Valganciclovir-Teva - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline 70.00 mg; mannitol 86.23 mg; silicon dioxide colloid 3.40 mg; crospovidone (type A) 10.05 mg; magnesium stearate 4.02 mg;

shell: Opadry II 32K54870 pink: hypromellose-15sR / HPMC2910 (E464) 10.720 mg; lactose monohydrate 6,700 mg; titanium dioxide (E171) 6.218 mg; triacetin (E1518) 2.948 mg; ferric iron oxide red (E172) 0.214 mg.

Description:

Oval tablets covered with a pink film shell, with a facet and engraved "93" on one side and "5465" on the other.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.B.14 Valganciclovir

J.05.A.B Nucleosides and nucleotides

Pharmacodynamics:

Mechanism of action

Antiviral drug. Valganciclovir represents 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 multiplication of herpes-group viruses in vitro and in vivo. To human viruses sensitive to ganciclovir, include cytomegalovirus (CMV), Herpes simplex type 1 and 2, human herpesvirus types 6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus, virus Varicella zoster 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 ganciclovertriphosphate. which is then subjected to a slow intracellular metabolism. It was shown that this metabolism occurs in cells infected with CMV and Herpes simplex, after the disappearance of ganciclovir from the extracellular fluid, the intracellular half-life of the drug is 18 hours and 6-24 hours, respectively. Since ganciclovir phosphorylation is highly dependent on the action of the viral kinase, it occurs predominantly in infected cells.

The virostatic activity of ganciclovir is due to the suppression of the synthesis of viral deoxyribonucleic acid (DNA) by:

1) competitive inhibition of the incorporation of deoxyguanosine triphosphate into DNA under the action of viral DNA polymerase;

2) including ganciclovir triphosphate in viral DNA, leading to an end to elongation or a very limited lengthening of the viral DNA. A typical inhibitory concentration that suppresses replication of CMV by 50% (IC₅₀), certain in vitro, is in the range of 0.08 μmol / L (0.02 μg / ml) to 0.14 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 with 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. The use of valganciclovir in induction therapy in patients with CMV retinitis has the same clinical efficacy compared with intravenous (iv) administration of the recommended 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 duration of the time to progression of CMV retinitis.

Prevention of CMV infection. Frequency of CMV disease (CMV syndrome + invasive tissue infection) during the first 6 months after transplantation of the heart, liver, kidneys in patients with high risk of infection with CMV (CMV-positive donor (D+) / CMV-negative recipient (R-) (D+/R-)) was 12.1% in patients who received valganciclovir in a dose of 900 mg / day and 15.2% - in patients taking orally ganciclovir in a dose of 1 g 3 times a day from the 10th to the 100th day 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 of valganciclovir appeared later than in the treatment group of ganciclovir. The incidence of acute rejection in the first 6 months was 29.7% in patients treated with valganczlovir and 36% in patients who received ganciclovir. Frequency graft survival at 12 months 98.2% in patients treated valgantsklovir to 100-th day, and 98.1% in patients treated valgantsklovir to 200-th day.The incidence of acute rejection of a biopsy-proven transplant in the first 12 months was 17.2% in patients treated with valganczlovir before the 100th day, and 11% in patients treated with valganczlovir before the 200th day.

Viral resistance. With prolonged use of valganciclovir, a virus resistant to ganciclovir may appear, which may be due to the selection of mutations either in the gene of the viral kinase (UL97), responsible for the monophosphorylation of ganciclovir, or in the gene of the viral DNA polymerase (UL54). A virus that only has a gene mutation UL97, is resistant only to ganciclovir, while the virus with mutations of the gene UL54 may have cross-resistance to other antiviral drugs with a similar mechanism of action, and vice versa.

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 the samples obtained on the 100th day (end of prophylactic administration of valganciclovir) in patients,host valganciclovir, and the presence of mutations in samples obtained from patients taking ganciclovir inside.

