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Valganciclovir, 450 mg 60 pcs
€521.10
Description
Pharmacological group: antiviral agent
ATX code: J05AB14
Pharmacological properties
Pharmacodynamics
Mechanism of action. Antiviral drug. Valganciclovir is the L-valyl ester (prodrug) of ganciclovir, which is rapidly converted to ganciclovir by intestinal and hepatic esterases after oral administration. Ganciclovir is a synthetic analog of 2′-deoxyguanosine, which inhibits the reproduction of herpes viruses in vitro and invivo. Human viruses susceptible to ganciclovir include cytomegalovirus (CMV), Herpes simplex types 1 and 2, human herpes virus types 6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus, Varicella zoster virus and hepatitis B virus.
In CMV-infected cells, under the action of the viral protein kinase UL97, ganciclovir is first phosphorylated to form ganciclovirmonophosphate. Herpes simplex, with an intracellular half-life of 18 h and 6-24 h after disappearance of ganciclovir from extracellular fluid, respectively. Since phosphorylation of ganciclovir is highly dependent on the action of viral kinase, it occurs predominantly in infected cells.
Virostatic activity of ganciclovir is due to suppression of viral deoxyribonucleic acid (DNA) synthesis by:
- competitive inhibition of deoxyguanosine triphosphate incorporation into DNA by viral DNA polymerase;
- inclusion of ganciclovir triphosphate in viral DNA, leading to cessation of elongation or very limited elongation of viral DNA. A typical inhibitory concentration that suppresses CMV replication by 50% (IC50), determined by inin vitro, ranges from 0.08 µmol/L (0.02 µg/mL) to 0.14 µmol/L (3.5 µg/mL).
The clinical antiviral effect of valganciclovir has been shown to reduce CMV excretion in patients with acquired immunodeficiency syndrome (AIDS) and newly diagnosed CMV retinitis from an initial rate of 46% to 7% after 4 weeks of treatment with valganciclovir.
Effectiveness
Treatment of CMV retinitis. The use of valganciclovir in induction therapy in patients with CMV retinitis has similar clinical efficacy compared with intravenous (IV) administration of the recommended doses of ganciclovir effective in treating CMV retinitis. The area under the concentration-time curve (AUC) of ganciclovir has been shown to correlate with the length of time before 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, and kidney transplantation in patients at high risk for CMV infection (CMV-positive donor (D+)/CMV-negative recipient (R-) (D+/R-)) was 12.1% in patients who received valganciclovir at a dose of 900 mg/day and 15.2% in patients receiving oral ganciclovir at a dose of 1 g 3 times daily from day 10 to day 100 after transplantation. Most of the cases occurred in the period after withdrawal of prophylactic therapy (after the 100th day of the post-transplant period). The incidence of CMV infection in the valganciclovir treatment group appeared later than in the ganciclovir treatment group. The incidence of acute rejection in the first 6 months was 29.7% in patients treated with valganciclovir and 36% in patients treated with ganciclovir. The 12-month graft survival rate was 98.2% in patients receiving valganciclovir until day 100 and 98.1% in patients receiving valganciclovir until day 200. The incidence of acute graft rejection confirmed by biopsy at the first 12 months was 17.2% in patients who received valganciclovir up to day 100 and 11% in patients who received valganciclovir up to day 200.
Viral resistance. A virus resistant to ganciclovir may emerge with long-term administration of valganciclovir, which may be due to selective mutations in either the viral kinase gene (UL97) responsible for monophosphorylation of ganciclovir or in the viral DNA polymerase gene (UL54). A virus with only a mutation in the UL97 gene is only resistant to ganciclovir, while a virus with mutations in the UL54 gene can 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 valganciclovir treatment, UL97 mutations were detected in 2.2%, 6.5%, 12.8% and 15.3% of leukocytes, respectively.
Preventing CMV infection in patients after solid organ transplantation
Genotyping of CMV in polymorphonuclear leukocytes showed:
- absence of ganciclovir resistance-causing mutations in samples obtained at day 100 (end of prophylactic valganciclovir administration) in patients taking valganciclovir and presence of mutations in samples obtained from patients taking oral ganciclovir.
