Tamovir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAMOVIR (TAMOVIR)

Composition:

Active substance: ganciclovir;

1 vial contains 500 mg of ganciclovir (as ganciclovir sodium);

Excipients: sodium hydroxide solution, hydrochloric acid.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties:

Lyophilisate: white lyophilized powder;

Reconstituted solution: clear, colorless solution.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Nucleosides and nucleotides, excluding reverse transcriptase inhibitors. Ganciclovir. ATC code J05A B06.

Pharmacological properties.

Pharmacodynamics.

Ganciclovir is a synthetic nucleoside analogue of 2’-deoxyguanosine that inhibits replication of herpesviruses both in vitro and in vivo. Human viruses sensitive to ganciclovir include cytomegalovirus (CMV), herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2), human herpesviruses types 6, 7, and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella-zoster virus (Varicella zoster), and hepatitis B virus. Clinical studies have primarily focused on evaluating the efficacy of the medicinal product in patients with cytomegalovirus infection.

In CMV-infected cells, ganciclovir is initially phosphorylated by the viral protein kinase UL97 to ganciclovir monophosphate. Subsequent phosphorylation is carried out by several cellular kinases, forming ganciclovir triphosphate, which undergoes slow intracellular metabolism. This metabolism has been demonstrated in cells infected with human cytomegalovirus and herpes simplex virus, with the intracellular half-life of ganciclovir being 18 hours and 6–24 hours, respectively, after ganciclovir disappears from the extracellular fluid. Since phosphorylation of ganciclovir largely depends on the action of viral kinase, it occurs predominantly in infected cells.

The antiviral activity of ganciclovir is due to inhibition of viral DNA synthesis via: (1) competitive inhibition of deoxyguanosine triphosphate incorporation into DNA by DNA polymerase; (2) incorporation of ganciclovir triphosphate into viral DNA, leading to termination or significant limitation of viral DNA elongation.

Antiviral activity. The in vitro determined antiviral activity (IS50) against cytomegalovirus ranges from 0.08 μM (0.02 μg/mL) to 14 μM (3.5 μg/mL).

Viral resistance. The possibility of developing viral resistance should be considered in patients who repeatedly show poor clinical response or in whom persistent viral shedding occurs during therapy. CMV resistance to ganciclovir may develop after prolonged treatment or prophylaxis with ganciclovir due to selective mutations in the viral kinase gene (UL97) responsible for monophosphorylation of ganciclovir, and/or, less frequently, in the viral polymerase gene (UL54). Viruses containing mutations in the UL97 gene are resistant only to ganciclovir, whereas viruses with mutations in UL54 may exhibit cross-resistance to other antiviral agents targeting viral polymerase.

Children. In a prospective study, 36 pediatric patients (aged 6 months to 16 years) with severe immunodeficiency (HIV-infected and CMV-infected) received intravenous ganciclovir at a dose of 5 mg/kg/day for 2 days, followed by oral ganciclovir for an average of 32 weeks. Ganciclovir was effective, and the toxicity profile was similar to that observed in adults. Reduction in CMV detection by culture or polymerase chain reaction (PCR) was associated with ganciclovir use. Neutropenia was the only severe adverse reaction observed during the study; although no child required discontinuation of treatment, 4 required granulocyte colony-stimulating factor (G-CSF) therapy to maintain absolute neutrophil count above 400 cells/mm³.

In a retrospective study of 122 children (aged 16 days to 18 years, mean age 2.5 years) who underwent liver transplantation, patients received at least 14 days of intravenous ganciclovir at 5 mg/kg twice daily, followed by preventive CMV monitoring using polymerase chain reaction (PCR). CMV risk was considered high in 43 patients and standard in 79. Asymptomatic CMV infection was detected by PCR in 34.4% of patients and was more frequently observed in those with high risk compared to recipients with standard risk (58.1% vs. 21.8%, p = 0.0001). CMV infection occurred in 12 patients (9.8%)—8 in the high-risk group versus 4 in the standard-risk group (p = 0.03). Acute rejection occurred in 3 patients within 6 months after CMV detection, whereas rejection preceded CMV infection in 13 patients. No deaths due to CMV infection were reported. Overall, 38.5% of patients did not receive antiviral drugs after initial postoperative prophylaxis.

In a retrospective analysis, the safety and efficacy of ganciclovir were compared with those of valganciclovir in 92 children (aged 7 months to 18 years, mean age 9 years) who underwent kidney and/or liver transplantation. All children received intravenous ganciclovir 5 mg/kg twice daily for 2 weeks after transplantation. Children treated before 2004 received oral ganciclovir at doses ranging from 30 mg/kg per dose to 1 g per dose three times daily (n = 41), while those treated after 2004 received valganciclovir up to 900 mg once daily (n = 51). The overall incidence of CMV was 16% (15 out of 92 patients). Time to CMV infection was comparable between both groups.

