Universal reference book for medicines
Product name: CIVALGAN (CIVALGAN)

Active substance: valganciclovir

Type: Antiviral drug

Manufacturer: ИЗВАРИНО ФАРМА (Russia)
Composition, form of production and packaging
The tablets covered with a film membrane of
pink color, biconvex, oval, with a risk on one side and embossing "f" on the other;
on the transverse section - the core is from white to white with a yellowish hue of color.
1 tab.

valganciclovir hydrochloride 496.3 mg,

which corresponds to the content of valganciclovir 450 mg

Excipients: povidone - 28.8 mg, tartaric acid - 21.6 mg, mannitol - 144.5 mg, crospovidone - 14.4 mg, sodium stearyl fumarate - 14.4 mg.

The composition of the coating: polyvinyl alcohol - 9.2 mg, titanium dioxide 5.58 mg, macrogol 3350 - 4.65 mg, talc 3.4 mg, iron oxide oxide yellow 0.08 mg, iron oxide red oxide 0.08 mg, ferric oxide black oxide 0.01 mg.

10 pieces.
- Packings contour mesh (1) - packs cardboard.
10 pieces.
- packings contour mesh (2) - packs cardboard.
10 pieces.
- Packings contour mesh (3) - packs cardboard.
10 pieces.
- packings contour mesh (6) - packs cardboard.
10 pieces.
- Packings contour mesh (9) - packs cardboard.
10 pieces.
- Packings contour mesh (12) - packs cardboard.
60 pcs.
- polyethylene bottles (1) - cardboard packs.
60 pcs.
- polyethylene cans (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2016.

PHARMACHOLOGIC EFFECT

Valganciclovir is an L-valyl ester (prodrug) of ganciclovir, which is rapidly converted into ganciclovir after ingestion by intestinal and hepatic esterases.
Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which suppresses the replication of herpesviruses 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 UL97 viral protein kinase, ganciclovir is first phosphorylated to form 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 h. Because 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 in vitro studies, a typical inhibitory concentration that inhibits CMV replication by 50% (IC 50 ) 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 with acquired immunodeficiency syndrome (AIDS) and newly diagnosed CMV retinitis from baseline of 46% to 7% after 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 use of recommended intravenous doses of ganciclovir effective in the treatment of CMV retinitis.
It was shown that the ganciclovir AUC correlates 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 receiving valganciclovir (900 mg / day) and 15.2% in the group of patients receiving ganciclovir orally (1000 mg 3 times / 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 valganciclovir group and 36% in the ganciclovir-treated group.
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 infection (D + / R-) was associated with greater efficacy in preventing CMV infection in the first 12 months after transplantation compared to 900 mg of valganciclovir day after transplantation.

The transplant survival rate in 12 months was 98.1% in the group of patients treated with valganciclovir before the 100th day and 98.2% in the group of patients treated with valganciclovir before the 200th day.
The incidence of acute graft rejection confirmed by biopsy in the first 12 months was 17.2% in the group treated with valganciclovir before the 100th day and 11.0% in the group receiving valganciclovir before the 200th day.
Viral Resistance

With prolonged use of valganciclovir, a virus 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). A virus having only a mutation of the UL97 gene is resistant only to ganciclovir, while 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.
Treatment of CMV retinitis

Genotyping 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 of UL97 are detected.

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 obtained on the 100th day (end of prophylactic administration of valganciclovir) in patients from valganciclovir group, and the presence of mutations in samples obtained from patients taking oral ganciclovir (1.9%);

2) the absence of resistance mutations in the samples obtained from patients randomized to valganciclovir with suspected CMV infection 6 months after transplantation and 6.9% for patients receiving oral ganciclovir.

Preclinical safety data

The results of carcinogenicity studies of valganciclovir in mice correspond to the positive results of the same studies of ganciclovir.
Like ganciclovir, valganciclovir 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 into ganciclovir, additional studies of reproductive toxicity with valganciclovir have not been conducted. Both drugs include the same warning of possible reproductive toxicity (see section "Special instructions"). In animals, ganciclovir disrupts fertility and has a teratogenic effect. Taking into account experiments on animals in which 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.
The 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, it is well absorbed in the digestive tract, in the intestinal wall and is 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.AUC 24 and C max represent approximately 1% and 3% of those of ganciclovir, respectively.
The proportional dependence of AUC ganciclovir on the dose after taking valganciclovir in doses from 450 to 2625 mg is indicated only for the case of taking the drug after a meal.
If valganciclovir is taken during meals at the recommended dose of 900 mg, the mean AUC 24 (approximately 30%) and the average C max(approximately 14%) of ganciclovir increase. Therefore, valganciclovir is recommended for taking with meals (see section "Dosage regimen").
Distribution .

