Universal reference book for medicines
Product name: VALCYT В® (VALCYTE)

Active substance: valganciclovir

Type: Antiviral drug

Manufacturer: F.Hoffmann-La Roche (Switzerland)
Composition, form of production and packaging
The tablets covered with a cover of
pink color, convex, oval form, with letters "VGC" on one party and digits "450" ​​- on another.

1 tab.

valganciclovir 450 mg

Excipients: povidone, crospovidone, microcrystalline cellulose, stearic acid (powder).

Shell fillers : hydroxypropylmethylcellulose, titanium dioxide (E171), polyethylene glycol, iron oxide red (E172), polysorbate, purified water.

60 pcs.
- vials of polypropylene (1) - packs cardboard.

Description of the drug approved by the manufacturer for the printed edition of 2011.


Antiviral drug.
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 multiplication of herpesviruses in vitro and in vivo. To human viruses sensitive to ganciclovir, include cytomegalovirus (CMV), herpes simplex virus type 1 and type 2 (Herpes simplex), human herpes virus types 6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus, varicella zoster virus (Varicella zoster) and 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 ganciclovir triphosphate, which then undergoes a slow intracellular metabolism. It was shown that this metabolism occurs in cells infected with CMV and herpes simplex virus, 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.
Virostatic activity of ganciclovir is due to suppression of viral DNA synthesis by: 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, leading to the cessation of elongation of viral DNA or very limited elongation. The antiviral IC 50 against CMV, determined in vitro, ranges from 0.14 ОјM (0.04 Ојg / ml) to 14 ОјM (3.5 Ојg / ml).
The clinical antiviral effect of Valcit was demonstrated by a decrease in the isolation of CMV from the patient's body from the baseline of 46% (32/69) to 7% (4/55) after 4 weeks of treatment with Valcitol.


The use of Valcitol allows to obtain the same systemic effect of ganciclovir as the use of recommended doses of ganciclovir (IV) effective in the treatment of CMV retinitis.
It was shown that the ganciclovir AUC correlates with the time to progression of CMV retinitis.
The incidence of CMV disease during the first 6 months after transplantation was 12.1% in patients treated with Valcit 900 mg / day and 15.2% in patients receiving oral ganciclovir at a dose of 1 g 3 times / day from 10th to 100th day after transplantation.
The incidence of acute rejection in the first 6 months was 29.7% in patients in the valganczlovir group and 36% in the ganciclovir group.
Viral Resistance

With prolonged administration of valganciclovir, a virus resistant to ganciclovir may appear, which is due to the selection of mutations either in the gene of the viral kinase (UL97) responsible for monophosphorylation of ganciclovir or in the gene of the viral 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.
Genotyping CMV in polymorphonuclear leukocytes showed that at 3, 6, 12 and 18 months of treatment with valganciclovir, respectively, in 2%, 7%, 14% and 18% of leukocytes, UL97 mutations are detected.
Phenotypic resistance was not, however, analysis was conducted on a very small number of CMV cultures.
Preclinical data no safety

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. Like 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 to ganciclovir.
Both drugs have the same warning of possible reproductive toxicity. 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 on a model using the human placenta ex vivo show that ganciclovir passes through the placental barrier, 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.

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

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 oral administration of valganciclovir in accordance with the dosing regimen depending on the function of the kidneys.

Valganciclovir is a prodrug of ganciclovir, well absorbed from the gastrointestinal tract and in the wall of the intestine and liver rapidly turning into ganciclovir.Absolute bioavailability of ganciclovir after taking valganciclovir is about 60%.
Systemic concentrations of valganciclovir are low and do not last long. AUC 24 and Cmax are 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 meals.
If valganciclovir is administered at a recommended dose of 900 mg during meals, both the mean AUC 24 (about 30%) and the average C max (about 14%) of ganciclovir increase. Therefore, it is recommended to take Valtsit during meals.

