.B.14 Valganciclovir

J.05.A.B Nucleosides and nucleotides

Pharmacodynamics:

Mechanism of action

Valganciclovir is a L-valyl ether (prodrug) of ganciclovir, after oral administration rapidly converted into ganciclovir under the influence of intestinal and hepatic esterases. Ganciclovir - synthetic analogue 2'-deoxyguanosine, which suppresses the replication of herpes-group 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, under the action of viral protein kinase UL97 ganciclovir first phosphorylated with the formation of ganciclovir monophosphate. Further phosphorylation occurs under the action of cellular kinases with the formation of ganciclovortriphosphate, which then undergoes a slow intracellular metabolism. After the disappearance of ganciclovir from the extracellular fluid, the intracellular half-life of ganciclovirtyphosphate in cells infected with CMV is 18 hours; in cells infected with the herpes simplex virus - 6-24 hours.Since ganciclovir phosphorylation is more dependent on the action of the viral kinase, it occurs predominantly in infected cells.

Virostatic activity of ganciclovir is due to suppression of viral DNA synthesis by the following mechanisms: (1) competitive inhibition of the incorporation of deoxyguanosine triphosphate into DNA under the action of viral DNA polymerase; (2) the inclusion of ganciclovir triphosphate in viral DNA, which leads to the cessation of elongation or very limited lengthening of the viral DNA. According to research in vitro, typical inhibitory concentration, which suppresses replication of CMV by 50% (IFROM₅₀), is in the range of 0.08 μmol / l (0,02 μg / ml) to 14 μmol / L (3.5 μg / ml).

The clinical antiviral effect of valganciclovir was demonstrated by a decrease in the isolation of CMV from the body of patients - Acquired Immunodeficiency Syndrome (AIDS) and newly diagnosed CMV retinitis from baseline of 46% to 7% at 4 weeks of treatment with valganciclovir.

Efficiency

Treatment of CMV retinitis

Clinical studies have been conducted in patients with AIDS and CMV retinitis. Valganciclovir demonstrated the same clinical efficacy in induction therapy for CMV retinitis as compared with intravenous ganciclovir.

The use of valganciclovir makes it possible to obtain the same systemic effect of ganciclovir as with the recommended intravenous doses of ganciclovir effective in the treatment of CMV retinitis. It is shown that the area under the concentration-time curve (AUC) of ganciclovir is correlated 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 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 who received valganciclovir (900 mg per day), and 15.2% in the group of patients who received ganciclovir inwards (1000 mg 3 times a day) with 10 100 days after transplantation. Most of the cases occurred after the abolition of preventive therapy (after 100day of the post-transplant period). In this case, the development of CMV infection in the treatment group with valganciclovir appeared later than in the group of treatment with ganciclovir.The frequency of acute graft rejection in the first 6 months was 29.7% in the group of patients who received valganciclovir, and 36% in the group of patients receiving ganciclovir.

An increase in the duration of administration of 900 mg of valganciclovir to the 200th day after kidney transplantation in patients at high risk of CMV infectionD+/R-) was associated with a greater efficacy of preventing CMV infection in the first 12 months after transplantation compared to taking 900 mg of valganciclovir before the 100th day after transplantation.

The survival rate of the transplant in 12 months was 98.1% in the group of patients receiving valganciclovir up to the 100th day, and 98.2% in the group of patients receiving valganciclovir up to the 200th day. 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 before 100day, and 11,0% in the group of patients receiving valganciclovir before 200th day.

Viral Resistance

With prolonged use of valganciclovir, viruses resistant to ganciclovir may appear. This may be due to either the selection of mutations of the viral kinase gene (UL97) responsible for monophosphorylation of ganciclovir or the gene of the viral DNA polymerase (UL54).Mutations of the UL97 gene occur at earlier times and are more common than the mutation of the UL54 gene. A virus having only a mutation of the UL97 gene is resistant only to ganciclovir; the most common mutations associated with the emergence of resistance are the M460V / I, H520Q, C592G, A594V, L595S, C603W. A virus with mutations of 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 by the type of substitution in the exonuclease domains and region V of the viral DNA polymerase. The development of cross-resistance to foscarnet is due to 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 treatment with valganciclovir, respectively 2,2%, 6,5%, 12,8% and 15,3% of leukocytes are detected mutations UL97.