Due to the rapid metabolism of valganciclovir to ganciclovir, the binding of valganciclovir to plasma proteins was not determined.
The binding of ganciclovir to plasma proteins at drug concentrations from 0.5 to 51 μg / ml is 1-2%. The equilibrium V d of ganciclovir after intravenous administration was 0.680 ± 0.161 l / kg.
Metabolism

Valganciclovir is rapidly hydrolyzed with the formation of ganciclovir, other metabolites have not been identified.
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 derived from valganciclovir, with a corresponding increase in T 1/2 in the terminal phase.Consequently, patients with impaired renal function require a dose adjustment (see subsection "Special instructions for dosing" in the "Dosage regimen" section and section "Special instructions").

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 of iv ganciclovir in a dose of 5 mg / kg to patients who underwent liver transplantation.
INDICATIONS

- treatment of CMV retinitis in patients with AIDS;

- Prevention of CMV infection after transplantation of solid organs in patients at risk.

DOSING MODE

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").
Induction therapy of CMV retinitis

In patients with active CMV retinitis, the recommended dose of valganciclovir is 900 mg (2 tablets to 450 mg) 2 times / 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 to 450 mg) 1 time / day.
If the course of retinitis worsens, the course of induction therapy can be repeated (see subsection "Induction therapy of CMV retinitis" in the "Dosage regimen" section).
Prevention of CMV infection after solid organ transplantation

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 to 450 mg) 1 time / day and continue therapy on the 200th day of the posttransplantation 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 to 450 mg) 1 time / day and continue therapy on 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 CC.
Dose adjustment in adult patients is performed depending on the CK, as shown in the table below (see subsection "Pharmacokinetics in special patient groups" in the section "Pharmacological properties" and section "Special instructions").
KK is calculated depending on the concentration of creatinine in the serum according to the following formula:

for men = (140 years [years])? (body weight [kg]) / (72)? (0.011? concentration of creatinine in the blood serum [μmol / l]);

for women = 0.85? an indicator for men.

CK (ml / min) Dose for induction therapy Dose for maintenance therapy / prophylaxis

? 60 900 mg 2 times / day 900 mg 1 time / day

40-59 450 mg 2 times / day 450 mg 1 time / day

25-39 450 mg once daily 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 treated with valganciclovir (and ganciclovir), severe cases of leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow suppression and aplastic anemia have been reported.
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 "Special instructions" and "Side effects" ").
Elderly patients

Efficiency and safety are not established.

Patients of childhood

Valganciclovir is not recommended for use in children and adolescents under 18 years of age,
efficacy and safety of use in this age group in the relevant controlled clinical trials is not established.
SIDE EFFECT

Clinical Trials Data

Valganciclovir is a prodrug of ganciclovir, which rapidly becomes ganciclovir after ingestion, so all known undesirable effects associated with ganciclovir are expected for valganciclovir.
All adverse events reported in clinical trials were previously observed with ganciclovir.
Treatment of CMV retinitis in patients with AIDS

The safety profiles of valganciclovir and ganciclovir were the same 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 common, and with ganciclovir IV treatment - 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

Adverse Event A group of patients receiving valganciclovir N = 79 A group of patients who received ganciclovir IV in N = 79