In a randomized controlled trial, 100 neonates (age ≤1 month) with symptomatic congenital CMV infection involving the central nervous system (CNS) received intravenous ganciclovir 6 mg/kg every 12 hours for 6 weeks or no treatment. Of the 100 patients enrolled, 42 met all study criteria and had audiometric results both at baseline and at 6 months of follow-up. Among them, 25 received ganciclovir and 17 received no treatment. Hearing improved or remained normal in 21 out of 25 patients receiving ganciclovir compared to 10 out of 17 in the control group (84% vs. 59%, p = 0.06). Hearing did not worsen in any patient receiving ganciclovir compared to 7 in the control group (p < 0.01). At one year, hearing deteriorated compared to baseline in 5 out of 24 patients receiving ganciclovir and in 13 out of 19 control patients (p < 0.01). Neutropenia occurred in 29 out of 46 patients receiving ganciclovir compared to 9 out of 43 in the control group (p < 0.1). There were 9 deaths during the study: 3 in the ganciclovir group and 6 in the control group. None were related to ganciclovir.

In a phase III randomized controlled trial, 100 neonates (aged 3 to 33 days, mean age 12 days) with severe symptomatic congenital CMV infection involving the CNS received intravenous ganciclovir 6 mg/kg twice daily for 6 weeks (n = 48) or no antiviral treatment (n = 52). Infants receiving ganciclovir showed improved neurodevelopmental outcomes at 6 and 12 months compared to those not receiving antiviral treatment. Although patients receiving ganciclovir had less delay and more normal neurological findings, most still lagged behind normal developmental milestones at 6 weeks, 6 months, or 12 months. Safety was not evaluated in this study.

In a retrospective study, the effect of antiviral therapy on delayed-onset hearing loss in infants with congenital CMV infection (age 4–34 months, mean age 10.3 ± 7.8 months, median age 8 months) was investigated. In a cohort of 21 infants with normal hearing at birth, all participants developed delayed-onset hearing loss. Antiviral therapy consisted of:

• intravenous ganciclovir 5 mg/kg daily for 6 weeks, followed by oral valganciclovir 17 mg/kg twice daily for 6 weeks, then once daily until age 1 year

or

• oral valganciclovir 17 mg/kg twice daily for 12 weeks, then once daily for 9 months.

No child required cochlear implantation, and hearing improved in 83% of cases with hearing impairment at baseline. Neutropenia was the only reported adverse effect, and no patient required treatment discontinuation.

Pharmacokinetics.

Systemic exposure. Systemic exposure (AUC0–∞) observed in adult liver transplant recipients after a single intravenous infusion of ganciclovir 5 mg/kg over 1 hour averaged 50.6 μg×h/mL (CV% 40). In this patient population, the mean maximum plasma concentration (Cmax) was 12.2 μg/mL (CV% 24).

Distribution. The volume of distribution of ganciclovir after intravenous administration correlates with body weight. The steady-state volume of distribution ranges from 0.54 to 0.87 L/kg. Plasma protein binding is 1–2% at ganciclovir concentrations of 0.5 and 51 μg/mL. Ganciclovir penetrates into cerebrospinal fluid, where it may reach concentrations of 24–67% of plasma levels.

Biological transformation. Ganciclovir is not significantly metabolized.

Elimination. Ganciclovir is primarily eliminated via renal excretion through glomerular filtration and active tubular secretion in unchanged form. In patients with normal renal function, more than 90% of the intravenously administered dose is excreted unchanged in urine within 24 hours.

Mean systemic clearance ranges from 2.64 ± 0.38 mL/min/kg (n = 15) to 4.52 ± 2.79 mL/min/kg (n = 6), and renal clearance ranges from 2.57 ± 0.69 mL/min/kg (n = 15) to 3.48 ± 0.68 mL/min/kg (n = 20), accounting for 90–101% of administered ganciclovir. The elimination half-life in individuals without renal impairment ranges from 2.73 ± 1.29 (n = 6) to 3.98 ± 1.78 (n = 8) hours.

Linearity/non-linearity. Intravenous ganciclovir exhibits linear pharmacokinetics in the dose range of 1.6–5.0 mg/kg.

Patients with renal impairment. Total ganciclovir clearance correlates linearly with creatinine clearance. In patients with mild, moderate, and severe renal impairment, mean systemic clearance was 2.1, 1, and 0.3 mL/min/kg, respectively. The elimination half-life is prolonged in patients with impaired renal function. In patients with severe renal impairment, the half-life increases up to 10-fold (for dosage adjustment information in patients with renal impairment, see section "Dosage and administration").

Patients on hemodialysis. Hemodialysis lasting 4 hours reduces plasma ganciclovir concentration by approximately 50% after both intravenous and oral administration.

With intermittent hemodialysis schedules, ganciclovir clearance ranges from 42 to 92 mL/min, and the elimination half-life during dialysis is 3.3–4.5 hours. The fraction of ganciclovir removed during a single hemodialysis session ranges from 50 to 63%. Ganciclovir clearance during continuous dialysis is lower (4.0–29.6 mL/min), but a higher percentage of the administered dose is eliminated between doses.