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

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

The main way of deducing valganciclovir, like ganciclovir, is glomerular filtration and active tubular secretion.
The renal clearance accounts for 81.5 В± 22% of the systemic clearance of ganciclovir.
Pharmacokinetics in special clinical cases

Patients with renal insufficiency.
Deterioration of renal function led to a decrease in clearance of ganciclovir formed from valganciclovir, with a corresponding increase in T 1/2 of the terminal phase. Therefore, patients with impaired renal function require a dose adjustment.
Patients who are on hemodialysis (CC less than 10 ml / min), it is not recommended to appoint Valcit.
This is due to the fact that such patients require an individual dose of Valtsita less than 450 mg.
Patients with hepatic insufficiency.
The pharmacokinetics of valganciclovir were studied in patients with a stable liver transplant. The absolute bioavailability of ganciclovir, derived from valganciclovir, was approximately 60%, which is the same as in other categories of patients. AUC 0-24 ganciclovir was comparable to that after iv injection of ganciclovir in a dose of 5 mg / kg to patients who underwent liver transplantation.

- treatment of cytomegalovirus retinitis in AIDS patients;

- prevention of CMV infection in patients after organ transplantation.


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

Standard dosing regimen

Valcyte should be taken orally during meals.
Valcyte quickly and heavily converted to ganciclovir. Bioavailability of ganciclovir from Valcit is 10 times higher than from capsules of ganciclovir, therefore it is necessary to strictly adhere to the following dosing regimen for Valtsita.
Induction therapy

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

After induction therapy or in patients with inactive CMV retinitis, the recommended dose is 900 mg (2 tablets of 450 mg) 1 time / day.
If the course of retinitis worsens, the course of induction therapy can be repeated.
For the prevention of CMV infection after organ transplantation, the recommended dose is 900 mg (2 tablets per 450 mg) 1 time / day from the 10th day to the 100th day after transplantation.

Special dosage requirements

In patients with renal insufficiency , the serum creatinine or QC content should be carefully monitored.
Correction of the dose is carried out depending on the QC, as shown in the table below.
The QC is calculated according to the serum creatinine content by the following formula:

for men

(140 - age) x body weight (kg) /0.814 x serum creatinine (Ојmol / L);

for women = 0.85 x for men.

KK (ml / min) Dose for induction therapy Dose for maintenance therapy

? 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

Patients on hemodialysis (CC less than 10 ml / min) are not recommended to appoint Valcit.

In patients with severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow suppression, aplastic anemia, treatment should not be started if the absolute number of neutrophils is less than 500 cells / Ојl or the platelet count is less than 25,000 cells / Ојl, and if the hemoglobin level is lower 80 g / l.


Clinical Trials Data

All adverse events reported in clinical studies of Valcit were previously observed with ganciclovir.

The most frequent adverse events that occurred when taking valganciclovir in patients with CMV retinitis and AIDS: diarrhea, neutropenia, fever, oral candidiasis, headache and weakness.

The most frequent undesirable effects, regardless of their severity and the connection with the administration of the drug in patients after organ transplantation: diarrhea, tremor, graft rejection, nausea, headache, edema of the lower extremities, constipation, insomnia, back pain, hypertension, vomiting.
Most of them were mild or moderate. The most frequent undesirable effects, regardless of the severity, but associated with taking the drug (probable or possible association) in patients after organ transplantation were: leukopenia, diarrhea, nausea, neutropenia.
Adverse events that occurred in patients after transplantation with a frequency of 2% and were not observed in the group of patients with CMV retinitis: hypertension, hypercreatinemia, hyperkalemia, impaired liver function.

Adverse effects observed in more than 5% of patients with CMV retinitis and after organ transplantation

On the part of the digestive system: diarrhea, nausea, vomiting, abdominal pain, constipation, pain in the upper abdomen, dyspepsia, enlarged abdomen, ascites, impaired liver function.

On the part of the body as a whole: fever, weakness, swelling of the lower extremities, peripheral edema, weakness, weight loss, decreased appetite, anorexia, cachexia, dehydration, graft rejection reaction.

From the hemopoietic system: neutropenia, anemia, thrombocytopenia, leukopenia.

Infectious complications: candidiasis of the oral cavity.

From the central nervous system and peripheral nervous system: headache, insomnia, peripheral neuropathy, paresthesia, tremor, dizziness, depression.

Dermatological reactions: dermatitis, increased sweating (at night), itching, acne.

On the part of the respiratory system: dyspnea, productive cough, discharge from the nose, pleural effusion, pharyngitis, nasopharyngitis, sinusitis, upper respiratory tract infections, pneumonia, pneumocystis pneumonia.