Diarrhea 16% 10%

Candidiasis of the oral mucosa 11% 6%

Headache 9% 5%

Weakness of 8% 4%

Nausea 8% 14%

Phlebitis and thrombophlebitis - 6%

The following table (see Table 2) presents undesirable events (regardless of their seriousness and the connection with taking 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 events (% of patients), regardless of their severity and the connection with taking the drug in patients with CMV retinitis, were: diarrhea (38%), fever (26%), nausea (25%), neutropenia (24%) and anemia (22%).
Most of them were mild or moderate.
The most common adverse reactions irrespective of seriousness, but according to the researchers associated with the administration of the drug (remote, probable or possible link) in patients with CMV retinitis were neutropenia (21%), anemia (14%), diarrhea (13%) and nausea (9%).
Prevention of CMV infection in patients after solid organ transplantation
Table 2 shows adverse events (irrespective of severity and connection with the reception of the preparation) with a frequency of occurrence of? 5% obtained in clinical studies (up to 28 days after the study) patients after solid organ transplantation treated with ganciclovir or valganciclovir orally, since administration of drugs for 10 days after transplantation and continuing reception of the 100-th day posttransplant period.
The most common adverse events (% of patients), regardless of their severity, and connection with the reception of valganciclovir in patients after transplantation of solid organs were diarrhea (30%), tremor (28%), graft rejection (24%), nausea (23%) , headache (22%), edema of lower extremities (21%), constipation (20%), back pain (20%), insomnia (20%), increased blood pressure (18%), vomiting (16%). These phenomena are met at the same frequency and with oral ganciclovir. Most of them were slightly or moderately expressed.
? Adverse events that occurred in patients after solid organ transplantation at 2% and were not observed in the group of patients with CMV retinitis were: increase in blood pressure (18%), hypercreatininemia (10%), hyperkalemia (14%), violation liver (9%). These phenomena occur at the same rate when administered orally and ganciclovir can be considered as a manifestation of the underlying disease.
The most common adverse reactions irrespective of seriousness, but according to the researchers associated with the administration of the drug (remote, probable or possible link) in patients after solid organ transplantation (reception on the 100 th day post-transplant period) were leukopenia (9%), diarrhea (7%), nausea (6%), neutropenia (5%).
Table 2. The proportion of patients with adverse events (AEs), occurs at? 5% of CMV retinitis or after solid organ transplantation in clinical trials in the treatment of valganciclovir or ganciclovir
systems organism / description AEs patients with CMV retinitis patients after solid organ transplantation, treated for 100 th day posttransplant 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
Abdominal pain 13 14 14
Constipation 20 June 20
pains in the upper abdomen 6 September 6
Dyspepsia 4 December 10
Bloating 2 6 6
Ascites - June 9
Abnormal liver function 3 and September 11
Co the body as a whole
Fever 26 13 14
Fatigue 20 13 15
edema lower limb 21 May 16
Pain 3 5 7
edema 1 11 September
Peripheral edema 1 6 7
Weakness 4 6 6
From the blood and lymphatic system
Neutropenia 24 August 3
Anemia December 22 15
Thrombocytopenia 5 5 5
Leukopenia 14 April 7
Infectious complications
Oral mucosal candidiasis March 20 3
Pharyngitis / nasopharyngitis 12 April 8
Sinusitis March 10 -
Upper respiratory tract infection 9 7 7
Flu 9 - -
Pneumonia 7 4 2
Bronchitis 6 - 1
Pneumocystis pneumonia 6 - -
Urinary tract infection 11 May 9
From the nervous system

Headache 18 22 27
Insomnia 14 20 16
Peripheral neuropathy 7 1 1
Paresthesia 6 5 5
Tremor February 28 25
Dizziness (except vertigo) 9 10 6
Depression 9 7 6
Skin and subcutaneous fat
Dermatitis 18 April 5
Night sweating March 7 4
Itching 6 7 4
Acne <1 4 6
From the respiratory system

Cough 16 June 8
Dyspnea September 11 10
Productive Cough 5 2 2
Nasal discharge 2 4 6
Pleural effusion <1 8 July
From the senses
Retinal Detachment 13 - -
Blurred vision 6 1 4
From the side of the musculoskeletal system

Back pain 20 August 15
Arthralgia 6 7 7
cramps in muscles 6 February 11
pains in the extremities 3 5 7
From the urinary system

Renal failure 7 January 12
dysuria 2 7 6
From the immune system

Reaction transplant rejection - 24 30
From the side of metabolism

Anorexia 5 3 -
Cachexia 5 - -
Loss of appetite 8 April 5
Dehydration June 5 6
Weight loss 9 3 3
From the side of the cardiovascular system