Patients with hepatic impairment. The safety and efficacy of ganciclovir have not been studied in patients with hepatic dysfunction. Hepatic impairment is not expected to affect ganciclovir pharmacokinetics, as it is primarily eliminated by the kidneys. Therefore, no specific dosage adjustments are recommended (see section "Dosage and administration").

Children. The pharmacokinetics of intravenously administered ganciclovir at a dose of 200 mg/m² were studied in two trials involving patients aged 3 months to 16 years after liver (n = 18) or kidney (n = 25) transplantation, evaluated using a population pharmacokinetic model.

Creatinine clearance (CrCl) was identified as a statistically significant independent variable (covariate) for ganciclovir clearance, and patient height was a statistically significant independent variable for ganciclovir clearance, steady-state volume of distribution, and peripheral volume of distribution. When covariates such as CrCl and height were included in the model, clear differences in ganciclovir pharmacokinetics across different age groups were observed, while age, gender, and type of organ transplant were not significant covariates in these populations. Table 1 presents calculated pharmacokinetic parameters by age group.

Table 1. Pharmacokinetic parameters of ganciclovir after intravenous administration based on body surface area (200 mg/m²) in patients with liver or kidney transplants, presented as medians (minimum–maximum values).

Parameters	Age < 6 years	Age from 6 to < 12 years	Age from ≥ 12 to ≤ 16 years
	n = 17	n = 9	n = 17
Clearance (L/h)	4.23 (2.11–7.92)	4.03 (1.88–7.8)	7.53 (2.89–16.8)
Vcent (L)	1.83 (0.45–5.05)	6.48 (3.34–9.95)	12.1 (3.6–18.4)
Vperiph (L)	5.81 (2.9–11.5)	16.4 (11.3–20.1)	27 (10.6–39.3)
Vss (L)	8.06 (3.35–16.6)	22.1 (14.6–30.1)	37.9 (16.5–57.2)
AUC0–24h (μg×h/mL)	24.3 (14.1–38.9)	40.4 (17.7–48.6)	37.6 (19.2–80.2)
Cmax (μg/mL)	12.1 (9.17–15)	13.3 (4.73–15)	12.4 (4.57–30.8)

In addition, the pharmacokinetic parameters of ganciclovir following intravenous administration according to the dosing regimen approved for adults (5 mg/kg administered as a 1-hour intravenous infusion) were studied in a small group of neonates and children aged 9 months to 12 years with normal renal function (n = 10, mean age 3.1 years). Exposure, defined as mean AUC_0–∞ on Day 1 (n = 10) and AUC_0–12 on Day 14 (n = 7), was 19.4 ± 7.1 and 24.1 ± 14.6 μg×h/mL, with corresponding C_max values of 7.59 ± 3.21 μg/mL (Day 1) and 8.31 ± 4.9 μg/mL (Day 14), respectively. With body weight-based dosing in this study, there was a trend toward lower exposure in younger children. In children under 5 years of age, mean AUC_0–∞ on Day 1 (n = 7) and AUC_0–12h on Day 14 (n = 4) were 17.7 ± 5.5 and 17.1 ± 7.5 μg×h/mL, respectively.

The intravenous ganciclovir dosing regimen based on body surface area and renal function (3 × BSA × CrCl) is derived from the valganciclovir pediatric dosing regimen and provides comparable ganciclovir exposure levels in children from birth to 16 years of age (see Table 2).

Table 2. Modeled* AUC_0–24h (μg × h/mL) values of ganciclovir in children receiving ganciclovir dosed according to the formula: 3 × BSA × CrCl, administered as a 1-hour infusion.

Parameters	Age < 4 months	Age ≥ 4 months to ≤ 2 years	Age > 2 to < 6 years	Age ≥ 6 to < 12 years	Age ≥ 12 to ≤ 16 years	All patients
Number of children in the model	781	384	86	96	126	1,473
Median	55.6	56.9	54.4	51.3	51.4	55.4
Mean value	57.1	58.0	55.1	52.6	51.8	56.4
Minimum	24.9	24.3	16.5	23.9	22.6	16.5
Maximum	124.1	133.0	105.7	115.2	94.1	133.0
Patients with AUC < 40 μg×h/mL	89 (11%)	38 (10%)	13 (15%)	23 (24%)	28 (22%)	191 (13%)
Patients with AUC 40–60 μg×h/mL	398 (51%)	195 (51%)	44 (51%)	41 (43%)	63 (50%)	741 (50%)
Patients with AUC > 60 μg×h/mL	294 (38%)	151 (39%)	29 (34%)	32 (33%)	35 (28%)	541 (37%)

AUC — area under the plasma concentration-time curve.

BSA — body surface area.

CrCl — creatinine clearance.

* Modeling was performed using a validated population pharmacokinetic model for children and demographic data from children who received valganciclovir or ganciclovir treatment in clinical trials (n = 1473 data records).

Elderly patients. Studies in individuals aged 65 years and older have not been conducted.

Clinical characteristics.

Indications.

The medicinal product is indicated for adults and adolescents aged 12 years and older for:

• treatment of cytomegalovirus (CMV) infection in patients with immunodeficiency;
• prevention of cytomegalovirus infection through preemptive therapy in patients with drug-induced immunosuppression (e.g., after organ transplantation or cancer chemotherapy).

