Valganciclovir, 450 mg 60 pcs

Indications

Treatment of CMV retinitis in AIDS patients;

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

Active ingredient

Composition

How to take, the dosage

The dosing recommendations must be strictly followed to avoid overdose.

The standard dosing regimen

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

Therapy for CMV retinitis

Adults

Induction therapy for CMV retinitis

In patients with active CMV retinitis, the recommended dose of Valganciclovir-Teva is 900 mg (2 450 mg tablets) twice daily for 21 days. Prolonged induction therapy increases the risk of myelotoxicity.

Supportive therapy for CMV retinitis

After a course of induction therapy or in patients with inactive CMV retinitis, the recommended dose is 900 mg (2 450 mg tablets) once daily. If the course of retinitis worsens, the course of induction therapy may be repeated.

Prevention of CMV infection after solid organ transplantation

Adults

Patients who have undergone kidney transplantation start therapy for the first 10 days after surgery with a dose of 900 mg (2 tablets of 450 mg) once daily. Therapy is continued until the 200th day of the post-transplant period.

In patients who have undergone transplantation of other solid organs, therapy is started during the first 10 days after surgery in a dose of 900 mg (2 tablets of 450 mg) once daily. Therapy is continued until the 100th day of the post-transplant period.

Particular dosing instructions

In patients with renal insufficiency, serum creatinine or CK concentrations should be monitored carefully. Dose adjustments are made depending on CK, as shown in the table below.

The CK is calculated according to the serum creatinine concentration using the following formula:

for men = (140 – age) x body weight (kg)/72 x (0.011 x serum creatinine concentration (μmol/L);

for women = 0.85 x index for men.

CK (ml/min)

Dose for induction therapy

Dose for maintenance therapy

At least 60

900 mg 2 times daily

900 mg 1 time per day

40-59

450 mg 2 times per day

450 mg 1 time per day

25-39

450 mg once daily

450 mg every 2 days

10-24

/td>

450 mg every 2 days

450 mg 2 times a week

In patients with severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, depressed bone marrow function, aplastic anemia, treatment should not be started if the ACH is less than 500/μL or platelet count is less than 25000/μL, or 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 discontinue the drug.

In elderly patients, caution should be exercised because efficacy and safety have not been established.

Children

Therapy of CMV retinitis

The use of Valganciclovir-Teva tablets in children under 18 years of age for therapy of CMV retinitis is not recommended because the efficacy and safety of Valganciclovir-Teva in this age group has not been established.

Prevention of CMV infection after transplantation of solid organs

The dosing regimen in children from 16 to 18 years of age does not differ from that in adults. Valganciclovir-Teva tablets are not recommended for use in children and adolescents under 16 years of age for prevention of CMV infection after solid organ transplantation because the efficacy and safety of Valganciclovir-Teva in this age group has not been established.

Interaction

No interactions of valganciclovir with valacyclovir, didanosine, nelfinavir, cyclosporine, omeprazole and mycophenolate mofetil were found in an in situ intestinal permeability model in rats.

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

Patients who received ganciclovir and imipenem/cilastatin concomitantly have had seizures. Simultaneous use of these drugs should be avoided unless the expected benefit exceeds the possible risk.

Concomitant oral administration of probenecid can lead to about 20% decrease in renal clearance of ganciclovir and increase its duration of action (40%). This is due to the mechanism of interaction – competition for renal tubular excretion. Patients taking probenecid and valganciclovir simultaneously should be monitored for ganciclovir toxicity.

When used concomitantly with oral ganciclovir, the AUC of zidovudine may increase slightly but statistically significantly (17%); in addition, there is a trend, statistically insignificant, to decrease the concentration of ganciclovir. Because both zidovudine and ganciclovir can cause neutropenia and anemia, some patients may not tolerate concomitant administration of these drugs at full doses.