Lowering blood pressure 1 3 8
The AD 18 Mar. 15
Laboratory indicators

Hyperkalemia <1 14 14
hypokalemia 2 8 8
Hypomagnesaemia <1 8 8
Hyperglycemia 1 6 7
Hypophosphatemia <1 9 6
Hypocalcemia <1 4 6
hypercreatininemia January 10 14
Postoperative complications
Postoperative complications 1 December 8
pain in the postoperative period 2 13 July
infection of surgical wounds 1 June 11
Increased frequency necessary drainage - 5 September
Poor healing of postoperative wounds <1 5 6
The following are serious adverse events occurred at a frequency of less than 5% in three clinical trials and described above.
From the blood and lymphatic system:pancytopenia, bone marrow depression, aplastic anemia; potentially threatening bleeding life associated with thrombocytopenia.
With the genitourinary system: decrease in QC.
On the part of the central and peripheral nervous system: convulsions, psychotic disorders, hallucinations, confusion, agitation.
On the part of the body as a whole: hypersensitivity reaction to valganciclovir.
Severe neutropenia (absolute neutrophil count of less than 500 in 1 mm) is more common in patients with CMV retinitis (16%) than in patients receiving valganciclovir (5%) or oral ganciclovir (3%) following solid organ transplantation (at 100- th day post-transplant period). In patients receiving both valganciclovir and oral ganciclovir after solid organ transplantation, compared to patients with CMV retinitis is observed a significant increase in the concentration of creatinine in serum. Impaired renal function is typical for patients undergoing solid organ transplantation.
The overall safety profile of valganciclovir does not change with an increase in the period of prophylactic use of up to 200 days in patients after kidney transplantation at risk.
Table 3. Changes in laboratory parameters, reports upon receipt of valganciclovir
Changes in laboratory parameters Patients CMV retinitis patients after solid organ transplantation, treated for 100 th day posttransplant period
Valganciclovir (n = 370) Valganciclovir (n = 244) Ganciclovir orally (PO = 126)
%%%
neutropenia (absolute neutrophil count / mm)
<500 May 16 3
500 <17 750 2 March
750- <1000 17 February 5
Anemia (hemoglobin g / l)
<65 7 1 2
65 <80 10 January 5
80 <95 14 31 25
Thrombocytopenia (platelet number / mm)
<000 3 0 25 2
25 000- <000 5 1 50 3
50 000 to <100 000 21 18 21
Concentration of creatinine in blood serum (mg / dl)
> 2.5 February 14 21
> 11 45 47 1.5-2.5
Experience with ganciclovir
Because valganciclovir rapidly metabolized to form ganciclovir below shows adverse events noted for the treatment and ganciclovir not mentioned above.
From the digestive system: cholangitis, dysphagia, eructation, esophagitis, fecal incontinence, flatulence, gastritis, gastrointestinal disorder, 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.
Skin and subcutaneous adipose tissue:alopecia, dry skin, sweating, urticaria.
On the part of the central and peripheral nervous system: sleep disorders, amnesia, anxiety, ataxia, coma, dry mouth, emotional disturbance, hyperkinetic syndrome, hypertonia, decreased libido, myoclonic jerks, nervousness, somnolence, disturbances of intelligence.
On the part of the musculoskeletal system: pain in the bones and muscles, myasthenic syndrome.
Genitourinary: hematuria, impotence, frequent urination.
From endocrine system: diabetes.
From the laboratory parameters: increase in activity of alkaline phosphatase, creatine kinase, lactate dehydrogenase in the blood, lowering blood glucose, hypoproteinemia.
From the senses: amblyopia, blindness, ear pain, eye hemorrhage, pain in eyeballs, deafness, glaucoma, taste dysfunction, tinnitus, blurred vision, changes in the vitreous body.
From the blood and lymphatic system: eosinophilia, leukocytosis, lymphadenopathy, splenomegaly, bleeding.
Cardio-vascular system: arrhythmia, including ventricular, migraine, phlebitis, tachycardia, deep vein thrombophlebitis, vasodilatation.
The respiratory system: stagnation in the paranasal sinuses.
Post-Marketing Experience the drug
Experience with ganciclovir
Below are undesirable phenomena described in the spontaneous post-marketing reports during use of ganciclovir (orally or w / w), not mentioned in any of the above sections, for which we can not exclude a causal relationship to the drug. Since valganciclovir quickly and largely converted to ganciclovir, such adverse reactions can develop: anaphylaxis, decreased fertility in men.
Undesirable phenomena described drug application at post-marketing, similar to those observed in clinical studies of valganciclovir and ganciclovir.
CONTRAINDICATIONS

- hypersensitivity to valganciclovir, ganciclovir or any of the components. Because of the similar chemical structure of acyclovir, valacyclovir and valganciclovir possible cross-reaction sensitivity to these drugs;
- absolute neutrophil count below 500 cells in 1 mm, the number of platelets of less than 25 000 cells in 1 mm or hemoglobin concentration below 80 grams / liter (see "Special instructions.");
- CC less than 10 ml / min;
- Children under 18 years.