Prevention of CMV infection in patients after solid organ transplantation

Genotyping of CMV in polymorphonuclear leukocytes showed:

1), the absence of mutations causing resistance to ganciclovir, in samples obtained on 100(end of prophylactic administration of valganciclovir) in patients from the valganciclovir group, and the presence of mutations in samples obtained from patients taking ganciclovir orally (1.9%);

2) 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 who received ganciclovir orally, in 6,9%.

Among patients who received valganciclovir up to the 100th day and 200th day of the post-transplant period, mutations in the type of substitution were more common during the period of preventive therapy than after its completion (5/12 [42%] compared with 4/58 [7%]) .

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

Preclinical safety data

The carcinogenicity of ganciclovir has been demonstrated in studies in mice. Valganciclovir, as well as 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 transformation of the drug in ganciclovir, additional studies of reproductive toxicity with valgan-cyclovir were not conducted. Both drugs include the same warning of possible reproductive toxicity (see section "Special instructions"). In animals ganciclovir violates fertility and has a teratogenic effect. Taking into account experiments on animals in which systemic effects of ganciclovir in concentrations below therapeutic have caused aspermia, it is very likely that ganciclovir and valganciclovir can inhibit spermatogenesis in humans.

Data obtained in the model using the human placenta ex vivo, show that ganciclovir penetrates the placenta, most likely through simple transfer. In the concentration range from 1 to 10 mg / ml, the drug transition through the placenta was unsaturated and was carried out by passive diffusion

Pharmacokinetics:

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

The parameters determining the exposure of ganciclovir after taking valganciclovir are bioavailability and renal function. Bioavailability of ganciclovir was similar in all patients receiving valganciclovir. Systemic exposure of ganciclovir for recipients of the heart, kidney, liver transplant was similar to that after oral administration of valganciclovir in accordance with the dosing regimen depending on the function of the kidneys.

Suction

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

Proportional dependence AUC Ganciclovir dose after taking valganciclovir in doses of 450 to 2625 mg is indicated only for the case of taking the drug after a meal. If valganciclovir taken with food at the recommended dose of 900 mg, increase as the average AUC₂₁ (by about 30%), and the average C_mOh (approximately 14%) of ganciclovir. Consequently, valganciclovir it is recommended to take during meals (see section "Method of administration and dose").

Distribution

Due to the rapid metabolism of valganciclovir in ganciclovir, the binding of valganciclovir to plasma proteins was not determined. The binding of ganciclovir to plasma proteins at drug concentrations of 0.5 to 51 μg / ml is 1-2%. The equilibrium volume of ganciclovir distribution after intravenous administration was 0.680 ± 0.16 L / kg.

Metabolism

Valganciclovir is rapidly hydrolyzed to form ganciclovir, and no other metabolites have been detected. After a single oral administration of 1000 mg radionuclide-labeled ganciclovir, the radioactivity of none of the metabolites in feces or urine did not exceed 1-2%.

Excretion

The main way of deducing valganciclovir, like ganciclovir, is glomerular filtration and active tubular secretion. The renal clearance is 81.5 ± 22% systemic clearance of ganciclovir.

Pharmacokinetics the special patient groups

Patients with renal insufficiency

Impaired renal function led to a decrease in clearance of ganciclovir formed from valganciclovir, with a corresponding increase in the half-life in the terminal phase. Therefore, patients with impaired renal function require a dose adjustment (see the "Specific dosage instructions" section of the "Administration and dose" section and the "Special instructions" section).

Patients with hepatic insufficiency

The pharmacokinetics of valganciclovir were studied in patients with a stable functioning liver transplant in an open study with a 4-component cross-over design. Absolute bioavailability of ganciclovir, formed from valganciclovir (with a single dose of 900 mg after meals), was approximately 60%, which is the same as in other groups of patients. AUC_0-₂₄ Ganciclovir was comparable to that after intravenous administration of ganciclovir in a dose of 5 mg / kg to patients who underwent liver transplantation.