2) absence of mutations causing resistance in samples obtained from patients taking valganciclovir, with suspected CMV infection 6 months after transplantation, and the presence of mutations in patients taking ganciclovir inside.

Preclinical safety data.

Valganciclovir and ganciclovir had a mutagenic effect in mouse lymphoma cells and a clastogenic effect in mammalian cells. These results are consistent with the positive results of a study of the carcinogenicity of ganciclovir in mice. As well as ganciclovir, valganciclovir is a potential carcinogen. Studies of reproductive toxicity with valganciclovir have not been repeated because of rapid and complete conversion of the drug into ganciclovir. Both drugs have the same warning of possible reproductive toxicity. In animals ganciclovir violates fertility and has a teratogenic effect. Taking into account experiments on animals,in whom systemic exposure to ganciclovir in concentrations below the therapeutic levels caused aspermia, it is very likely that ganciclovir and valganciclovir can inhibit spermatogenesis in humans. Data obtained on a model using the human placenta ex vivo, show that ganciclovir passes through the placental barrier, most likely by 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, as well as after transplantation of solid organs.

Bioavailability and renal function cause exposure of ganciclovir after taking valganciclovir. 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 ingestion of valganciclovir in accordance with the dosing regimen depending on the function of the kidneys.

Suction. Valganciclovir is a prodrug of ganciclovir. well absorbed from the gastrointestinal tract, in the wall of the intestine and liver rapidly turning into a ganciclovir. Absolute bioavailability of ganciclovir after taking valganciclovir is about 60%. The systemic exposure of valganciclovir is low and short-term. AUC24 and the maximum concentration in the blood plasma (C_mOh) are approximately 1% and 3% of those of ganciclovir, respectively. Proportional dependence AUC ganciclovir dose after valganciclovir in doses ranging from 450 to 2625 mg is shown only for the case of valganciclovir postprandial. If valganciclovir used during meals at the recommended dose of 900 mg. increases as the average AUC24 (by about 30%). and the average C_max (approximately 14%) of ganciclovir. Consequently, valganciclovir it is recommended to eat while eating.

Distribution. Due to the rapid metabolism of valganciclovir in ganciclovir. the binding of valganciclovir to proteins was not determined. Binding of ganciclovir to plasma proteins at concentrations of 0.5 to 51 ug / ml of 1-2%.The equilibrium volume of ganciclovir distribution after IV injection was 0.680 ± 0.161 l / kg.

Metabolism. Valganciclovir rapidly hydrolyzed to form ganciclovir; no other metabolites were found. After a single oral administration of 1000 mg radiolabeled ganciclovir, the radioactivity of none of the metabolites in feces or urine was no more than 1-2%.

Excretion. The main way of deducing valganciclovir. as well as ganciclovir. is glomerular filtration and active tubular secretion. The renal clearance accounts for 81.5 ± 22% of the systemic clearance of ganciclovir.

Pharmacokinetics in special clinical cases

Patients with renal insufficiency

Impairment of kidney function led to a decrease in clearance of ganciclovir. formed from valganciclovir, with a corresponding increase T_1/2in the terminal phase. Therefore, patients with impaired renal function require dose adjustment.

Patients with hepatic insufficiency

The pharmacokinetics of valganciclovir were studied in patients with a stable liver transplant. Absolute bioavailability of ganciclovir.formed with valganciclovir (with a single oral intake of 900 mg after meals) was approximately 60%, which is the same as in other patients. AUC_0-24Ganciclovir 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 AIDS patients;

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

Contraindications:

Hypersensitivity to valganciclovir, ganciclovir or other components of the drug. Because of the similar chemical structure of acyclovir, valaciclovir and valganciclovir, cross-sensitivity reactions are possible;

The absolute number of neutrophils (ACH) is less than 500 / μL; the number of platelets is less than 25,000 / μL; the concentration of hemoglobin is less than 80 g / l;

CK 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 of age (treatment of CMV retinitis in adults with AIDS).