The medicinal product is also indicated for children from birth onwards for:

• prevention of cytomegalovirus infection through universal prophylaxis in patients with drug-induced immunosuppression (e.g., after organ transplantation or cancer chemotherapy).

Official guidelines on the appropriate use of antiviral agents should be followed.

Contraindications.

• Hypersensitivity to ganciclovir, valganciclovir, or to any of the excipients of the medicinal product.
• Breastfeeding period.

Safety precautions.

Precautions regarding preparation of ganciclovir solution

Since ganciclovir is considered potentially teratogenic and carcinogenic in humans, the medicinal product should be handled with care.

Inhalation or direct contact with the powder contained in vials, as well as direct contact with the reconstituted solution and skin or mucous membranes, should be avoided. The medicinal product solution is alkaline (pH approximately 11). Preparation of the solution should be performed wearing polyethylene gloves and protective goggles.

If ganciclovir comes into contact with skin or mucous membranes, the affected area should be thoroughly washed with soap and water; eyes should be rinsed with sterile or running water if sterile water is not available.

Interaction with other medicinal products and other types of interactions.

Pharmacokinetic interactions.

Probenecid. When probenecid is administered concomitantly with oral ganciclovir, a statistically significant reduction in renal clearance of ganciclovir (20%) has been observed, leading in turn to a statistically significant increase in exposure (40%). These changes are consistent with a mechanism of interaction involving competition for renal tubular secretion. Therefore, patients receiving this combination should be closely monitored for signs of ganciclovir toxicity.

Didanosine. It has been established that concomitant administration of didanosine with intravenous or oral ganciclovir results in consistently increased plasma concentrations of didanosine. When ganciclovir is administered intravenously at doses of 5–10 mg/kg per day, the AUC of didanosine increases by 38–67%. No clinically significant changes in ganciclovir concentrations were observed. However, due to the increased plasma concentration of didanosine in the presence of ganciclovir, patients receiving this combination should be closely monitored for signs of didanosine toxicity (see section "Special precautions for use").

Other antiretroviral agents: Cytochrome P450 isoenzymes are not involved in the metabolism of ganciclovir. As a result, pharmacokinetic interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors are not expected.

Pharmacodynamic interactions.

Imipenem/cilastatin. Seizures have been observed in patients receiving ganciclovir and imipenem/cilastatin concomitantly. These agents should be used in combination with ganciclovir only if the expected benefit outweighs the risk (see section "Special precautions for use").

Zidovudine. Both zidovudine and ganciclovir may cause neutropenia and anemia. A pharmacodynamic interaction may occur when these agents are used concomitantly. Some patients may poorly tolerate concomitant therapy with full doses of these agents (see section "Special precautions for use").

Other possible interactions.

Increased toxicity may occur when ganciclovir is administered concomitantly with other agents that may have myelosuppressive effects or cause renal impairment. These include: antibacterial agents (e.g., dapsone, pentamidine, flucytosine, amphotericin B, trimethoprim/sulfamethoxazole); immunosuppressants (cyclosporine, tacrolimus, mycophenolate mofetil); antineoplastic agents (e.g., vincristine, vinblastine, doxorubicin, and hydroxyurea); nucleosides (including zidovudine, stavudine, and didanosine); nucleotide analogs (including tenofovir, adefovir). Therefore, these medicinal products should be used concomitantly with ganciclovir only when the potential benefit of treatment outweighs this risk (see section "Special precautions for use").

Children.

Interaction studies have been conducted exclusively in adults.

Special precautions for use.

Cross-sensitivity risk.

Due to the similarity in chemical structure between ganciclovir, acyclovir, and penciclovir, cross-hypersensitivity reactions may occur among these agents. The medicinal product should be used with caution in patients with known hypersensitivity to acyclovir or penciclovir (or their inactive forms (prodrugs) valganciclovir or famciclovir, respectively).

Mutagenicity, teratogenicity, carcinogenicity, fertility, and contraception.

Patients should be informed of the potential risk to the fetus before initiating treatment. In animal studies, ganciclovir demonstrated mutagenic, teratogenic, aspermatogenic, and carcinogenic effects, as well as suppression of fertility. Based on clinical and preclinical findings, ganciclovir is considered likely to cause temporary or permanent inhibition of spermatogenesis (see sections "Use during pregnancy or breastfeeding" and "Side effects").

Ganciclovir has potential teratogenic and carcinogenic effects and may cause congenital malformations and malignant neoplasms.

Women of childbearing potential should be advised to use reliable contraceptive methods during treatment and for 30 days after completion of therapy. Men are recommended to use barrier contraception during treatment and for at least 90 days after its completion, unless it has been established that the female partner has no risk of pregnancy (see sections "Use during pregnancy or breastfeeding" and "Side effects").

Use in children and adolescents requires particularly careful consideration due to the potential for delayed carcinogenicity and toxic effects on reproductive function. The benefits of treatment should be carefully evaluated in each individual case, with a clear assessment of risks. Appropriate treatment guidelines should be followed.

