Valcit - instructions for use, dose, side effects, contraindications

shell:18.00 mg (hypromellose 2910-3 cP, hypromellose 2910-6 cP, titanium dioxide (E171), macrogol 400, iron dye red oxide (E172), polysorbate 80); it is allowed to use the finished mixture Opadry Pink 15B24005.

Description:

Two-convex, oval-shaped tablets covered with a pink film shell, engraved with "VGC"on one side of the pill and" 450 "on the other side.

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 - a synthetic analogue of 2-deoxyguanosine, which suppresses the replication of herpes-group viruses in vitro and in vivo. Human cytomegalovirus-sensitive viruses include cytomegalovirus (CMV), herpes simplex viruses 1 and 2, human herpesvirus types 6, 7 and 8, the Epstein-Barr virus, the varicella-zoster virus and the hepatitis B virus.

In CMV-infected cells, under the action of viral protein kinase UL97 ganciclovir is first phosphorylated to form ganciclovir monophosphate. Further phosphorylation occurs under the action of cellular kinases with the formation of gancyclobutriphosphate, 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, a typical inhibitory concentration that inhibits replication of CMV by 50% (IC50), is in the range from 0.08 μmol / l (0.02 μg / ml) to 14 μmol / l (3.5 μg / ml).

The clinical antiviral effect of Valcit® was demonstrated by a decrease in the isolation of CMV from the body of patients with acquired immunodeficiency syndrome (AIDS) and newly diagnosed CMV retinitis from baseline of 46% to 7% after 4 weeks of treatment with Valcit®.

Efficiency

Adults

Treatment of CMV retinitis

Clinical studies have been conducted in patients with AIDS and CMV retinitis. Valcit® showed similar clinical efficacy in induction therapy for CMV retinitis compared to intravenous ganciclovir.The use of the preparation Valtsit® allows obtaining 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 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 at high risk of CMV infection (CMV positive donor (B +) / CMV negative recipientR-) (D+/R-)) was 12.1% in the group of patients who received the preparation of Valcit® (900 mg per day), and 15.2% in the group of patients receiving ganciclovir inside (1000 mg 3 times a day) from 10 to 100 days after transplantation. Most of the cases occurred during the period after the abolition of preventive therapy (after the 100th day of post-transplantation 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 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.

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

The transplant survival rate in 12 months was 98.2% in the group of patients treated with Valtit® up to the 100th day, and 98.1% in the group of patients treated with Valcit® 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 up to the 100th day, and 11.0% in the group of patients who received valgancyclovir before the 200th day.

Viral Resistance

With prolonged use of valganciclovir, viruses resistant to ganciclovir may appear. This may be due either to the selection of mutations in the viral kinase gene (UL97), which is responsible for the monophosphorylation of ganciclovir, or the gene of the viral DNA polymerase (UL54). Mutations of the gene UL97 occur at earlier times and are more common than a gene mutation UL54. A virus that only has a gene mutation UL97, resistant only to ganciclovir; In this case, the most common mutations of the type of substitution associated with the emergence of resistance are M460V/I, H520Q, C592G, A594V, L595S, C603W. Virus with gene mutations UL54 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 in 2.2%, 6.5%, 12.8% and 15.3% of leukocytes, mutations UL97.

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

1) absence of mutations causing resistance to ganciclovir, in samples,received on the 100th day (end of prophylactic administration of valganciclovir) in patients from the group of valganciclovir, 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, at 6.9%.

Among patients who received valganciclovir up to the 100th day and up to the 200th day of post-transplantation period, in general mutations by type of substitution were more frequent in the period 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 valganciclovir 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 organ transplantation.

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 in the liver is rapidly metabolized with the formation of ganciclovir. The absolute bioavailability of ganciclovir after taking valgancyclovir is about 60%. Systemic exposure of valganciclovir is low and has a short-term character. Area under the curve "concentration-time" (AUC24) and the maximum concentration in the blood plasma (C_max) 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 the valganciclovir taken with food at the recommended dose of 900 mg, increase as the average AUC24 (by about 30%), and the average C_max (approximately 14%) of ganciclovir. Therefore, the preparation Valtsit® is recommended to be taken with meals (see section "Dosage and Administration").

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 from 0.5 to 51 μg / ml is 1-2%. The equilibrium volume of ganciclovir distribution after intravenous administration was 0.680 ± 0.161 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 accounts for 81.5 ± 22% of the systemic clearance of ganciclovir.

Pharmacokinetics in specific 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. Consequently, patients with impaired renal function require a dose adjustment (see subsection "Special instructions for dosing" in the "Application and dose" section and section "Special instructions").

Patients with hepatic insufficiency

The pharmacokinetics of ganciclovir derived from valganciclovir was 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. AUC₀_-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 of CMV retinitis in adults with AIDS.
Prevention of 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 component 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 under 16 years of age (prevention of CMV infection after transplantation of solid organs in adults and children over 16 years of age at risk).
Children under 18 years (treatment of CMV retinitis in adults with AIDS).

Carefully:

Elderly age (safety and efficacy of the drug are not established).