Carefully:

Older patients (safety and efficacy not established).

Pregnancy and lactation:

Studies of reproductive toxicity with valganciclovir have not been repeated because of rapid and complete conversion of valganciclovir into ganciclovir. Ganciclovir violates fertility and has a teratogenic effect in animals.

During treatment with valganciclovir-Teva, women of reproductive age should be encouraged to use effective methods of contraception. Men are recommended to use the barrier method of contraception during treatment with Valganciclovir-Teva and not less than 90 days after the end.

The safety of valganciclovir during pregnancy in humans is not established. In pregnancy, Valganciclovir-Teva should be avoided, unless the expected benefit to the mother exceeds the possible risk to the fetus.

Peri-and postnatal development with valganciclovir and ganciclovir has not been studied, but it can not be ruled out that ganciclovir can be excreted in breast milk and serious side effects may develop in the infant. Thus, the decision to revoke Valganciclovir-Teva or to stop breastfeeding should be taken based on an assessment of the potentialthe effect of treatment for a nursing mother and the risk for an infant.

Dosing and Administration:

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

Standard dosing regimen

The drug Valganciclovir-Teva should be taken orally during meals. The drug Valganciclovir-Teva is rapidly and largely metabolized in ganciclovir. Bioavailability of ganciclovir with the drug Valganciclovir-Teva is 10 times higher than in the case of oral ganciclovir. therefore it is necessary to adhere strictly to the dosing regimen of Valganciclovir-Teva described below.

Therapy of CMV retinitis

Adults

Induction therapy of CMV retinitis

In patients with active CMV retinitis, the recommended dose of Valganciclovir-Teva is 900 mg (2 tablets of 450 mg) 2 times a day for 21 days. Long-term induction therapy increases the risk of myelotoxicity.

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.

Prevention of CMV infection after solid organ transplantation

Adults

Patients who underwent renal transplantation receive therapy within the first 10 days after the operation at a dose of 900 mg (2 tablets of 450 mg) once a day. Continue therapy for the 200th day of the post-transplant period.

Patients who underwent transplantation of other solid organs receive therapy within the first 10 days after the operation at a dose of 900 mg (2 tablets of 450 mg) once a day. Continue therapy for the 100th day of the post-transplant period.

Special instructions for dosing

Have patients with renal insufficiency it is necessary to carefully monitor the concentration of creatinine in serum or CC. Correction of the dose is carried out depending on the QC, as shown in the table below.

KK is calculated depending on the concentration of creatinine in the serum according to the following formula:

for men = (140 - age) x body weight (kg) / 72 x (0.011 x creatinine concentration in blood serum (μmol / l);

for women = 0.85 x figure for men.

CK (ml / min)	Dose for induction therapy	Dose for maintenance therapy
Not less than 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

Patients on hemodialysis (CC less than 10 ml / min) it is not recommended to apply valganciclovir.

In patients with severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, suppression of bone marrow function, aplastic anemia treatment is not should be started if the ACN is less than 500 / μL or the platelet count is less than 25,000 / μl, and if the hemoglobin concentration is below 80 g / l.

Patients with severe leukopenia, neutropenia, anemia and / or thrombocytopenia are recommended to prescribe hematopoietic growth factors and / or interrupt the use of the drug.

In elderly patients Care should be taken since efficiency and safety are not established.

Childhood

Therapy of CMV retinitis

It is not recommended to use valganciclovir-Teva tablets in children under 18 years of age with the aim of treating CMV retinitis, since the efficacy and safety of Valganciclovir-Teva is not established in this age group.

Prevention of CMV infection after solid organ transplantation

Dosage regimen in children aged 16 to 18 years does not differ from the dosing regimen in adults. Tablets of the drug Valganciclovir-Teva 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 Valganciclovir-Teva is not established in this age group.

Side effects:

Valganciclovir is a prodrug of ganciclovir. Valganciclovir after oral administration quickly turns into ganciclovir, therefore, all known adverse events (AEs) recorded with ganciclovir are expected when using valganciclovir.