From the side of the organ of vision: detachment of the retina, indistinct vision.

From the musculoskeletal system: pain in the back, arthralgia, pain in the limbs, muscle cramps.

From the urinary system: renal failure, dysuria, urinary tract infections.

From the cardiovascular system: arterial hypertension, arterial hypotension.

Laboratory indicators: hypercreatininaemia, hyperkalemia, hypokalemia, hypomagnesemia, hyperglycemia, hypophosphatemia, hypocalcemia.

Other: postoperative complications, pain after surgery, infectious complications of the postoperative wound, increased drainage of the wound, poor wound healing.

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

From the hemopoietic system: pancytopenia, oppression of bone marrow function, aplastic anemia.
Severe neutropenia (less than 500 cells / Ојl) was more common in patients with CMV retinitis (16%) than in patients after organ transplant (5%).
From the side of the urinary system: a decrease in the clearance of creatinine, hypercreatininaemia.
The increase in creatinine was noted more often in patients after organ transplantation compared with patients treated with CMV retinitis. Impaired renal function is a characteristic complication in patients after transplantation.
From the coagulating blood system: life-threatening hemorrhages, possibly associated with the development of thrombocytopenia.

From the central nervous system and peripheral nervous systems: convulsions, mental deviations, hallucinations, confusion, agitation.

Other: increased sensitivity to valganciclovir.

Experience with ganciclovir

Because Valcite is rapidly converted to Ganciclovir, the following are undesirable phenomena described with ganciclovir and not mentioned above.

On the part of the digestive system: dry mouth, cholangitis, dysphagia, belching, esophagitis, fecal incontinence, flatulence, gastritis, gastrointestinal disorders, gastrointestinal bleeding, ulcerative stomatitis, pancreatitis, glossitis, hepatitis, jaundice.

On the part of the body as a whole: bacterial, fungal and viral infections, malaise, mucositis, tremors, sepsis.

Dermatological reactions of alopecia, exfoliative dermatitis, photosensitivity reactions, dry skin, sweating, urticaria.

From the side of the central nervous system and the peripheral nervous system: asthenia, migraines, nightmares, amnesia, anxiety, ataxia, coma, emotional disorders, hyperkinesia, hypertonia, decreased libido, myoclonic twitching, nervousness, drowsiness, intellectual impairment.

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

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

Laboratory indicators: increased activity of alkaline phosphatase, CKK, LDH in the blood, lowering of blood glucose level, hypoproteinemia.

From the sense organs: amblyopia, blindness, ear pain, eye hemorrhages, pain in the eyeballs, deafness, glaucoma, eating disorders, non-systemic dizziness, changes in the vitreous.

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

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

On the part of the respiratory system: stagnation in the paranasal sinuses.

On the part of the endocrine system: diabetes.

Experience in postmarketing drug use

The following are the undesirable phenomena 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 the drug can not be ruled out.
Since Valcit is rapidly and heavily converted to ganciclovir, these side effects can also develop with Valcitol: anaphylaxis, decreased fertility in men.
The undesirable phenomena described in the post-marketing use of the drug are similar to those observed in the clinical studies of Valcit and

- absolute neutrophil count below 500 / mm;
- platelet count less than 25,000 / ul;
- a hemoglobin level below 80 g / l;
- a creatinine clearance less than 10 mL / min;
- children's age till 12 years;

- Pregnancy;

- the period of lactation (breastfeeding);

- hypersensitivity to valganciclovir, ganciclovir or to any component of the drug. Because of the similar chemical structure Valtsita and aciclovir and valaciclovir are possible cross-sensitivity reactions to these drugs.
With care should be prescribed to patients with renal insufficiency, elderly patients (safety and efficacy have not been established).