Myelosuppression risk.

The medicinal product should be used with caution in patients with pre-existing hematological cytopenia or a history of hematological cytopenia associated with drug use, as well as in patients receiving radiotherapy.

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, myelosuppression, and aplastic anemia have been observed in patients treated with ganciclovir. The medicinal product should not be administered if the absolute neutrophil count is less than 500 cells/µL, platelet count is less than 25,000 cells/µL, or hemoglobin level is less than 8 g/dL (see sections "Dosage and administration" and "Side effects").

Complete blood count monitoring, including platelet count, is recommended during treatment. Enhanced hematological monitoring may be necessary for patients with renal impairment, as well as for newborns and infants (see section "Side effects"). During the first 14 days of treatment, leukocyte counts (preferably with differential count) should be assessed every other day; in patients with low baseline neutrophil counts (<1,000 neutrophils/µL), those who experienced leukopenia during prior therapy with myelotoxic agents, and those with renal impairment, monitoring should be performed daily.

Patients who develop severe leukopenia, neutropenia, anemia, and/or thrombocytopenia should be considered for treatment with hematopoietic growth factors and/or interruption of ganciclovir therapy (see sections "Dosage and administration" and "Side effects").

Use in patients with renal impairment.

Patients with impaired renal function are at increased risk of toxicity (particularly hematological toxicity).

Dose adjustment of the medicinal product is recommended in such patients (see sections "Dosage and administration" and "Pharmacokinetics").

Use with other medicinal products.

Seizures have been reported in patients receiving imipenem/cilastatin and ganciclovir. Therefore, the medicinal product should not be used concomitantly with imipenem/cilastatin unless the potential benefits outweigh the possible risks (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ganciclovir with didanosine or agents with myelosuppressive (e.g., zidovudine) or nephrotoxic effects should be closely monitored, as co-administration may lead to additive toxicity (see section "Interaction with other medicinal products and other forms of interaction").

Excipients.

One vial of the 500 mg medicinal product contains 2 mmol (43 mg) of sodium. This should be taken into account if the patient requires sodium intake restriction.

Use during pregnancy or breastfeeding.

Fertility. In a small clinical study involving kidney transplant patients who received valganciclovir for cytomegalovirus (CMV) infection prophylaxis for up to 200 days, an effect of valganciclovir/ganciclovir on spermatogenesis was demonstrated, with reduced sperm concentration and motility observed after completion of treatment. This effect was reversible, and approximately six months after discontinuation of valganciclovir, mean sperm concentration and motility returned to levels comparable to those in untreated control groups.

In animal studies, ganciclovir caused fertility disturbances in male and female mice and suppressed spermatogenesis and induced testicular atrophy in mice, rats, and dogs at doses considered clinically relevant.

Based on clinical and preclinical findings, ganciclovir is considered likely to cause temporary or permanent suppression of spermatogenesis in humans (see section "Special precautions for use").

Pregnancy.

There are no safety data on the use of ganciclovir in pregnant women. However, ganciclovir rapidly crosses the placental barrier. Animal studies have shown reproductive toxicity and teratogenic effects with ganciclovir administration. The medicinal product should not be used during pregnancy except when clinically necessary and when the benefit to the woman outweighs the potential teratogenic risk to the fetus.

Contraception for men and women.

Women of childbearing potential should be advised to use effective contraceptive methods during treatment and for at least 30 days after therapy, due to the potential for reproductive toxicity and teratogenicity. Male patients should be advised to use barrier contraception during treatment and for at least 90 days after ganciclovir therapy, unless it has been established that the female partner has no risk of pregnancy.

Lactation period.

It is unknown whether ganciclovir is excreted in human breast milk; however, ganciclovir may be excreted in breast milk and may cause serious adverse reactions in the nursing infant. Animal data indicate that ganciclovir is excreted in milk during lactation in rats. Breastfeeding should be discontinued during treatment with the medicinal product.

Ability to affect reaction speed when driving or operating machinery.

Ganciclovir may substantially affect the ability to drive or operate machinery (see section "Side effects").

Method of Administration and Dosage

The medicinal product is intended for intravenous administration only, preferably using a plastic cannula into a vein with adequate blood flow. Rapid or bolus intravenous injections must not be used! The toxicity of ganciclovir may increase due to excessively high plasma levels. Intramuscular and subcutaneous injections of the medicinal product may cause severe tissue irritation due to the high pH (9–11) of the ganciclovir solution.

Dosage.

Treatment of CMV infection.

Adults and adolescents aged 12 years and older with normal renal function:

• Induction therapy: administer the medicinal product at a dose of 5 mg/kg as a 1-hour intravenous infusion every 12 hours (10 mg/kg/day) for 14–21 days.
• Maintenance therapy: for patients whose immune system has not recovered and who remain at risk of relapse, maintenance therapy may be administered — 5 mg/kg as a 1-hour intravenous infusion once daily for 7 days, or 6 mg/kg once daily for 5 days per week. The duration of maintenance therapy should be determined individually, following current treatment guidelines.
• Treatment of progressive disease: in any patient with progression of CMV infection either during maintenance therapy or after discontinuation of ganciclovir, treatment may be reinitiated according to the induction regimen.