Plasma concentrations of didanosine have been found to be persistently elevated with concomitant administration of both IV and oral ganciclovir. When ganciclovir is administered orally at a dose of 3 g and 6 g/day. AUC of didanosine increased by 84-124%, and when ganciclovir was administered intravenously in doses of 5-10 mg/kg/day. AUC of didanosine increased by 38-67%. This increase cannot be explained by competition for renal tubular excretion, as the percentage of didanosine excretion increased. The reason for this increase may be either increased bioavailability or inhibition of metabolism. No clinically significant effect on ganciclovir concentrations was observed. However, given the increased plasma concentrations of didanosine in the presence of ganciclovir, patients should be closely monitored for symptoms of didanosine toxicity.

. Given the results of a study of a single administration of the recommended dose of intravenous ganciclovir and oral mycophenolate mofetil, and the known effect of renal dysfunction on the pharmacokinetics of ganciclovir and mycophenolate mofetil, one would expect that the concurrent use of these drugs that compete in tubular secretion would increase the concentration of ganciclovir and mycophenolic acid phenol glucuronide. No significant changes in mycophenolic acid pharmacokinetics are expected; no dose adjustment of mycophenolate mofetil is required. In patients with impaired renal function who simultaneously receive valganciclovir and mycophenolate mofetil, dose adjustment recommendations for ganciclovir and close monitoring should be followed.

Zalcitabine increases the AUC0-8 of oral ganciclovir by 13%. No statistically significant changes in other pharmacokinetic parameters were observed. There were also no clinically significant changes in the pharmacokinetics of zalcitabine with concomitant oral administration of ganciclovir, despite a slight increase in the elimination rate constant.

There were no statistically significant pharmacokinetic interactions with oral administration of stavudine and ganciclovir.

Trimethoprim statistically significantly (by 16.3%) decreases renal clearance of oral ganciclovir, which is accompanied by a statistically significant decrease in the rate of terminal elimination and a corresponding increase in Tx by 15%. However, the clinical significance of these changes is unlikely, since the AUC0-8 and Cmax do not change. The only statistically significant change in the pharmacokinetic parameters of trimethoprim with concomitant administration of ganciclovir was an increase in Cmin. However, this is unlikely to be of clinical significance, so no dose adjustment is required.

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

Other possible drug interactions: since the main route of excretion of ganciclovir is glomerular filtration and active tubular secretion, using valganciclovir simultaneously with antiretroviral drugs that are also excreted by active tubular secretion (such as nucleos(t)ide reverse transcriptase inhibitors) may affect the concentration of valganciclovir and/or the drugs used together. Using ganciclovir concomitantly with other drugs that have myelosuppressive or nephrotoxic effects (e.g. dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogues, hydroxycarbamide and pegylated interferons/ribavirin) may increase their toxic effects. Therefore, these drugs can be used simultaneously with valganciclovir only if the expected benefit of the ongoing treatment exceeds the possible risk.

Special Instructions

Mutagenic, teratogenic, spermatocidal, and carcinogenic effects of ganciclovir were revealed in experimental studies on animals. The drug Valganciclovir-Teva should be considered a potential teratogen and carcinogen for humans, the use of which can cause birth defects and cancer. In addition, it is likely that Valganciclovir-Teva may temporarily or irreversibly suppress spermatogenesis.

Synopsis

Contraindications

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

Abstract neutrophil count (ANR) less than 500/μL; platelet count less than 25000/μL; hemoglobin concentration less than 80 g/l;

Detoxication and hypersensitivity to valganciclovir are possible./p>

CKG less than 10 ml/min;

Children under 16 years of age (prevention of CMV infection after solid organ transplantation in adults and children over 16 years of age at risk);

Children under 18 years of age (treatment of CMV retinitis in adult AIDS patients).

Elderly patients (safety and efficacy not established).

Side effects

The safety profiles of valganciclovir and ganciclovir were similar when administered intravenously for 28 days. The most frequent NTs were diarrhea, neutropenia, and fever. Oral candidiasis, headache and weakness were more common in patients taking valganciclovir, but nausea and injection site NCDs (phlebitis and thrombophlebitis) were more common when using ganciclovir by injection (see Table 1).

Table 1. Percentage of patients (%) with selected NIHs during CMV retinitis therapy

Indesirable phenomenon

Treatment with oral valganciclovir (N=79)

Treatment with ganciclovir w/v (N=79)

Diarrhea

16%

10%

Candidiasis of the oral mucosa

11%

6%

Headache

9%

5%

Weakness

8%

4%

Nausea

8%

14%

Phlebitis and thrombophlebitis

–

Table #2 shows the most frequent NTs (regardless of their severity or association with valganciclovir administration) with a frequency of occurrence of at least 5% obtained with valganciclovir treatment either in patients with CMV retinitis or in patients after solid organ transplantation.