Reproductive toxicity studies with valganciclovir repeatedly not held because of the rapid and complete conversion of the drug ganciclovir. Ganciclovir violates fertility and is teratogenic in animals.
During treatment should be recommended for women of childbearing age use reliable methods of contraception. Men are recommended to use a barrier method of contraception during treatment Valtsitom and not less than 90 days after its completion.
Valtsita safety in pregnancy has not been established in humans. When pregnancy Valtsita destination should be avoided, unless the potential benefit to the mother justifies the potential risk to the fetus.
Peri- and postnatal development using valganciclovir and ganciclovir has not been studied, but we can not exclude the possibility of elimination of ganciclovir with breast milk and developing serious adverse reactions in the infant. Therefore, taking into account the potential benefits of therapy Valtsitom to a nursing mother, you must decide on the abolition of the drug or the termination of breastfeeding.

In patients with renal impairment should be carefully monitored and the level of serum creatinine or creatinine clearance. Dose correction is carried out depending on the creatinine clearance, as shown in the table below.
Creatinine clearance was calculated based on serum creatinine using the following formula:
Men :
(140 - age) x weight [kg] / 0.011 x 72 x serum creatinine [umol / l]
for women = 0.85 x that of men.
Creatinine clearance (ml / min) dose for induction therapy dose for maintenance therapy
is 60 900 mg of 2 times / day 900 mg 1 time / day
40-59 450 mg of 2 times / day 450 mg 1 time / day
25-39 450 mg 1 time / day 450 mg every 2 days
10-24 450 mg every 2 days 450 mg 2 times a week,
patients on hemodialysis (CC less than 10 ml / min) , is not recommended rollers.

Contraindicated: children up to 12 years.

With care should be prescribed to elderly patients (safety and efficacy have not been established).

In experimental studies on animals showed mutagenic, teratogenic, and carcinogenic spermicidal effect of ganciclovir. Valcyte should be considered a potential teratogen and carcinogenic to humans, the use of which may cause birth defects and cancer. In addition it is likely that Valcyte may temporarily or permanently suppress spermatogenesis.
In patients receiving Valcyte (and ganciclovir), there have been cases of severe leucopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia. Treatment should not be initiated if the absolute neutrophil count below 500 cells / l, or platelet count of less than 25 000 cells / ml, and if the hemoglobin level below 80 g / l.
Valcyte is not recommended for children. Pharmacokinetic properties, safety and efficacy in this population has not been established.
The bioavailability of ganciclovir from Valtsita 10 times higher than that of ganciclovir capsules. Ganciclovir can not be replaced on the rollers in the ratio of 1: 1.Patients who are transferred from ganciclovir capsules should be advised of the risk of overdose if they will accept a greater number of Valtsita tablets than recommended.
In the course of treatment is recommended on a regular basis to determine the complete blood count with platelets. Patients with severe leucopenia, neutropenia, anemia or trombotsitopepiey encouraged to nominate hematopoietic growth factors and / or discontinue the drug.
Patients with renal failure requires correction dose based on the value QC.
Impact on the ability to drive vehicles and manage mechanisms

Convulsions, sedation, dizziness, ataxia and confusion, which are described in the treatment of Valtsitom and ganciclovir, may impair the ability to perform tasks that require a certain level of consciousness, including driving and working with machines and mechanisms.
Handling the drug
tablets can not crush or pulverize. Since Valcyte is potentially teratogenic and carcinogenic to humans, care should be taken if the tablet fractures. Avoid direct contact faults or crushed tablets with skin or mucous membranes. In cases where such contact is necessary to thoroughly wash it with soap and water, if eye contact with them thoroughly with water.

One adult patient to use the drug for several days, at doses at least 10 times higher than recommended for him in view of kidney damage (decrease of creatinine clearance), developed bone marrow suppression (medullar aplasia) with a fatal outcome.
It is possible that an overdose of valganciclovir could manifest signs of renal toxicity.
Reduce the concentration of valganciclovir in patients with an overdose patient plasma can be achieved by dialysis and hydration.
Overdosing ganciclovir administered in / in
During clinical studies and post-marketing the drug overdose cases have been described in / administered ganciclovir. Some of them were not accompanied by adverse events. The majority of the patients had one or more of the following adverse effects: hematological toxicity (pancytopenia, bone marrow depression, medullary aplasia, leucopenia, neutropenia, granulocytopenia), hepatotoxicity (hepatitis, abnormal liver function), nephrotoxicity (increased haematuria in a patient with pre-existing renal disease, acute renal failure, elevated serum creatinine level), gastrointestinal toxicity (abdominal pain, diarrhea, vomiting), neurotoxicity (generalized tremor, court horns).