Indications:

- Treatment CMV retinitis in adult patients with AIDS;

- prevention CMV infection after transplantation of solid organs in adults and children over 16 years of age at risk.

Contraindications:

- Hypersensitivity to valganciclovir, ganciclovir or any of the components of the drug. Because of the similar chemical structure of acyclovir, valaciclovir 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 25,000 cells per 1 μl or hemoglobin concentration below 80 g / l (see section "Special instructions");

- creatinine clearance less than 10 ml / min;

- children's age to 16 years (prevention of CMV infection after transplantation of solid organs 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);

- the period of breastfeeding.

Carefully:

Elderly age (efficacy and safety not established).

Pregnancy and lactation:

Additional studies of reproductive toxicity with valgancyclovir have not been carried out because of the rapid and complete conversion of valganciclovir to ganciclovir. Ganciclovir violates fertility and has a teratogenic effect in animals (see subsection "preclinical safety data" in "Pharmacological properties").

During treatment with valganciclovir, women of childbearing age should be recommended to use reliable methods of contraception, men are recommended to use barrier method of contraception during treatment and not less than 90 days after the end (see subsection "Preclinical safety data" in the section "Pharmacological properties").

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

Studies of the effects of valganciclovir and ganciclovir on peri- and postnatal development have not been carried out, and the possibility of isolating ganciclovir with breast milk and developing serious adverse reactions in the infant can not be ruled out. If it is necessary to use the drug during lactation it is necessary to stop breastfeeding.

Dosing and Administration:

To avoid overdose, it is necessary to follow the recommendations for the dosing regimen.

Standard dosing regimen

Valganciclovir should be taken orally during meals (see subsections "Absorption" and "Pharmacokinetics in special groups of patients" in the section "Pharmacological properties").

Valganciclovir is rapidly and largely metabolized with the formation of ganciclovir. Bioavailability of ganciclovir in case of valganciclovir is 10 times higher than in case of oral administration of ganciclovir (see sections "Special instructions" and "Overdose").

Therapy of CMV retinitis

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) twice daily for 21 days. Prolonged induction therapy increases the risk of myelotoxicity (see section "Special instructions").

Supportive therapy for CMV retinitis

After the 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.subsection "Induction therapy of CMV retinitis" in the section "Method of administration and dose").

Prevention of CMV infection after solid organ transplantation

Adults

Patients who underwent kidney transplantation should begin valganciclovir therapy within the first 10 days after the operation 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 underwent transplantation of other solid organs should begin valganciclovir therapy within the first 10 days after the operation 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 instructions for dosing

Patients with renal insufficiency

It is necessary to carry out a careful control of the concentration of creatinine in the blood serum or the clearance of creatinine. Dose adjustment in adult patients is carried out depending on the creatinine clearance, as shown in the table below (see subsection "Pharmacokinetics in special patient groups" in the section "Pharmacological properties" and section "Special instructions").

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

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

for women = 0.85 x indicator for men

Creatinine clearance (ml / min)	Dose for induction therapy	The dose for maintenance therapy / prevention
>60	900 mg twice a day	900 mg once a day
40-59	450 mg twice daily	450 mg once a day
25-39	450 mg once a day	450 mg every 2 days
10-24	450 mg every 2 days	450 mg twice a week
<10	Not recommended	Not recommended

Patients with hepatic insufficiency

Efficiency and safety are not established.

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

In patients who received valganciclovir (and ganciclovir), cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow suppression and aplastic anemia. Treatment should not be started if the absolute number of neutrophils is less than 500 cells per 1 μl or the platelet count is less than 25,000 cells per 1 μl, and also if hemoglobin is below 80 g / l. Patients with severe leukopenia, neutropenia, anemia, and / or thrombocytopenia are recommended to prescribe hematopoietic growth factors and / or interrupt drug intake (see p.sections "Special instructions" and "Side effect").

Elderly patients

Efficiency and safety are not established.

Patients of childhood

Therapy of CMV retinitis

Contraindicated apply valganciclovir in children under 18 years with the aim of treating CMV retinitis, since the effectiveness and safety of valganciclovir in this age group is not established.