Pregnancy and lactation:

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

During treatment with Valcit®, 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 it end (see subsection "Preclinical safety data" in the section "Pharmacological properties" and section "Special instructions").

The safety of the use of the drug Valcit® in pregnancy in humans is not established. When pregnancy is prescribed, the drug Valcit® 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. Thus, the decision to discontinue the drug or stop breastfeeding should be taken based on an assessment of the potential positive effect of treatment for the nursing mother and the risk to the infant.

Dosing and Administration:

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

Standard dosing regimen

The preparation Valtsit® 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 taking Valtsit® tablets is 10 times higher than in case of oral 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 Valcit is 900 mg (2 tablets of 450 mg) 2 times a day 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 transplantation kidneys, it is necessary to begin therapy with Valcit® for 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 other solid bodies, it is necessary to start therapy with Valcit® for 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 for men

Creatinine clearance (ml / min)	Dose for induction therapy	Dose for maintenance therapy / prophylaxis
≥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, thobebocytopenia or pancytopenia

In patients who received the preparation Valtsit® (and ganciclovir), cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow suppression 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. Patients with severe leukopenia, neutropenia, anemia, and / or thrombocytopenia are recommended to prescribe hematopoietic growth factors and / or discontinue the drug (see p.sections "Special instructions" and "Side effect").

Elderly patients

Efficiency and safety are not established.

Patients of childhood

Therapy of CMV retinitis

It is not recommended to use tablets of the preparation Valtsit ® in children under 18 years with the aim of therapy of CMV retinitis, since the effectiveness and safety of the Valcit ® preparation 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 "Method of administration and dose"). Tablets of the preparation Valtsit ® are not recommended for use in children and adolescents under 16 years with the goal of preventing CMV infection after solid organ transplantation, as the efficacy and safety of Valcit ® in this age group is not established.

Side effects:

Clinical Trials Data

Experience with Valcitol®

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 the Valcit® preparation. All the adverse events reported in the clinical trials of the drug Valcit ®, were previously observed in the treatment of 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 the preparation Valtsit® orally, candidiasis of the oral mucosa, headache and weakness were more frequent, and with intravenous 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	The group of patients who received valganciclovir N=79	A group of patients who received ganciclovir intravenously N = 79
Diarrhea	16%	10%
Candidiasis of mucous membranes	11%	6%
lobules of the oral cavity
Headache	9%	5%
Weakness	8%	4%
Nausea	8%	14%
Phlebitis and thrombophlebitis	-	6%

The following table (see. Table 2) presents the undesirable phenomena (regardless of the severity and connection with the reception of the preparation) with a frequency of occurrence of ≥5%, obtained in the clinical studies on the use of valganciclovir or in patients with CMV retinitis, or in patients after Transplantation of solid organs. The most common adverse reactions irrespective of seriousness, but, according to the researchers, drug-related (remote, probable or possible link) in patients with CMV retinitis were: neutropenia, anemia, diarrhea and nausea.

Prevention of CMV infection in patients after organ transplantation

Table 2 shows the adverse events (up to 28 days after the completion of the study), regardless of their severity and the connection with taking the drug, with a 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) occurring in> 5% of patients with CMV retinitis or after organ transplantation in clinical trials with valganciclovir or ganciclovir.

Body systems / description	Patients with CMV- retinitis				Patients after organ transplantation who received treatment before 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	11
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
On the part of 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 infection		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
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		33		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		22		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 the company believes are associated with taking Valcit®, occurring at a frequency of less than 5% in three clinical trials and not listed above.

On the part of the blood and lymphatic system: pancytopenia, oppression of bone marrow function, aplastic anemia, febrile neutropenia; 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 before the 100th day of post-transplantation period or in patients receiving valganciclovir (10%) to the 200th day of the post-transplant period. In patients receiving both valganciclovir and ganciclovir orally after organ transplantation to the 100th day or 200th day of the post-transplant period, compared with patients with CMV retinitis, there is a greater increase in creatinine concentration in thethe collar blood. Abnormal kidney function is characteristic for patients who underwent organ transplantation.

The overall profile of the safety of the Valcit® preparation does not change with an increase in the period of preventive use up 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 Valcit® in adults.

Changes in the laboratory	Patients with CMV-	Patients after transplantation of solid
indicators	retinitis	bodies receiving treatment up to the 100th day
		post-transplant period
	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	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
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.

From the body as a whole: asthenia, bacterial, fungal and viral infections, malaise, mucositis, photosensitivity reaction, tremors, 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 side of 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.

On the part of the blood and lymphatic system: eosinophilia, leukocytosis, lymphadenopathy, splenomegaly, bleeding.

From the side of 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 overall safety profile of the Valcit® preparation 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 incidence of adverse events.

Table 4. Adverse events that occur with a frequency> 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 post-transplantation period (n = 56)
	%	%
Infectious complications
Urinary tract infection	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 pressurethe	22	16
From the immune system
Trance rejection transplantation	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 for up to 6 months for the therapy of congenital

CMV infection in newborns 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 performance when applied Valcit® 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 100th 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 (number of platelets / 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 converted to gancyclovir, undesirable phenomena observed with the use of ganciclovir, can develop and when treated with the drug Valtsit®.