Carefully

Older age (efficacy and safety have been established).
PREGNANCY AND LACTATION

Additional studies of reproductive toxicity with valganciclovir has not carried out due to the rapid and complete conversion of valganciclovir to ganciclovir. Ganciclovir violates fertility and is teratogenic in animals (see. See the "Preclinical safety data" section "Pharmacological properties").
During treatment with valganciclovir women of childbearing potential should be advised to use reliable methods of contraception for men is recommended to use a barrier method of contraception during treatment and for at least 90 days after the end (see. See the "Preclinical safety data" section "Pharmacological properties").
Valganciclovir safety in pregnancy has not been established in humans. In pregnancy, the appointment of valganciclovir should be avoided, except in cases where the potential for the mother justifies the potential risk to the fetus.
Studies of the effect of ganciclovir and valganciclovir on peri- and postnatal development has not been, at the same time we can not exclude the possibility of allocating ganciclovir with breast milk and developing serious adverse reactions in the infant. Thus, the abolition of the drug solution or the termination of breastfeeding should be based on an assessment of the potential positive effect of the treatment to a nursing mother and the risk to the infant.
APPLICATION FOR FUNCTIONS OF THE LIVER

It is necessary to carefully control the concentration of creatinine in serum or KK. Correction dose in adult patients is carried out depending on the spacecraft.
Use of the drug for patients with CC less than 10 ml / min contraindicated.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Efficacy and safety of the drug to patients with hepatic failure are not installed.
APPLICATION FOR CHILDREN

Use of the drug for children and adolescents under the age of 18 years is contraindicated.
APPLICATION IN ELDERLY PATIENTS

Use with caution in elderly patients.

SPECIAL INSTRUCTIONS

In animal experiments, it was revealed mutagenic, teratogenic, and carcinogenic effects aspermatogennoe ganciclovir. Valganciclovir should be considered a potential teratogen and carcinogen for humans, the use of which can cause birth defects and cancers (see. See the "Handling the preparation" section "Special instructions"). In addition it is likely that valganciclovir may temporarily or permanently suppress spermatogenesis (see. Sections on "Side effects", "Pregnancy and lactation", subsection "Preclinical safety data" section "Pharmacological properties").
In patients receiving valganciclovir (and ganciclovir), there have been cases of severe leucopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia function. Treatment should not be initiated if the absolute neutrophil count below 500 cells in 1 mm or platelet count of less than 25 000 cells in 1 mm and if the hemoglobin is below 80 g / l (see. Subsection "Specific guidance on dosing" of " dosing regimen, "and the section" Side effects ").
In the course of treatment is recommended to regularly control the expanded formula of blood and platelets. Patients with severe leucopenia, neutropenia, anemia and / or thrombocytopenia, it is recommended to appoint hematopoietic growth factors and / or discontinue the drug (see. See the "Special instructions for dispensing" section "Dosage" and "Side effects" section).
With simultaneous use of ganciclovir and imipenem / cilastatin in patients with seizures were observed. Avoid the simultaneous application of valganciclovir and imipenem / cilastatin in cases where the potential benefits of treatment does not exceed a possible risk (see. The section "Interaction with other drugs").
Since both zidovudine and ganciclovir can cause anemia and neutropenia, some patients may experience intolerance while receiving valganciclovir and zidovudine in full doses (see. The section "Interaction with other drugs").
In connection with the possible increase in didanosine plasma concentrations in the presence of ganciclovir, patients should be carefully observed for the occurrence of symptoms of toxic action of didanosine (see. Section "Interaction with other medicinal products"). Application valganciclovir concurrently with other drugs that provide myelosuppressive or nephrotoxic effect (see. The section "Interaction with other drugs") may potentiate their toxic effects.
The bioavailability of ganciclovir from valgantsiklo
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