Prevention of CMV infection after solid organ transplantation

The dosage regimen in children aged 16 to 18 years does not differ from the adult dosing regimen (see subsection "Prevention of CMV infection after solid organ transplantation" in the section "Dosing and Administration").

The use of valganciclovir is contraindicated in children and adolescents under 16 years with the goal of preventing CMV infection after solid organ transplantation, since the effectiveness and safety of valganciclovir in this age group has not been established.

Side effects:

Clinical Trials Data

Valganciclovir is a prodrug of ganciclovir, which after oral administration quickly turns into ganciclovir, therefore all known undesirable effects associated with ganciclovir are expected for valganciclovir. All adverse events reported in clinical trials were previously observed with ganciclovir.

Adults

Treatment of CMV retinitis in patients with AIDS

The safety profiles of valganciclovir and ganciclovir were similar for intravenous administration for 28 days. The most common adverse events were diarrhea, neutropenia and fever. In patients who received valganciclovir Orally, candidiasis of the oral mucosa, headache and weakness were more frequent, and intravenous therapy with ganciclovir - nausea and undesirable events at the injection site (phlebitis and thrombophlebitis) (see Table 1).

Table 1. Proportion of patients with certain adverse events occurring during the randomized phase of the study

Unwanted phenomenon	Group of patients treated with valganciclovir (N = 79)	The group of patients who received ganciclovir intravenously (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 undesirable events (regardless of their severity and association with the drug) with a incidence of> 5%, obtained in clinical studies on the use of valganciclovir in either patients with CMV retinitis, or in patients after Transplantation of solid organs.

The most frequent adverse reactions, regardless of severity, but, in the opinion of the researchers, associated with taking the drug (distant, probable or possible connection) in patients with CMV retinitis were: neutropenia, anemia, diarrhea and nausea.

Prevention CMV infection the patients after organ transplantation

Table 2 presents undesirable events (up to 28 days after completion of the study), regardless of their severity and the connection with taking the drug, with the incidence of ≥ 5%, obtained in clinical studies in patients after organ transplantation, valganciclovir or ganciclovir orally, taking medication for 10 days after transplantation and continuing to receive up to the 100th day of the post-transplant period.

The most frequent adverse reactions, regardless of severity, but, in the opinion of the researchers, associated with taking the drug (distant, probable or possible association) in patients after transplantation of solid organs treated prior to the 100th day of the posttransplant period: leukopenia, diarrhea, nausea, neutropenia; in patients who underwent kidney transplantation and received treatment before the 200th day of the posttransplant 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

Body systems / description	Patients with CMV retinitis	Patients after organ transplantation who received treatment on the 100th day of the post-transplant period
	Valganciclovir (n = 370)	Valganciclovir (n = 244)	Ganciclovir orally (n = 126)
	%	%	%
From the digestive system
Diarrhea	38	30	29
Nausea	25	23	23
Vomiting	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
Impaired liver function	3	9	1 1
From the body as a whole
Fever	26	13	14
Fatigability	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 to the 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
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
From the respiratory system
Cough	16	6	8
Dyspnea	9	11	10
Productive cough	5	2	2
Discharge from the nose	2	4	6
Pleural effusion	<1	7	8
From the sense organs
Retinal disinsertion	13	-	-
Unclear vision	6	1	4
From the side of the musculoskeletal system
Back pain	8	20	15
Arthralgia	6	7	7
Muscle cramps	2	6	11
Pain in the extremities	3	5	7
From the urinary system
Renal insufficiency	1	7	12
Dizuria	2	7	6
From the immune system
Transplant rejection reaction		24	30
From the side of metabolism
Anorexia	5	3	-
Cachexia	5	-	-
Decreased appetite	8	4	5
Dehydration	6	5	6
Weight loss	9	3	3
From the side of the cardiovascular system
Reduction of 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
Hyperglycaemia	1	6	7
Hypophosphatemia	<1	9	6
Hypocalcemia	<1	4	6
Hypercreatinemia	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
Increasing the frequency of drainage	-	5	9
Poor healing of the postoperative wound	<1	5	6

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

From the side of the blood and lymphatic system: pancytopenia, oppression of bone marrow function, aplastic anemia; potentially life-threatening hemorrhages associated with the development of thrombocytopenia.