When treating CMV retinitis in patients with AIDS

The safety profiles of valganciclovir and ganciclovir were the same for intravenous administration for 28 days. The most frequent AEs were diarrhea, neutropenia and fever. In patients receiving valganciclovir Inside, more often, candidiasis of the oral mucosa. headache and weakness, with ganciclovir IV, patients were more likely to experience nausea and AE at the site of administration (phlebitis and thrombophlebitis).table number 1).

Table №1. Percentage of patients (%) with individual AEs in the treatment of CMV retinitis

Unwanted phenomenon	Treatment with valganciclovir inside (N = 79)	Treatment with ganciclovir I / O (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%

Table 2 shows the most frequent AEs (regardless of their severity and connection with taking valganciclovir) with a frequency of at least 5%, obtained with valganciclovir or in patients with CMV retinitis. or in patients after organ transplantation.

Neutropenia (21%), diarrhea (14%), nausea (9%), anemia (14%), neuromuscular complications (14%), neuromuscular complications were the most frequent AEs regardless of severity, but related to valganciclovir (remote, probable or possible) ).

In the prevention of CMV retinitis the 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 number 2. Proportion of patients (%) with AEs that occurred in at least 5% of patients with CMV retinitis or after organ transplantation with valganciclovir and ganciclovir

Unwanted phenomenon	Proportion of patients (%) with CMV retinitis	Percentage of patients (%) after transplantation of solid organs treated on the 100th day of the post-transplant period
Unwanted phenomenon	Valganciclovir (N = 370)	Valganciclovir (N = 244)	Ganciclovir (for oral administration) (N=126)
From the digestive system
Diarrhea	38	30	29
Nausea	25	23	23
Vomiting	20	16	14
Abdominal pain	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 Infections	5	11	9
From the nervous system
Headache	18	22	27
Insomnia	14	20	16
Peripheral Neuropathy	7	1	1
Paresthesia	6	5	5
Tremor	2	28	25
Dizziness (except vertigo)	9	10	6
Depression	9	7	6
From the skin and subcutaneous tissues
Dermatitis	18	4	5
Night sweats	7	3	4
Itching	6	7	4
Acne	Less than 1	4	6
Rash	9	Less than 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	Less than 1	7	8
From the sense organs
Retinal disinsertion	13	-	-
Unclear vision	6	1	4
From the side of the musculoskeletal system
Backache	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
Decreased blood pressure	1	3	8
Increased blood pressure	3	18	15
Laboratory indicators
Hyperkalemia	Less than 1	14	14
Hypokalemia	2	8	8
Hypomagnesemia	Less than 1	8	8
Hyperglycaemia	1	6	7
Hypophosphatemia	Less than 1	9	6
Hypocalcemia	Less than 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 wound healing	Less than 1	5	6

The following are serious adverse events associated with taking valganciclovir, occurring with a frequency of less than 5%, not mentioned above.

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

From the urinary system: decrease in QC.

From the nervous system: convulsions, psychotic abnormalities, hallucinations, confusion, agitation.

Other: 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.

Patients receiving both valganciclovir, and ganciclovir orally after organ transplantation to 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 for 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 number 3. Laboratory parameters when using valganciclovir

Laboratory indicators	Proportion of patients (%) with CMV retinitis	Percentage of patients (%) after transplantation of solid organs treated on the 100th day of the post-transplant period
Laboratory indicators	Valganciclovir (N = 370)	Valganciclovir (N = 244)	Ganciclovir (for oral administration) (N=126)
Neutropenia (ACHN (cells / μl))
Less than 500	16	5	3
500 - less than 750	17	3	2
750 - less than 1000	17	5	2
Anemia (hemoglobin (g / l))
Less than 65	7	1	2
65 - less than 80	10	5	7
80 - less than 95	14	31	25
Thrombocytopenia (number of platelets (cells / μl))
Less than 25,000	3	0	2
25000 - less than 50000	5	1	3
50000 - less than 100000	21	18	21
Concentration of serum creatinine (mg / dL)
More than 2.5	2	14	21
More than 1,5-2,5	11	45	47

Experience with ganciclovir

Because the valganciclovir quickly turns into a ganciclovir, below are the AEs described in the treatment with ganciclovir and not mentioned above.