Children from birth to 12 years of age.

Current information on the use of the medicinal product in children is provided in the section "Pharmacological Properties"; however, no dosage recommendations can be given.

Prevention of CMV infection through prophylactic therapy.

Adults and adolescents aged ≥ 12 years with normal renal function:

• Induction therapy: administer the medicinal product at a dose of 5 mg/kg as a 1-hour intravenous infusion every 12 hours for 7–14 days.
• Maintenance therapy: administer the medicinal product at a dose of 5 mg/kg as a 1-hour intravenous infusion once daily for 7 days, or at a dose of 6 mg/kg once daily for 5 days per week. The duration of prophylaxis should be determined based on the risk of CMV infection; current treatment guidelines should be followed.

Children from birth to 12 years of age.

Available data on the use of the medicinal product in children are presented in the section "Pharmacological Properties"; however, no dosage recommendations can be provided.

Prevention of CMV infection through universal prophylaxis.

Adults and adolescents aged 16 years and older.

Administer the medicinal product at a dose of 5 mg/kg as a 1-hour intravenous infusion once daily for 7 days, or at a dose of 6 mg/kg once daily for 5 days per week. The duration of prophylaxis should be determined individually based on the risk of CMV infection; current treatment guidelines should be followed.

Children from birth to ≤ 16 years of age.

Current information on the use of the medicinal product in children is provided in the section "Pharmacological Properties"; however, no dosage recommendations can be given.

The recommended single daily dose of ganciclovir administered as a 1-hour intravenous infusion should be calculated based on body surface area (BSA), determined using the Mosteller formula, and creatinine clearance (CrCl), determined using the Schwartz formula. Calculation formulas are provided below. The duration of universal prophylaxis should be determined individually, taking into account the risk of developing CMV infection.

Pediatric dose (mg) = 3 × BSA × CrCl (see formulas for BSA by Mosteller and CrCl by Schwartz below).

If the creatinine clearance calculated by the Schwartz formula exceeds 150 mL/min/1.73 m², the maximum value to be used in the formula is 150 mL/min/1.73 m².

where k = 0.33 for patients < 1 year of age with low body weight after birth, 0.45 for patients < 2 years of age, 0.55 for boys aged 2 to < 13 years and girls aged 2 to 16 years, and 0.7 for boys aged 13 to 16 years. For patients aged 16 years and older, adult dosage recommendations should be applied.

The k values listed above are based on serum creatinine determination by the Jaffe method and may require adjustment if enzymatic methods are used.

Regular monitoring of serum creatinine levels, height, and body weight is recommended, and the dose should be adjusted as necessary.

Patients with impaired renal function.

Children (from birth to 16 years of age) with impaired renal function receiving a prophylactic dose of ganciclovir calculated as 3 × BSA × CrCl do not require additional dose adjustment, as this dose is already adjusted for creatinine clearance.

For patients aged 12 years and older with impaired renal function receiving prophylactic therapy or CMV infection treatment at a dose based on body weight, the ganciclovir dose should be adjusted according to creatinine clearance as shown in the table below.

Dose adjustment for patients with impaired renal function

Creatinine clearance (mL/min)	Induction dose	Maintenance dose
> 70	5 mg/kg every 12 hours	5 mg/kg per day
50–69	2.5 mg/kg every 12 hours	2.5 mg/kg per day
25–49	2.5 mg/kg per day	1.25 mg/kg per day
10–24	1.25 mg/kg per day	0.625 mg/kg per day
< 10	1.25 mg/kg 3 times/week after hemodialysis	0.625 mg/kg 3 times/week after hemodialysis

Creatinine clearance (ml/min) can be calculated from serum creatinine using the following formula:

(140 – age [years] × body weight [kg])

For men = 72 × 0.011 × serum creatinine [μmol/L]

For women = 0.85 × value for men.

Since dose adjustment is recommended for patients with impaired renal function, serum creatinine levels or calculated creatinine clearance should be monitored.

Patients with hepatic impairment.

The safety and efficacy of ganciclovir have not been studied in patients with hepatic impairment (see section "Pharmacological properties").

Patients with severe leukopenia, neutropenia, anemia, thrombocytopenia, and pancytopenia (see section "Special precautions" before initiation of therapy).

If significant decreases in blood cell counts occur during treatment, consider treatment with hematopoietic growth factors and/or interruption of ganciclovir therapy (see "Special precautions" and "Adverse reactions").

Elderly patients.

The efficacy and safety of ganciclovir in elderly patients have not been studied. Since renal function is often reduced in elderly patients, the drug should be administered with consideration of renal function (see section "Pharmacological properties").

Children.

Experience with treatment of children under 12 years of age is limited (see sections "Special precautions" and "Pharmacokinetics"). Reported adverse reactions were similar to those observed in adults. However, ganciclovir use in children requires extreme caution due to the potential for long-term carcinogenic and reproductive toxicity. The benefit of treatment must outweigh the risks. The drug is not indicated for the treatment of congenital and neonatal CMV infection.