From the genitourinary system: decrease in the clearance of creatinine.

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 (an absolute number of neutrophils 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 organ transplantation up to the 100th day after the transplantation period or in patients receiving valganciclovir (10%) to the 200th day of the post-transplant period. Patients receiving both valganciclovir, and ganciclovir orally after transplantation of solid organs before the 100th day or 200th day of the post-transplant period, compared to patients with CMV retinitis, there is a greater increase in serum creatinine concentration. Abnormal kidney function is characteristic for patients who underwent organ transplantation.

The overall safety profile of valganciclovir does not change with an increase in the period of preventive use to 200 days in patients after kidney transplantation from the risk group. In patients receiving valganciclovir up to the 200th day of the post-transplant period, compared with patients receiving valganciclovir up to the 100th day of post-transplantation period, there is a slight increase in the incidence of leukopenia. The frequency of development of neutropenia, anemia and thrombocytopenia is similar in patients receiving treatment before the 100th day and 200th day of the post-transplant period.

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

Changes in laboratory indicators	Patients with CMV retinitis	Patients after organ transplantation
	Valganciclovir (n = 370)	Valganciclovir (n = 244)	Ganciclovir orally (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	1
80 - <95	14	31	25
Thrombocytopenia (platelet count / μl)
<25000	3	0	2
25000 - <50000	5	1	3
50000 -<100000	21	18	21
Concentration of serum creatinine (mg / dL)
>2,5	2	14	21
>1,5-2,5	11	45	47

Experience with ganciclovir

Because the valganciclovir is rapidly metabolized with the formation of ganciclovir, the following are undesirable phenomena noted in the treatment of ganciclovir and not mentioned above.

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

On the part of the body as a whole: asthenia; bacterial, fungal and viral infections; malaise; 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, hypertension, decreased libido, myoclonic twitching, nervousness, drowsiness, intellectual impairment.

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

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

From the endocrine system: diabetes.

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

From the sense organs: amblyopia, blindness, ear pain, eye hemorrhage, eyeball pain, deafness, glaucoma, eating disorders, tinnitus, vision impairment, changes in the vitreous.

From the side of 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 shows the undesirable events (developed up to 28 days after the completion of the study), regardless of their severity and the connection with the drug.

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

The general safety profile of valganciclovir in children does not differ from the safety profile of the drug in adults. Some adverse events have been observed in children with a greater frequency than in adults, for example, upper respiratory tract infections, fever, abdominal pain and dysuria, which may reflect the characteristics of the child population.In the children's population there was a slight increase in the frequency of neutropenia, but this did not lead to an increase in the incidence of infections.

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

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

Body systems / description	Patients of childhood after transplantation of solid organs
	Treatment with valganciclovir before the 100th day of the post-transplant period (n = 63)	Treatment with valganciclovir before 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
Vomiting	21	13
On the part of the blood and lymphatic system
Leukopenia	2	25
Anemia	14	16
Neutropenia	13	23
From the body as a whole
Fever	24	16
Laboratory indicators
Hypercreatinemia	2	16
From the urinary system
Hematuria	6	11
Dizuria	2	18
From the nervous system
Tremor	3	18
Headache	6	21
From the side of the cardiovascular system
Increased blood pressure	22	16
pressures
From the immune system
Transplant rejection reaction	10	5

Severe neutropenia was more often observed in children who underwent kidney transplantation and received valganciclovir up to the 200th day of the post-transplant period, compared with children receiving valganciclovir up to the 100th day of post-transplantation period, and also in comparison with adults who underwent kidney transplantation and received valganciclovir up to the 100th and 200th day of the post-transplant period.

Congenital CMV infection

The limited data available indicate that the safety profile for valganciclovir or ganciclovir up to 6 months for the treatment of congenital CMV infection in infants aged 2 to 31 days does not differ from that in adults.

When ganciclovir was used, the most frequently reported neutropenia was grade 3 and 4 (38%). Only in one case, antiviral therapy was abolished because of the development of neutropenia, in other cases, neutropenia was amenable to correction without the abolition of therapy. All newborns showed an increase in the indicators that characterize growth and development (height, body weight, average head circumference).