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 the preparation Valcit® 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 effects observed with an overdose of ganciclovir, may be expected in case of an overdose of the preparation Valcit®.

During clinical trials and post-marketing use of the drug, cases of overdoseGanciclovir with intravenous administration. 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 renal dysfunction, acute renal failure, increased serum creatinine concentration; gastrointestinal toxicity: abdominal pain, diarrhea, vomiting; neurotoxicity: generalized tremor, convulsions.

Interaction:

Drug Interactions of Valcit®

On the model of intestinal permeability in situ in rats, the interactions of valganciclovir with valacyclovir, didanosine, nelfinavir, cyclosporine, omeprazole, and mycophenolate mofetil were not detected.

Valganciclovir is converted into ganciclovir, so interactions that are characteristic of ganciclovir can be expected even with the use of the drug Valcit®.

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 possible risk (see 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 Valcit® should be closely monitored for 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").

Didaiosin: 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 the Valcit preparation (see section "Special instructions"),

Mycophenolate mofetil: based on the results of a 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 the simultaneous use of valganciclovir and mycophenolate mofetil having a competitive interaction in tubular secretion, will lead to an increase in the concentration of ganciclovir and phenolic glucuronide of mycophenolic acid. A significant change in the pharmacokinetics of mycophenolic acid is not expected, so adjust the dose of mycophenolate mofetil is 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 AUC₀_-₈orally taken ganciclovir by 13%. No statistically significant changes in other 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 statistically significantly decreased by 16.3% the 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%. Nevertheless, the clinical significance of these changes is unlikely, since AUC₀_-₈ and C_max 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) by 12%. However, this is unlikely to be of clinical importance, therefore, valganciclovir dose adjustment is not required.

Cyclosporin: 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 excrete ganciclovir is glomerular filtration and active tubular secretion (see the section "Derivation" of the section "Pharmacological properties"), the use of valganciclovir concomitantly with antiretroviral drugs that are also excreted via active tubular secretion (eg, nucleosome (t) transcriptase), 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 (for example, dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogs, hydroxycarbamide and pegylated interferons / ribavirin) may 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. The drug Valtsit® 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 section "Special instructions"). In addition, it is likely that the preparation Valtit® can temporarily or irreversibly suppress spermatogenesis (see the sections "Side effect", "Application in pregnancy and during breastfeeding", subsection "Preclinical safety data" in the "Pharmacological properties" section)

In patients receiving the preparation of Valcit® (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 number of platelets is less than 25,000 cells per 1 μl, and also if hemoglobin is below 80 g / l (see Fig.subsection "Special instructions for dosing" in the "Method of administration and dose" section 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 encouraged to prescribe hematopoietic growth factors and / or interrupt drug intake (see the "Specific dosage instructions" section of the "Dosage and Administration" section and the "Side effect" section).

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

With simultaneous use of ganciclovir and imipenem / cilastatin, patients had convulsions. Avoid simultaneous use of valganciclovir and imipenem / cilastatin in cases where the potential benefits of treatment do not exceed the possible risk (see "Interactions with Other Drugs").

Since both zidovudine, and ganciclovir may cause neutropenia and anemia, some patients may experience intolerance while taking valganciclovir and zidovudine in full doses (see Table 1).section "Interaction with other drugs"),

In connection with the possible increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be carefully observed for symptoms of toxic effects of didanosine (see section "Interaction with other drugs").

The use of Valcit ® simultaneously with other drugs that have a myelosuppressive or nephrotoxic effect (see the section "Interaction with other drugs") can increase their toxic effect. 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 tablets of the preparation Valtsit® is 10 times higher than that of capsules of ganciclovir. Ganciclovir It should not be replaced with Valtit® in a ratio of 1: 1. Patients who are transferred from ganciclovir capsules should be informed of the risk of overdose if they take a larger number of Valcyte tablets than recommended (see.sections "Dosage and Administration" and "Overdose"),

Rules for handling the drug

Tablets can not be broken or crushed. Because Valcit ® is potentially teratogenic and carcinogenic to humans, care should 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 treating drug Valtsit® and / or ganciclovir may cause seizures, sedation, dizziness, ataxia and / or confusion that could adversely affect the activities that require high concentration of attention, including the management of vehicles and working with machinery.Therefore, during the treatment with Valcit®, caution should be exercised when driving vehicles 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:For 60 tablets in a bottle of high-pressure polyethylene with a screw cap made of polypropylene, which opens when pressed. The method of opening the vial is shown on the lid in the form of a diagram with explanatory inscriptions. Free space in the vial is filled with cotton or other sealing material; The neck of the bottle to ensure the control of the opening is hermetically sealed with aluminum foil with PVC coating. Each vial with the instruction for use is placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015446 / 01

Date of registration:18.11.2009 / 19.11.2013

Expiration Date:Unlimited

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

PATHEON, Inc. Canada

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp20.01.2017

Illustrated instructions

Instructions

Valcit® (Valcyte®)