From the digestive system: dryness of the oral mucosa, cholangitis, dysphagia, belching, 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, tremors, sepsis.

From the skin and subcutaneous tissues: alopecia, photosensitivity reactions, dry skin, sweating, urticaria.

From the nervous system: sleep disturbance, amnesia, anxiety, ataxia, coma, emotional disorders, hyperkinesis, hypertonia, decreased libido, myoclonic twitching, nervousness, drowsiness, intellectual impairment.

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

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

Laboratory indicators: increased activity of alkaline phosphatase, creatinine phosphokinase, lactate dehydrogenase in blood plasma, a decrease in the concentration of glucose in the blood, hypoproteinemia.

From the sense organs: amblyopia, blindness, ear pain, eye hemorrhages, eyeball pain, deafness, glaucoma, eating disorders, tinnitus, visual impairment, nonsystemic dizziness, changes in the vitreous.

On the part of the hematopoiesis system: eosinophilia, leukocytosis, lymphadenopathy, splenomegaly, bleeding.

From the cardiovascular system: arrhythmias (including ventricular), thrombophlebitis of deep veins, migraine, phlebitis, tachycardia, vasodilation.

From the respiratory system: congestion in the paranasal sinuses.

From the endocrine system: diabetes.

Children

Prevention of CMV infection in patients after organ transplantation

Table 4 shows the undesirable effects (developed up to 28 days after the completion of the study), regardless of their severity and in connection with taking the drug.

The table includes undesirable events with a incidence of ≥10% reported in clinical studies in children aged 3 weeks to 16 years after transplantation of solid organs who started valganciclovir for 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 incidence of adverse events.

Table 4. Unwanted phenomena that occur with frequency ≥ 10% in children after organ transplantation.

Body systems / description	Patients (%) of childhood after organ transplantation
Body systems / description	Treatment Valganciclovir up to the 100th day of the post-transplant period (N=63)	Treatment valganciclovir up to the 200th day 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
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%). In only one case, antiviral therapy was abolished because of the development of neutropenia. in other cases, neutropenia was amenable to correction without canceling 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, liver dysfunction and diarrhea (it should be noted that these undesirable effects were observed 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 organ transplantation
Changes in laboratory indicators	Treatment valganciclovir 100 days post-transplant period (N=63)	Treatment valganciclovir 100 days post-transplant period (N=56)
Neutropenia (ACHN (cells / μl))
Less than 500	5	30
500 - less than 750	8	7
750 - less than 1000	5	11
Anemia (hemoglobin (g / l))
Less than 65	0	0
65 - less than 80	14	5
80 - less than 95	38	29
Thrombocytopenia (number of platelets (cells / μl))
Less than 25,000	0	0
25000 - less than 50000	10	0
50000 - less than 100000	3	4
Concentration of serum creatinine (mg / dL)
More than 2.5	2	5
More than 1,5-2,5	11	20

Experience in postmarketing drug use

Below are the AEs described in spontaneous reports during the post-marketing application of ganciclovir. not mentioned in any of the above sections, for which a causal relationship with valganciclovir can not be excluded. Because the valganciclovir quickly and to a large extent turns into ganciclovir, these adverse reactions may also develop with valganciclovir: anaphylaxis, decreased fertility in men.

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

Overdose:

In one adult patient, the use of the drug for several days at doses no less than 10 times greater than those recommended for it, taking into account the kidney damage (decrease in creatinine clearance), the depression of bone marrow function (medullary aplasia) with lethal outcome developed.