When using valganciclovir, the most frequent adverse events were neutropenia, anemia, impaired liver function, and diarrhea (it should be noted that these undesirable events occurred in patients who did not receive the drug, and more frequently than patients who received the drug).

The only serious adverse events associated with treatment were neutropenia and anemia (also more common in patients who did not receive the drug).

There were no statistically or clinically significant differences between patients who received and did not receive valganciclovir, in terms of growth and development (height, body weight, average head circumference).

Table 5. Changes in laboratory parameters with valganciclovir in children

Changes in laboratory indicators	Patients of childhood after transplantation of solid organs
	Treatment with valganciclovir before the 100th day of the post-transplant period (n = 63)	Treatment with valganciclovir before the 200th day of the post-transplant period (n = 56)
	%	%
Neutropenia (absolute number of neutrophils / μL)
<500	5	30
500 - <750	8	7
750 - <1000	5	11
Anemia (hemoglobin g / l)
<65	0	0
65 - <80	14	5
80 - <95	38	29
Thrombocytopenia (platelet count / μl)
<25000	0	0
25000 - <50000	10	0
50000 - <100000	3	4
Concentration of serum creatinine (mg / dL)
>2,5	2	5
>1,5-2,5	11	20

Experience in postmarketing drug use

Experience with ganciclovir and valganciclovir

Because the valganciclovir rapidly and to a large extent is transformed into ganciclovir, undesirable phenomena observed with the use of ganciclovir, can develop and when treated with valganciclovir.

Adverse events described in spontaneous reports during post-marketing application of ganciclovir (orally or intravenously), not mentioned in any of the above sections, for which a causal relationship with the drug can not be excluded: anaphylaxis, decreased fertility in men.

The undesirable phenomena described in the post-marketing application of the drug are similar to those observed in the clinical studies of valganciclovir and ganciclovir.

Overdose:

In one adult patient with valganciclovir, a bone marrow depression (medullary aplasia) with a lethal outcome developed for several days at doses no less than 10-fold greater than those recommended in view of renal function impairment (decreased creatinine clearance).

It is possible that an overdose of valganciclovir may lead to an increase in nephrotoxicity (see sections "Special instructions" and "Method of administration and dose").

Reduce the concentration of valganciclovir in plasma in patients with an overdose can be by hemodialysis and hydration.

Overdose of ganciclovir with intravenous administration

Because the valganciclovir rapidly and to a large extent is transformed into ganciclovir, undesirable phenomena observed with an overdose of ganciclovir, may be expected in case of an overdose of valganciclovir. In the course of clinical trials and post-marketing use of the drug, cases of ganciclovir overdose with intravenous administration were described. Some of them were not accompanied by undesirable phenomena. Most of the patients reported one or more of the following adverse events:

- hematotoxicity: pancytopenia, oppression of bone marrow function, medullary aplasia, leukopenia, neutropenia, granulocytopenia;

- hepatotoxicity: hepatitis, a violation of liver function;

- nephrotoxicity: increased hematuria in patients with an existing impaired renal function, acute renal failure increased serum creatinine concentration;

- gastrointestinal toxicity: abdominal pain, diarrhea, vomiting;

- neurotoxicity: generalized tremor, convulsions.

Interaction:

Drug Interactions of Valganciclovir

On the model of intestinal permeability in situ in rat interactions, the ganciclovir shaft with valacyclovir, didanosine, nelfinavir, cyclosporin, omeprazole, and mycophenolate mofetil was not detected. Valganciclovir is transformed into ganciclovir, so interactions that are characteristic of ganciclovir can also occur with valganciclovir.

Drug Interactions of Ganciclovir

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

Imipenem / cilastatin: while simultaneous use of ganciclovir and imipenem / cilastatin in patients showed convulsions. Avoid simultaneous use of valganciclovir and imipenem / cilastatin in cases where the potential benefits of treatment do not exceed the potential risk (see Table 1).section "Special instructions").