- absence of resistance mutations in samples obtained from patients taking valganciclovir with suspected CMV infection 6 months after transplantation, and presence of mutations in patients taking oral ganciclovir.
Doclinical data nosafety
Valganciclovir and ganciclovir had mutagenic effects in murine lymphoma cells and clastogenic effects in mammalian cells. These results are consistent with the positive results of a carcinogenicity study of ganciclovir in mice. Like ganciclovir, valganciclovir is a potential carcinogen.
Reproductive toxicity studies with valganciclovir have not been repeated because of the rapid and complete conversion of the drug to ganciclovir. The same warning about possible reproductive toxicity applies to both drugs. In animals, ganciclovir impairs fertility and has a teratogenic effect. Given animal experiments in which systemic exposure to ganciclovir in concentrations below therapeutic levels caused aspermia, it is likely that both ganciclovir and valganciclovir can inhibit spermatogenesis in humans.
Data from 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 of 1 to 10 mg/ml, the drug’s passage through the placenta was unsaturated and was by passive diffusion.
Pharmacokinetics
.The pharmacokinetic characteristics of valganciclovir have been studied in HIV- and CMV-seropositive patients, in patients with AIDS and CMV retinitis, and after solid organ transplantation.
Bioavailability and renal function determine ganciclovir exposure after valganciclovir administration. Bioavailability of ganciclovir was similar in all patients receiving valganciclovir. Systemic exposure of ganciclovir for heart, kidney, and liver transplant recipients was similar to that after oral valganciclovir administration according to the dosing regimen depending on renal function.
Eabsorption. Valganciclovir is a prodrug of ganciclovir that is well absorbed from the gastrointestinal tract and is rapidly converted to ganciclovir in the intestinal wall and liver. Absolute bioavailability of ganciclovir after taking valganciclovir is about 60%. Systemic exposure of valganciclovir is low and of short duration. AUC24 and maximum plasma concentration (Cmax) are approximately 1% and 3% of those of ganciclovir, respectively.
A proportional dose dependence of the AUC of ganciclovir after doses of valganciclovir between 450 and 2625 mg has been shown only for the case of valganciclovir taken after meals. If valganciclovir is administered with meals at the recommended dose of 900 mg, both the mean AUC24 (approximately 30%) and mean Cmax (approximately 14%) of ganciclovir are increased. Consequently, valganciclovir is recommended to be taken with meals.
Distribution. Metabolism. Valganciclovir is rapidly hydrolyzed to form ganciclovir; no other metabolites have been found. After a single oral ingestion of 1000 mg of radioactively labeled ganciclovir, the radioactivity of none of the metabolites in the feces or urine was greater than 1-2%. Elimation. The main route of excretion of valganciclovir, like that of ganciclovir, is glomerular filtration and active tubular secretion. Renal clearance accounts for 81.5±22% of the systemic clearance of ganciclovir. Pharmacokinetics in special clinical cases Patients with renal insufficiency. Deterioration of renal function resulted in decreased clearance of valganciclovir, with a corresponding increase in T1/2 during the terminal phase. Consequently, patients with impaired renal function require dose adjustment. Patients with hepatic impairment.The pharmacokinetics of valganciclovir were studied in patients with a stably functioning liver transplant. Absolute bioavailability of ganciclovir formed from valganciclovir (at a single oral dose of 900 mg after meal) was about 60%, which is the same as in other patients. The AUC0-24 of ganciclovir was comparable to that after an IV dose of 5 mg/kg of ganciclovir in patients who underwent liver transplantation.
Indications
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
Active ingredient
Valganciclovir
Composition
Composition
1 tablet contains: the active ingredient valganciclovir hydrochloride 496.300 mg (valganciclovir 450,000 mg); excipients: Microcrystalline cellulose (type 112) 70,000 mg; mannitol 86,230 mg; colloidal silica 3,400 mg; crosspovidone (type A) 10,050 mg; magnesium stearate 4,020 mg; Opadray II 32K54870 pink shell 26,800 mg: Hypromellose-15cP / HPMC 2910 (E464) 10.720 mg; lactose monohydrate 6.700 mg; titanium dioxide (E171) 6.218 mg; triacetin (E1518) 2.948 mg; iron oxide red dye (E172) 0.214 mg.