It is possible that an overdose of valganciclovir may lead to nephrotoxicity. Reduce the concentration of valganciclovir in blood plasma in patients with an overdose can be by hemodialysis and hydration.

Overdose of ganciclovir with iv introduction

In the course of clinical trials and post-registration use of the drug, cases of overdosing of iv injectable ganciclovir have been described. Some of them were not accompanied by AEs. Most of the patients reported one or more of the following AEs:

- hematological toxicity (pancytopenia, oppression of bone marrow function, medullary aplasia, leukopenia, neutropenia, granulocytopenia);

- hepatotoxicity (hepatitis, a violation of liver function);

- nephrotoxicity (increased hematuria in patients with existing renal disease, acute renal failure, increased creatinine concentration);

- gastrointestinal toxicity (abdominal pain, diarrhea, vomiting);

- neurotoxicity (generalized tremor, convulsions).

Interaction:

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

Valganciclovir is converted into ganciclovir. therefore, interactions that are characteristic of ganciclovir can also be expected with valganciclovir.

The binding of ganciclovir to plasma proteins is only 1-2%, therefore, reactions associated with substitution of protein binding should not be expected.

In patients receiving concomitantly ganciclovir and imipenem / cilastatin, seizures were noted. The simultaneous use of these drugs should be avoided, unless the expected benefit does not exceed the possible risk.

Simultaneous ingestion of probenecid can lead to approximately a 20% decrease in renal clearance of ganciclovir and an increase in the duration of its action (40%). This is explained by the mechanism of interaction - competition for tubular renal excretion.Patients simultaneously taking probenecid and valganciclovir, it is necessary to observe for the toxicity of ganciclovir.

When applied simultaneously with ganciclovir for oral administration AUC zidovudine may be slightly, but statistically significantly increased (17%); In addition, there is a trend, statistically insignificant, to a decrease in the concentration of ganciclovir. Since both zidovudine, and ganciclovir may cause neutropenia and anemia, some patients may not tolerate simultaneous administration of these drugs in full doses.

It was found that the concentrations of didanosine in plasma with simultaneous both IV and oral administration of ganciclovir are steadily increasing. When taking ganciclovir inside at a dose of 3 g and 6 g / day. AUC Didanosine increased by 84-124%, and with / in the administration of ganciclovir in doses of 5-10 mg / kg / day. AUC didanosine increased by 38-67%. This increase can not be explained by competition for renal tubular excretion, as the percentage excretion of didanosine increased. The cause of this increase may be either increased bioavailability, or inhibition of metabolism.There was no clinically significant effect on the concentration of ganciclovir. However, taking into account the increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be carefully monitored for symptoms of toxic effects of didanosine.

Taking into account the results of the study on a single administration of the recommended dose of iv in ganciclovir and oral administration of mycophenolate mofetil, as well as the known effect of renal dysfunction on the pharmacokinetics of ganciclovir and mycophenolate mofetil, it can be expected that the simultaneous use of these drugs, competing in tubular secretion, increase in the concentration of ganciclovir and phenolic glucuronide of mycophenolic acid. A significant change in the pharmacokinetics of mycophenolic acid is not expected, correcting the dose of mycophenolate mofetil is not required. In patients with renal dysfunction who simultaneously receive valganganciclovir and mycophenolate mofetil, it is necessary to follow the recommendations for correcting the dose of ganciclovir and to carry out careful monitoring.

Zalcitabine increases AUC_0-8Ganciclovir ingested 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 absent, despite a slight increase in the elimination rate constant.

With simultaneous ingestion of stavudine and ganciclovir, there is no statistically significant pharmacokinetic interaction.

Trimethoprim statistically significantly (by 16.3%) reduces the renal clearance of ganciclovir ingested, which is accompanied by a statistically significant decrease in the rate of terminal elimination and a corresponding increase in Tm of 15%. However, the clinical significance of these changes is unlikely, since AUC_0-8and C_maxthey do not change. The only statistically significant change in the pharmacokinetic parameters of trimethoprim with simultaneous administration of ganciclovir was an increase C_min. However, this is unlikely to be of clinical significance, so dose adjustment is not required.