In in situ model of intestinal permeability in rats with the interaction of valganciclovir valaciclovir, didanosine, nelfinavir, cyclosporin, omeprazole and mycophenolate mofetil has been detected.
Valganciclovir converted to ganciclovir, however interactions characteristic of ganciclovir can be expected when using Valtsita.
Ganciclovir Binding to plasma proteins is only 1-2%, so reactions associated with the replacement of the binding protein, can not be expected.
Patients treated with both ganciclovir and imipenem / cilastatin, convulsions were observed. Concomitant administration of these drugs should be avoided, unless the potential benefits do not exceed the risks.
Simultaneous Oral administration of probenecid may be approximately 20% decrease renal clearance of ganciclovir and statistically significant (40%) increase its AUC. This is due to the interaction mechanism - competition for tubular renal excretion. Patients concurrently taking probenecid and Valcyte should be monitored for ganciclovir toxicity.
When assigning simultaneously with oral ganciclovir AUC of zidovudine may be slightly, but statistically significant increase (17%); In addition, there is a trend, although not statistically significant, in lower concentrations of ganciclovir. Since both zidovudine and ganciclovir can cause anemia and neutropenia, some patients can not tolerate simultaneous reception of these drugs at full doses.
It is found that the plasma concentration of didanosine, while as the I / and oral administration of ganciclovir steadfastly increased. When receiving ganciclovir oral dose of 3 g and 6 g / day of ddI AUC increased by 84-124%, and with / in a ganciclovir at doses of 5-10 mg / kg / day of ddI AUC increased by 38-67%. This increase can not be explained by competition for renal tubular excretion, as the hatching percentage of didanosine is increased. The reason for this increase may be either increasing bioavailability or metabolism inhibition. Clinically significant effect on ganciclovir concentrations were noted. However, given the increase of plasma concentrations of didanosine in the presence of ganciclovir, patients should be carefully observed for the occurrence of symptoms of toxic action of didanosine.
Considering the results of studies on single injection of the recommended dose in / ganciclovir and ingestion of mycophenolate mofetil, as well known effect of renal impairment on the pharmacokinetics of ganciclovir and mycophenolate mofetil, it may be expected that co-administration of these drugs competing in tubular secretion lead to increasing concentrations of ganciclovir, and the phenolic glucuronide of mycophenolic acid. Significant changes the pharmacokinetics of mycophenolic acid is not expected to adjust the dose of mycophenolate mofetil is required. In patients with impaired renal function, which simultaneously receive ganciclovir and mycophenolate mofetil, observe the guidelines for dose adjustment of ganciclovir and careful monitoring.
DdC increases AUC0-8 ganciclovir, taken orally, by 13%. No statistically significant changes in other pharmacokinetic parameters is not happening. Clinically significant changes in pharmacokinetics zalcitabine while oral ganciclovir also absent, although a slight increase in the elimination rate constant.
When simultaneous administration of stavudine and oral ganciclovir statistically significant pharmacokinetic interaction is not marked.
Trimethoprim statistically significantly (16.3%) reduces renal clearance oral ganciclovir ingested, which is accompanied by a statistically significant decrease in terminal elimination rate and corresponding increase in T 1/215%. However, the clinical significance of these changes is unlikely, since the AUC 0-8 and C max are not changed. The only statistically significant change in trimethoprim pharmacokinetic parameters while taking ganciclovir was an increase of the C min . However, this is unlikely to have clinical importance, therefore no dose adjustment is required.
When comparing cyclosporin concentrations before taking the next dose data that alters the pharmacokinetics of ganciclovir cyclosporin has been received. However, after the start of ganciclovir there was a slight increase in the maximum level of serum creatinine.
Purpose ganciclovir concurrently with other drugs that provide myelosuppressive or disruptor effect of renal function (e.g., dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogues and hydroxyurea), may enhance their toxic effects. Therefore, these drugs can be used in conjunction with ganciclovir only if the potential benefits outweigh the possible risk.

The drug is released by prescription.


List B. The drug should be stored out of reach of children at a temperature of no higher than 30 В° C.
Shelf life - 3 years. The drug should not be used beyond the expiration date printed on the package.
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