How to take, the dosage
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 |
Patients on hemodialysis (KC less than 10 ml/min) are not recommended to use valganciclovir.
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
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.
Valganciclovir is converted to ganciclovir, so interactions specific to ganciclovir can be expected with valganciclovir as well.
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.
When comparing cyclosporine concentrations before the next dose, there was no evidence that ganciclovir alters the pharmacokinetics of cyclosporine. Nevertheless, some increase in maximum serum creatinine concentration was observed after the start of ganciclovir administration.
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
Influence on driving ability.:
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. In the course of treatment, regular monitoring of the detailed blood count and platelets is recommended. Patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia are recommended to use hematopoietic growth factors and/or discontinue the drug.
Long-term induction therapy with Valganciclovir-Teva increases the risk of myelotoxicity.
Concomitant use of ganciclovir and imipenem/cylastatin may cause seizures in patients. Concomitant use of valganciclovir and imipenem/cilastatin should be avoided in cases where the expected benefit does not exceed the possible risk.
Because both zidovudine and ganciclovir can cause neutropenia and anemia, some patients may experience intolerance when valganciclovir and zidovudine are used concomitantly in full doses.
Due to the possible increase in plasma concentrations of didanosine in the presence of ganciclovir, patients should be closely monitored for symptoms of didanosine toxicity.
The use of Valganciclovir-Teva concomitantly with other drugs with myelosuppressive or nephrotoxic effects may increase their toxic effects.
The use of the drug Valganciclovir-Teva in children is not recommended. The pharmacokinetic characteristics, safety and efficacy of the drug in this population have not been established.
The bioavailability of ganciclovir from Valganciclovir-Teva is 10 times greater than that of ganciclovir capsules. Ganciclovir should not be substituted for Valganciclovir-Teva in a 1:1 ratio. Patients being switched from ganciclovir capsules should be informed of the risk of overdose if they take more Valganciclovir-Teva tablets than recommended.
Patients with renal impairment require dose adjustments based on CK values.
Treatment instructions
The tablets should not be crushed or crushed. Because Valganciclovir-Teva is potentially teratogenic and carcinogenic to humans, care should be taken if the tablet breaks. Direct contact of the broken or crushed tablet with skin and mucous membranes should be avoided. In cases of such contact, the area should be thoroughly washed with soap and water, and in case of contact with the eyes, they should be thoroughly rinsed with water.
The release of the medication into the environment should be kept to a minimum. The drug should not be disposed of with wastewater or with household waste. If possible, special systems should be used to dispose of medications.
The treatment with Valganciclovir-Teva and/or ganciclovir may cause convulsions, sedation, dizziness, ataxia and/or confusion, which may adversely affect activities requiring increased concentration, including driving vehicles and operating machines and mechanisms. In this regard, during the treatment with Valganciclovir-Teva, caution should be exercised when driving vehicles and working with machines and mechanisms. In case of occurrence of the described adverse events it is necessary to refrain from performing the mentioned activities.
.
Synopsis
Synopsis
Oval pink film-coated tablets, beveled and engraved “93” on one side and “5465” on the other.
Contraindications Cautions:
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
16 5 15 – p> 9 7 colspan=”4″> Dyspnea 3 13
Side effects
Valganciclovir is a prodrug of ganciclovir. Valganciclovir is rapidly converted to ganciclovir after oral administration, so all known adverse events (AEs) reported with ganciclovir are expected with valganciclovir.