Method of administration.

Caution!

The drug must be administered by intravenous infusion over 1 hour at a concentration not exceeding 10 mg/mL. Rapid or bolus intravenous injection must not be used, as the toxicity of ganciclovir may increase due to excessively high plasma levels.

The drug must not be administered by intramuscular or subcutaneous injection, as this may cause severe tissue irritation due to the high pH (~11) of the ganciclovir solution (see section "Adverse reactions").

Recommended doses, frequency, or infusion rate of the drug must not be exceeded.

The drug is a lyophilisate (powder) for solution for infusion. After reconstitution, it is a clear, colorless solution.

Infusion should be administered into a vein with adequate blood flow, preferably through a plastic cannula.

Preparation of the concentrate must be performed under aseptic conditions.

Preparation of reconstituted concentrate:

1. Remove the cap to access the center of the rubber stopper.
2. Draw 10 mL of water for injection into a syringe and slowly transfer it into the vial through the center of the rubber stopper; do not use bacteriostatic water for injection containing parabens (parahydroxybenzoates), as they are incompatible with the drug,
3. Gently shake the vial to ensure complete wetting of the lyophilisate.
4. Gently rotate the vial in circular motions for several minutes to obtain a fully reconstituted solution.
5. Carefully inspect the reconstituted solution for the presence of mechanical particulates before dilution with a compatible diluent.

The reconstituted concentrate is a clear, colorless solution.

Preparation of the final diluted infusion solution.

Withdraw the required volume calculated according to the patient's body weight from the vial and further dilute in 100 mL of an appropriate infusion diluent.

Infusion solutions with a concentration higher than 10 mg/mL are not recommended.

The following infusion solutions are compatible with the drug: 0.9% sodium chloride solution; 5% dextrose solution; Ringer's solution; and lactated Ringer's solution.

The drug must not be mixed with other intravenous preparations.

The diluted solution must not be infused for longer than 1 hour.

The solution reconstituted with water for injection has demonstrated chemical and physical stability for 12 hours when stored at 25°C. The reconstituted solution must not be refrigerated or frozen.

From a microbiological standpoint, the reconstituted solution should be used immediately. Otherwise, the duration and conditions of storage prior to use are the responsibility of the user.

The diluted infusion solution has demonstrated chemical and physical stability for 24 hours at 2–8°C. The ready-to-use infusion solution must not be frozen. From a microbiological standpoint, the ready-to-use infusion solution of the drug should be used immediately. Otherwise, the duration and conditions of storage prior to use are the responsibility of the user. In this case, the shelf life must not exceed 24 hours at 2–8°C, provided that reconstitution and dilution were performed under controlled and validated aseptic conditions.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Children.

Experience with treatment of children under 12 years of age is limited — see sections "Pharmacological properties", "Indications", "Interaction with other medicinal products and other forms of interaction", "Special precautions", "Dosage and administration", "Overdose", "Adverse reactions".

Overdose.

Symptoms.

Cases of ganciclovir overdose, some with fatal outcomes, have been reported during clinical trials and post-marketing use. In these cases, either no adverse reactions occurred or at least one of the following adverse reactions occurred:

• hematological toxicity: myelosuppression, including pancytopenia, leukopenia, neutropenia, granulocytopenia, bone marrow aplasia;
• hepatotoxicity: hepatitis, liver function disorders;
• renal toxicity: increased hematuria in patients with pre-existing renal impairment, acute renal failure, elevated creatinine levels;
• gastrointestinal toxicity: abdominal pain, diarrhea, vomiting;
• neurotoxicity: generalized tremor, seizures.

Treatment.

Ganciclovir is removed during hemodialysis; therefore, hemodialysis may be used to reduce its plasma levels in patients who have received an excessive dose (see section "Pharmacokinetics").

Patients with renal impairment: Overdose of ganciclovir is expected to increase renal toxicity in patients with renal impairment (see section "Special precautions").

Children: Specific information is lacking.

Adverse Reactions.

Safety Profile.

Note: Valganciclovir is an inactive prodrug of ganciclovir, and adverse reactions associated with valganciclovir use are expected to occur with ganciclovir use as well. Ganciclovir for oral administration is no longer manufactured; however, adverse reactions reported during its use are also expected in patients receiving intravenous ganciclovir. Therefore, the list includes adverse reactions observed during intravenous or oral administration of ganciclovir or valganciclovir.

In patients treated with ganciclovir/valganciclovir, the most serious and common adverse reactions were neutropenia, anemia, and thrombocytopenia. Other adverse reactions are listed below.

The frequency of adverse reactions was determined based on pooled data from HIV-infected patients (n = 1704) receiving maintenance therapy with ganciclovir or valganciclovir. Exceptions are agranulocytosis, granulocytopenia, and anaphylactic reaction; frequency data for these were obtained from post-marketing experience. Adverse reactions are listed by organ system according to MedDRA [Medical Dictionary for Regulatory Activities]. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000).