Probenecid: simultaneous oral administration of probenecid resulted in a statistically significant decrease in renal clearance of ganciclovir (20%) and an increase in the duration of its action (40%). This is explained by the mechanism of interaction - competition for tubular renal excretion. Patients taking both probenecid and valganciclovir, should be under close supervision because of the possible toxic effects of ganciclovir.

Zidovudine: when applied simultaneously with oral ganciclovir, there was a small but statistically significant increase AUC zidovudine (17%); In addition, there was a statistically insignificant tendency to reduce the concentration of ganciclovir. Since both zidovudine, and ganciclovir may cause neutropenia and anemia, some patients may experience intolerance while taking valganciclovir and zidovudine in their entire doses (see section "Special instructions").

Didanosine: a persistent increase in the concentration of didanosine in plasma was observed with simultaneous use with ganciclovir (both with intravenous and oral administration). In the case of oral administration of ganciclovir in a dose of 3 and 6 g / day, there was an increase AUC didanosine by 84-124%, with intravenous administration of ganciclovir in doses of 5-10 mg / kg / day AUC didanosine increased by 38-67%. This increase can not be explained by the competitive interaction for renal tubular excretion, as the percentage excretion didanosine increased in this case. The reasons for this increase may be an increase in bioavailability or a slowing of metabolism. There was no clinically significant effect on the concentration of ganciclovir. However, given the increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be closely monitored for symptoms of toxic effects of didanosine when using valganciclovir (see section "Specific guidance").

Mycophenolate mofetil: based on the results of the single intravenous administration of the recommended dose of ganciclovir and oral administration of mycophenolate mofetil, as well as the known effect of renal dysfunction on the pharmacokinetics of mycophenolate mofetil and ganciclovir, it can be expected that 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 phenolic glucoronide of mycophenolic acid.

A significant change in the pharmacokinetics of mycophenolic acid is not it is expected, therefore, to adjust the dose mycophenolate mofetil not required. In patients with impaired renal function, which simultaneously receive mycophenolate mofetil and valganciclovir, it is necessary to follow the recommendations for correcting the dose of valganciclovir and to carry out careful monitoring.

Zalcitabine: zalcitabine increased AUC_0-8 orally Ganciclovir by 13%. Statistically significant changes in other no pharmacokinetic parameters were noted. 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: with simultaneous oral administration of ganciclovir and stavudine, there was no statistically significant pharmacokinetic interaction.

Trimethoprim: trimethoprim is statistically significant at 16.3% decreased renal clearance of ganciclovir taken orally, which was also accompanied by a statistically significant decrease in the rate of terminal elimination and a corresponding increase in the half-life of 15%. However, the clinical significance of these changes is unlikely, since AUFROM_0-₈ and C_mOh while not changing. The only statistically significant change in the pharmacokinetic parameters of trimethoprim with simultaneous administration of ganciclovir was an increase in the minimum concentration (C_min) on 12%. However, this is unlikely to be of clinical importance, therefore, valganciclovir dose adjustment is not required.

Cyclosporine: when comparing the concentrations of cyclosporine before taking the next dose of data indicating that ganciclovir changed the pharmacokinetics of cyclosporine, was not obtained. Nevertheless, after the initiation of ganciclovir, there was a slight increase in the maximum serum creatinine concentration.

Other possible drug interactions: since the main way to remove ganciclovir is glomerular filtration and active tubular secretion (see Fig.the use of valganciclovir concomitantly with antiretroviral drugs, which are also excreted via active tubular secretion (eg, nucleosome (t), by reverse transcriptase inhibitors), may affect the concentration of valganciclovir and / or co-administered drugs.

The use of ganciclovir concomitantly with other drugs that have a myelosuppressive or nephrotoxic effect (eg, dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogs, hydroxy and urea and pegylated interferons / ribavirin) can enhance their toxic effects. Therefore, these drugs can be used concomitantly with valganciclovir only if the expected benefit of the treatment exceeds the possible risk (see section "Special instructions").

Special instructions:

In animal experiments, mutagenic, teratogenic, aspermatogenic and carcinogenic effects of ganciclovir have been identified. Valganciclovir should be considered a potential teratogen and a carcinogen for a person whose use can cause congenital malformations and cancer (see the section on "Handling the drug" in the "Special instructions" section). In addition, it is likely that valganciclovir can temporarily or irreversibly suppress spermatogenesis (see the sections "Side effect", "Application during pregnancy and during breastfeeding", subsection "Preclinical safety data" of the section "Pharmacological properties").