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 | – | 6% |
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 <
23
Vomiting
20
16
14
Abdominal pain
13
14
14
Constipation
6
20
20
Upper abdominal pain
6
9
6
Dyspepsia
4
12
10
Stomach bloating
2
6
6
Ascites
–
9
6
Liver impairment
3
9
11
From the body as a whole
Fever
26
13
14
Fatigue
20
13
15
Lower extremity edema
5
21
Pain
3
7
Oedema
1
11
9
Peripheral edema
1
6
7
Weakness
4
6
6
<
Blood and lymphatic system disorders
Neutropenia
24
8
3
Anemia
22
12
Thrombocytopenia
5
5
5
Leukopenia
4
14
7
Infectious complications <
Mucosal candida
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
–
–
Urogenital tract infections
5
11
9
Nervous system side
Headache
18
22
27
Insomnia
14
20
16
Peripheral neuropathy
7
1
1
Paresthesias
6
5
5
Tremor
2
28
25
Headiness (except vertigo)
10
6
Depression
9
7
6
On the skin and subcutaneous tissue side
Dermatitis
18
4
5
Night sweats
7
3
4
Itching
6
4
Eels
Less than 1
4
/td>
6
Rash
9
/td>
Less than 1
–
Respiratory system side
Cough
td>
16
6
8
9
11
10 <
Productive cough
5
2
2
Nasal discharge
2
4
6
Pleural effusion
Less than 1
7
8
Sensory organs
Retinal detachment
13
–
–
Blurred vision
6
1
4
Musculoskeletal side
Back pain
8
20
15
Arthralgia
6
7
7
Muscle cramps
2
6
11
Limb pain
3
5
7
Urinary system disorders
Renal failure
1
7
12
Dysuria
2
7
6
Immune system side <
Transplant rejection reaction
–
24
30
Metabolic side
Anorexia
5
3
–
Cachexia
5
–
–
Lower appetite
8
4
5
Dehydration
6
5
6 <
Lower body weight
9
3
Cardiovascular system side
A BP decrease
1
3
8
Elevation of BP
3
18
15
Lab indicators
Hyperkalemia
Less than 1
14
14
Hypokalemia
2
8
Hypomagnesemia
Less than 1
8
8
Hyperglycemia
1
6
7
Hypophosphatemia
Less than 1
9
6
/p>
Hypocalcemia
Less than 1
4
6
Hypercreatininemia
1
10
14
Hypercreatininemia./tr>
Postoperative complications
Postoperative complications
1
12
8
Pain in the postoperative period
2
7
Postoperative wound infection
1 <
11
6
Increased frequency of need for drainage
p> 5
9
Poor wound healing <
Less than 1
5
6
The following are serious adverse events associated with taking valganciclovir that occur with a frequency of less than 5%, not mentioned above.
Blood and lymphatic system disorders: pancytopenia, suppression of bone marrow function, aplastic anemia, febrile neutropenia, potentially life-threatening bleeding associated with the development of thrombocytopenia.
Urinary system disorders: decreased CK.
Nervous system disorders: seizures, psychotic abnormalities, hallucinations, confusion, agitation.
Others: hypersensitivity reactions to valganciclovir.
Serious neutropenia (absolute neutrophil count less than 500 per 1 µl) is more common in patients with CMV retinitis (16%) than in patients receiving valganciclovir (5%) or oral ganciclovir (3%) after organ transplantation until day 100 of the post-transplant period or in patients receiving valganciclovir (10%) until day 200 of the post-transplant period.
Patients receiving both valganciclovir and ganciclovir orally after organ transplantation up to day 100 or day 200 of the post-transplant period, compared to patients with CMV retinitis have a more significant increase in serum creatinine concentration. Impaired renal function is characteristic of patients who have undergone organ transplantation.
The overall safety profile of valganciclovir does not change when the period of prophylactic use is increased to 200 days in patients after renal transplantation from the risk group. In patients receiving valganciclovir up to 200 days for the post-transplant period, compared to patients receiving valganciclovir up to 100 days post-transplant period, there is a slight increase in the incidence of leukopenia.
The incidence of neutropenia, anemia and thrombocytopenia is similar in patients treated up to day 100 and day 200 of the posttransplant period.