When comparing the concentrations of cyclosporine before taking the next dose of data indicating that ganciclovir changes the pharmacokinetics of cyclosporine, it was not received. Nevertheless, after the initiation of ganciclovir, there was a slight increase in the maximum serum creatinine concentration.

The use of ganciclovir concomitantly with other drugs that have a myelosuppressive effect or impair renal function (for example, dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogues and hydroxyurea) may enhance their toxic effects. Therefore, these drugs can be used simultaneously with ganciclovir only if the potential benefit exceeds the possible risk.

Other possible drug interactions: because the main way Ganciclovir excretion is glomerular filtration and active tubular secretion, the use of valganciclovir concomitantly with antiretroviral drugs, which are also excreted via active tubular secretion (eg, nucleos (t), by reverse transcriptase inhibitors), may affect the concentration of valganciclovir and / or co-administration.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.

Special instructions:

In experimental animal studies, mutagenic, teratogenic, spermatocidal and carcinogenic effects of ganciclovir have been identified. The drug Valganciclovir-Teva should be considered a potential teratogen and a carcinogen for a person whose use can cause congenital malformations and cancer. In addition, it is likely that Valganciclovir-Teva can temporarily or irreversibly suppress spermatogenesis.

In patients receiving Valganciclovir-Teva (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 ACN is less than 500 / μL, or the platelet count is less than 25,000 / μl, and if the hemoglobin concentration is below 80 g / l.

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 use hematopoietic growth factors and / or interrupt drug intake.

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

With simultaneous use of ganciclovir and imipenem / cilastatin, patients may develop seizures. Avoid simultaneous use of valganciclovir and imipenem / cilastatin in cases where the expected benefit does not exceed the possible risk.

Since both zidovudine, and ganciclovir can cause neutropenia and anemia, some patients may be intolerant while using valganciclovir and zidovudine in full doses.

In connection with the possible increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be carefully monitored for the appearance of toxic effects of didanosine.

The use of Valganciclovir-Teva simultaneously with other drugs that have a myelosuppressive or nephrotoxic effect may enhance their toxic effect.

It is not recommended to use Valganciclovir-Teva in children. Pharmacokinetic characteristics, safety and efficacy of the drug in this population are not established.

The bioavailability of ganciclovir from Valganciclovir-Teva is 10 times that of ganciclovir capsules. Ganciclovir It is impossible to replace Valganciclovir-Teva in the ratio 1: 1. Patients who are transferred from ganciclovir capsules should be informed of the risk of overdose if they take a larger number of Valganciclovir-Teva tablets than recommended.

Patients with renal insufficiency require a dose adjustment taking into account the value of CC.

Rules for handling the drug

Tablets can not be broken or crushed. Since Valganciclovir-Teva is 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 rinse the area thoroughly with soap and water, when in contact with eyes, they are thoroughly washed with 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:

Valganciclovir-Teva and / or ganciclovir may cause seizures, sedation, dizziness, ataxia and / or confusion, which can adversely affect activities requiring increased concentration, including vehicle management and handling of machinery and mechanisms. Therefore, during the treatment with Valganciclovir-Teva, 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 30 or 60 tablets in a polyethylene jar with an internal hermetic valve with a polypropylene lid, equipped with a device that prevents the opening of the bottle by children, and a container with a dehumidifier. 1 bank together with instructions for use in a cardboard bundle.

10 tablets per blister of PVC/ACLAR/PVC//Al. For 3 or 6 blisters in a pack of cardboard along with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003443

Date of registration:04.02.2016

Expiration Date:04.02.2021

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

PLIVA HRVATSKA, d.o.o. Croatia

Representation: & nbspTeva Teva Israel

Information update date: & nbsp14.01.2017

Illustrated instructions

Instructions

Valganciclovir-Teva (Valganciclovir-Teva)