In patients receiving valganciclovir (and ganciclovir), cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, suppression of bone marrow function and aplastic anemia were noted. Treatment should not be started if the absolute number of neutrophils is less than 500 cells per 1 μl, or the platelet count is less than 25,000 cells per 1 μl, and also if hemoglobin is below 80 g / l (see the "Specific dosage instructions" section of Method application and dose "and" Side effect "section).

During the treatment it is recommended to regularly monitor the developed formula of blood and platelets.Patients with severe leukopenia, neutropenia, anemia and / or thrombocytopenia are recommended to prescribe hematopoietic growth factors and / or interrupt drug intake (see section "Specific dosage instructions" in the "Application and dose" section and "Side effect" section).

Patients with renal insufficiency may require increased control of the developed blood formula, at least every time they visit a transplant clinic. Patients with renal insufficiency require a dose adjustment taking into account the clearance of creatinine (see the sections "Dosing and Administration" and "Pharmacological properties"). Patients with creatinine clearance less than 10 ml / min are not allowed to use valganciclovir.

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

With simultaneous use of ganciclovir and imipenem / cilastatin, patients had convulsions. The simultaneous use of ganciclovir and imipenem / cilastatin should be avoided in cases where the potential benefits of treatment do not exceed the potential risk (see "Interactions with Other Drugs" section). Since both zidovudine, and ganciclovir may cause neutropenia and anemia, some patients may be intolerant while taking valganciclovir and zidovudine in full doses (see "Interactions with Other Drugs").

In connection with 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 drugs"). The use of valganciclovir concomitantly with other drugs that have a myelosuppressive or nephrotoxic effect (see section "Interaction with other drugs") can enhance their toxic effects.

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

Bioavailability of ganciclovir from valganciclovir tablets is 10 times higher than that of ganciclovir capsules. Ganciclovir can not be replaced by valganciclovir in the ratio 1: 1.Patients who are transferred from ganciclovir capsules should be informed of the risk of overdose if they take more valganciclovir tablets than recommended (see "Dosage and Administration" and "Overdose" sections).

Rules for handling the drug

Tablets can not be broken or crushed. Because the valganciclovir potentially teratogenic and carcinogenic to humans, care must be taken if the tablet breaks down. Do not directly contact broken or crushed tablets with skin and mucous membranes. In cases of such contact, it is necessary to thoroughly wash this area with soap and water, if it gets into the eyes - they are thoroughly washed with sterile water, and in its absence - with plain water. The presence of drugs in the environment should be minimized. Do not dispose of the product with sewage or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

Effect on the ability to drive transp. cf. and fur:

When treated with valganciclovir and / or ganciclovir, there may be seizures, sedation, dizziness,ataxia and / or confusion, which can adversely affect activities requiring increased concentration of attention, including vehicle management and work with machines and mechanisms. Therefore, during treatment with valganciclovir, caution should be exercised when operating the vehicle and working with machines and mechanisms. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:Tablets, film-coated, 450 mg.

Packaging:

10 tablets are placed in a contour mesh box made of a polyvinylchloride film and aluminum foil printed lacquered.

For 60 tablets are placed in a bottle or jar of high-pressure polyethylene with a screw cap. Free space in the bottle and or a can is filled with cotton, the neck of the bottle is sealed with aluminum foil with a polymer coating.

By 1, 2, 3, 6, 9 or 12 contour mesh packages or 1 bottle or jar, together with the instruction for use, is placed in a pack of cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003056

Date of registration:24.06.2015

Expiration Date:24.06.2020

The owner of the registration certificate:IZVARINO PHARMA, LLC IZVARINO PHARMA, LLC Russia

Manufacturer: & nbsp

IZVARINO PHARMA, LLC Russia

Representation: & nbspIZVARIN PHARMA LLC IZVARIN PHARMA LLC Russia

Information update date: & nbsp29.06.2016

Illustrated instructions

Instructions

Tsivilgan (CIVALGAN)