Table 3. Laboratory parameters with valganciclovir
Laboratory indices | Percentage of patients (%) with CMV retinitis | Proportion of patients (%) after solid organ transplantation who received treatment until the 100th day of post-transplantation period | |||
Valganciclovir (N=370) | Valganciclovir (N=244) | Ganciclovir (oral) (N=126) | |||
Neutropenia (ACH (cells/μl)) | |||||
Less than 500 | 16 | 5 | 3 | ||
500 – less than 750 | 17 | 3 | 2 | ||
750 – less than 1000 | 17 /td> | 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/p> | 25 | ||
Thrombocytopenia (platelet count (cells/μL)) | |||||
Less than 25,000 | 3 | 0 | 2 | ||
25,000 – less than 50,000 < | 5 | 1 | 3 | ||
50,000 – less than 100,000 | 21 | 18 | 21 | ||
Serum creatinine concentration (mg/dL) | |||||
> 2.5 | 2 | 14 | 21 | ||
Over 1.5-2.5 | 11 | 45 | 47 | ||
Ganciclovir experience
Because valganciclovir converts quickly to ganciclovir, the following are the NPOs described when treated with ganciclovir that were not mentioned above.
Digestive system disorders: dry oral mucosa, cholangitis, dysphagia, belching, esophagitis, fecal incontinence, flatulence, gastritis, gastrointestinal disorders, gastrointestinal bleeding, ulcerative stomatitis, pancreatitis, glossitis, hepatitis, jaundice.
In the body in general: asthenia, bacterial, fungal and viral infections, malaise, mucositis, shivering, sepsis.
Skin and subcutaneous tissue disorders: alopecia, photosensitization reactions, dry skin, sweating, urticaria.
Nervous system disorders: sleep disturbance, amnesia, anxiety, ataxia, coma, emotional disorders, hyperkinesias, hypertonicity, decreased libido, myoclonic twitches, nervousness, somnolence, intellectual disability.
Musculoskeletal system disorders: bone and muscle pain, myasthenic syndrome.
Urogenital system disorders: hematuria, impotence, frequent urination.
Laboratory measures: increased activity of alkaline phosphatase, creatinine phosphokinase, lactate dehydrogenase in plasma, decreased concentration of glucose in blood, hypoproteinemia.
Senses: amblyopia, blindness, ear pain, ocular hemorrhages, pain in the eyeballs, deafness, glaucoma, disorders of taste perception, tinnitus, visual disturbances, non-systemic dizziness, changes in the vitreous body.
Hematopoietic system disorders: eosinophilia, leukocytosis, lymphoadenopathy, splenomegaly, bleeding.
Cardiovascular system disorders: arrhythmias (including ventricular), deep vein thrombophlebitis, migraine, phlebitis, tachycardia, vasodilation.
Respiratory system disorders: nasal sinus congestion.
Endocrine system: diabetes mellitus.
Children
Prevention of CMV infection in patients after organ transplantation
Table 4 shows adverse events (developed up to 28 days after study completion), regardless of their severity and in relation to the drug.
The table includes adverse events with an incidence of ≥10% reported in clinical trials in children aged 3 weeks to 16 years after solid organ transplantation who started valganciclovir within 10 days after transplantation and continued treatment until day 100 of the post-transplant period, and in children after kidney transplantation who started valganciclovir within 10 days after transplantation and continued treatment until day 200 of the post-transplant period.
The overall safety profile of valganciclovir in children does not differ from the safety profile of the drug in adults. Some adverse events were observed more frequently in children than in adults, such as upper respiratory tract infections, fever, abdominal pain, and dysuria, which may reflect the characteristics of the pediatric population. In the pediatric population, there was a slight increase in the frequency of neutropenia, but this did not lead to an increase in the frequency of infections.
In children who have undergone a kidney transplant, increasing the period of prophylactic use to 200 days does not increase the incidence of adverse events.
Table 4: Adverse events occurring with a frequency of ≥10% in children after solid organ transplantation.