The most frequent NTs regardless of severity but associated with valganciclovir administration (remote, probable, or possible association) in patients with CMV retinitis were neutropenia (21%), diarrhea (14%), nausea (9%), and anemia (14%).

In the prevention of CMV retinitis in patients after organ transplantation

In the prevention of CMV retinitis in patients after organ transplantation

The following table shows the adverse events. Table 2 presents adverse events (up to 28 days after study completion) regardless of their severity and association with drug administration, with an incidence of ≥5%, obtained in clinical trials in patients after solid organ transplantation who received valganciclovir or ganciclovir orally, starting the drugs within 10 days after transplantation and continuing them until day 100 of the post-transplant period.

The most common adverse reactions, regardless of severity but, according to researchers, associated with taking the drug (remote, probable or possible relationship) in patients after solid organ transplantation who received treatment before day 100 of the post-transplant period: leukopenia, diarrhea, nausea, neutropenia; in renal transplantation patients who received treatment before day 200 of the post-transplant period: leukopenia, neutropenia, anemia and diarrhea.

Table 2. Proportion of patients (%) with NTs that occurred in at least 5% of patients with CMV retinitis or after organ transplantation on valganciclovir and ganciclovir therapy

Particlestable cellspacing=”0″ cellpadding=”0″>

Indesirable event

Proportion of patients (%) with CMV retinitis

/p>

Valganciclovir (N=370)

Valganciclovir (N=244)

Ganciclovir (oral) (N=126)

Digestive system disorders

Diarrhea

38

30

29

/td>

Nausea

25

23

Respiratory system side

Cough

td>

16

6

8

Urinary tract infections caused by E. coli

–

13

Upper respiratory tract infections

22

34

65 – less than 80

14

5

80 – less than 95

38

Thrombocytopenia (platelet count (cells/μL))

Less than 25,000

0

0

/p>

25,000 – less than 50,000

10

50,000 – less than 100,000

3

Serum creatinine concentration (mg/dl)

More than 2.5

5

Over 1.5-2.5

11

20

Postmarketing experience with the drug

The NTs described during post-registration use of valganciclovir are similar to those observed in clinical trials of valganciclovir and ganciclovir.

Overdose

In one adult patient, the use of the drug for several days in doses at least 10 times higher than recommended for him with regard to kidney damage (decreased creatinine clearance) developed suppression of bone marrow function (medullary aplasia) with fatal outcome.

It is possible that overdose of valganciclovir may lead to nephrotoxicity. Plasma concentrations of valganciclovir in patients with overdose can be reduced by hemodialysis and hydration.

Ingestion overdose of ganciclovir by IV administration

In clinical studies and post-registration use of the drug, there have been cases of overdose of IV administered ganciclovir. Some of these were without NS. Most patients, however, experienced one or more of the following NTs:

Hematologic toxicity (pancytopenia, suppression of bone marrow function, medullary aplasia, leukopenia, neutropenia, granulocytopenia);

Hepatotoxicity (hepatitis, liver function impairment);

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

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

– neurotoxicity (generalized tremors, seizures).

Pregnancy use

Women of reproductive age should be advised to use effective contraceptive methods during treatment with Valganciclovir-Teva. Men are recommended to use a barrier method of contraception during treatment with Valganciclovir-Teva and for at least 90 days after its completion.

The safety of valganciclovir in human pregnancy has not been established. Valganciclovir-Teva should be avoided in pregnancy unless the expected benefit to the mother exceeds the possible risk to the fetus.

Peri- and postnatal development with valganciclovir and ganciclovir have not been studied, but the possibility of excretion of ganciclovir with breast milk and the development of serious adverse reactions in the infant cannot be excluded. Thus, the decision to discontinue Valganciclovir-Teva or to stop breastfeeding should be made based on an assessment of the potential effect of treatment on the nursing mother and the risk to the infant.