Body systems/description of NIHs | Patients (%) of pediatric age after solid organ transplantation < | |||
Treatment with valganciclovir until day 100 of post-transplant period (N=63) | Valganciclovir treatment until day 200 of the posttransplant period (N=56) | |||
Infectious complications | ||||
Urinary tract infections | 6 | p> 34 | ||
Urinary tract infections caused by E. coli | – | 13 | ||
Upper respiratory tract infections | 22 | 34 < | ||
Digestive system side | ||||
Diarrhea | 32 | |||
Constipation | 11 | 5 < | ||
Nausea | 11 | 9 | ||
Abdominal pain | 6 | 18 | ||
Vomiting | 21 | 13 | ||
Blood and lymphatic system side | ||||
Leukopenia | 2 | 25 | ||
Anemia | 14 | 16 | ||
Neutropenia | 13 | 23 | ||
Body side in general | ||||
Fever | 24 | 16 | ||
Lab values | ||||
Hypercreatinemia | 16 | |||
Urinary system disorders | ||||
Hematuria | 6 | 11 | ||
Dysuria < | 2 | 18 | ||
Nervous system disorders | ||||
Tremors | 18 | |||
Headache < | 6 | 21 | ||
Cardiovascular system side | ||||
Increased blood pressure | 22 | 16 | ||
Immune system side | ||||
Transplant rejection reaction | 10 | |||
Severe neutropenia was more common in children who underwent a kidney transplant and received valganciclovir before day 200 of the posttransplant period, compared with children who received valganciclovir before day 100 of the posttransplant period, and compared with adults who underwent a kidney transplant and received valganciclovir before day 100 and 200 of the posttransplant period.
Congenital CMV infection
The limited data available suggest that the safety profile of valganciclovir or ganciclovir up to 6 months for therapy of congenital CMV infection in neonates aged 2 to 31 days does not differ from that of adults. Grade 3 and 4 neutropenia (38%) were the most frequently reported when ganciclovir was used. Only in one case antiviral therapy was withdrawn due to the development of neutropenia. In the remaining cases the neutropenia was correctable without withdrawal of therapy. All the newborns showed an increase in growth and development parameters (height, body weight, average head circumference). Neutropenia, anemia, hepatic dysfunction and diarrhea were the most common adverse events during valganciclovir administration (it should be noted that these adverse events occurred in patients who did not receive the drug, and with a higher frequency than in patients who received it). The only serious treatment-related adverse events were neutropenia and anemia (also more frequently observed in patients not receiving the drug). There were no statistically or clinically significant differences between patients receiving and not receiving valganciclovir in growth and development parameters (height, body weight, mean head circumference).
Table 5. Changes in laboratory parameters with valganciclovir in children
Changes in laboratory indices | Patients (%) of pediatric age after solid organ transplantation | Patients (%) of pediatric age after solid organ transplantation/p> | ||
Valganciclovir treatment on day 100 of post-transplant period (N=63) | Valganciclovir treatment on day 100 of posttransplant period (N=56) | |||
Neutropenia (ACH (cells/μL)) | ||||
Less than 500 | 5 | | ||
500 – less than 750 | 8 | 7 | ||
750 – less than 1000 | 5 | 11 | ||
Anemia (hemoglobin (g/l)) | ||||
Less than 65 | 0 | 0 /p> | ||
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 | 0 | ||
50,000 – less than 100,000 | 3 | | ||
Serum creatinine concentration (mg/dl) | ||||
More than 2.5 | 2 | 5 | ||
Over 1.5-2.5 | 11 | 20 | ||
Postmarketing experience with the drug
The following are the NFRs described in spontaneous reports during post-registration use of ganciclovir. not mentioned in any of the sections above, for which a causal relationship with valganciclovir cannot be excluded. Since valganciclovir is rapidly and largely converted to ganciclovir, these adverse reactions can also develop when treated with valganciclovir: anaphylaxis, decreased fertility in men.
The NTs described during post-registration use of valganciclovir are similar to those observed in clinical trials of valganciclovir and ganciclovir.
Overdose
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
Pregnancy use
Reproductive toxicity studies with valganciclovir have not been repeated because of the rapid and complete conversion of valganciclovir to ganciclovir. Ganciclovir impairs fertility and has teratogenic effects in animals.
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.
Additional information
| Weight | 0.086 kg |
|---|---|
| Shelf life | 3 years. Do not use after the expiration date. |
| Conditions of storage | Store at a temperature not higher than 25 ° C. KEEP OUT OF REACH OF CHILDREN! |
| Manufacturer | Pliva Hrvatska d.o.o., Croatia |
| Medication form | pills |
| Brand | Pliva Hrvatska d.o.o. |
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