The overall safety profile of ganciclovir/valganciclovir is comparable between HIV-infected patients and organ transplant recipients, except that retinal detachment was observed only in HIV-infected patients with CMV retinitis. However, there are differences in the frequency of certain reactions. Intravenous ganciclovir is associated with a lower risk of diarrhea compared to oral valganciclovir. Fever, candidiasis, depression, severe neutropenia (ANC [absolute neutrophil count] < 500/µL), and skin reactions occurred more frequently in HIV-infected patients. Renal and hepatic dysfunction were more frequently observed in organ transplant recipients.

Infections and infestations:

Very common — Candida infections, including oral candidiasis, upper respiratory tract infections; common — sepsis, influenza, cellulitis, urinary tract infection.

Blood and lymphatic system disorders:

Very common — neutropenia, anemia; common — thrombocytopenia, leukopenia, pancytopenia; uncommon — bone marrow failure; rare — agranulocytosis*, aplastic anemia, granulocytopenia*.

Immune system disorders:

Common — hypersensitivity; uncommon — anaphylactic reactions*.

Metabolism and nutrition disorders:

Very common — decreased appetite; common — weight loss.

Psychiatric disorders:

Common — depression, confusion, anxiety; uncommon — agitation, psychotic disorders, thinking abnormalities, hallucinations.

Nervous system disorders:

Very common — headache; common — insomnia, dysgeusia (taste disturbance), hypoesthesia, paresthesia, peripheral neuropathy, seizures, dizziness; uncommon — tremor.

Eye disorders:

Common — corneal edema, retinal detachment, floaters, eye pain, visual disturbance, conjunctivitis.

Ear and labyrinth disorders:

Common — ear pain; uncommon — deafness.

Cardiac disorders:

Uncommon — arrhythmia.

Vascular disorders:

Common — hypotension.

Respiratory, thoracic and mediastinal disorders:

Very common — dyspnea, cough.

Gastrointestinal disorders:

Very common — diarrhea, nausea, vomiting, abdominal pain; common — upper abdominal pain, constipation, flatulence, dysphagia, dyspepsia, bloating, oral ulcers, pancreatitis.

Hepatobiliary disorders:

Common — increased plasma alkaline phosphatase and AST [aspartate aminotransferase], liver function abnormalities, increased plasma ALT [alanine aminotransferase].

Skin and subcutaneous tissue disorders:

Very common — dermatitis; common — night sweats, pruritus, rash, alopecia; uncommon — dry skin, urticaria.

Musculoskeletal and connective tissue disorders:

Common — myalgia, arthralgia, back pain, muscle spasms.

Renal and urinary disorders:

Common — decreased creatinine clearance, renal function abnormalities, increased plasma creatinine; uncommon — hematuria, renal failure.

Reproductive system and breast disorders:

Uncommon — male infertility.

General disorders and administration site conditions:

Very common — chills, asthenia; common — pain, chills, malaise, fatigue, injection site reactions; uncommon — chest pain.

* Frequency data obtained from post-marketing experience. Frequencies for all other adverse reactions were determined from clinical trial data.

Description of selected adverse reactions.

Neutropenia.

The risk of neutropenia cannot be predicted based on pre-treatment neutrophil counts. Neutropenia usually occurs during the first or second week of induction therapy and after cumulative doses ≤ 200 mg/kg. Cell counts usually normalize within 2–5 days after discontinuation or dose reduction of ganciclovir (see section "Dosage and Administration").

Severe neutropenia.

Severe neutropenia occurred more frequently in HIV-infected patients (14%) receiving maintenance therapy with valganciclovir, oral ganciclovir, or intravenous ganciclovir (n = 1704) compared to organ transplant recipients receiving valganciclovir or oral ganciclovir. In patients receiving valganciclovir or oral ganciclovir up to day 100 post-transplantation, the frequency of severe neutropenia was 5% and 3%, respectively. In patients receiving valganciclovir up to day 200 post-transplantation, the frequency of severe neutropenia was 10%.

Thrombocytopenia.

Patients with low baseline platelet counts (< 100,000/µL) have an increased risk of developing thrombocytopenia. Patients with iatrogenic immunosuppression due to immunosuppressive therapy have a higher risk of thrombocytopenia than patients with AIDS (see section "Dosage and Administration"). Severe thrombocytopenia may be associated with life-threatening bleeding.

Seizures.

Seizures have been observed in patients receiving concomitant imipenem-cilastatin and ganciclovir (see sections "Dosage and Administration" and "Interaction with Other Medicinal Products and Other Forms of Interactions").

Retinal detachment.

This adverse reaction has been reported only in clinical trials involving HIV-infected patients receiving ganciclovir for the treatment of CMV retinitis.

Injection site reactions.

Injection site reactions are common in patients receiving ganciclovir. The drug should be administered according to the recommendations in the section "Dosage and Administration" to minimize the risk of local tissue irritation.

Paediatric population.

Formal safety studies of ganciclovir in children ≤ 12 years of age have not been conducted. However, based on experience with valganciclovir, the inactive prodrug of ganciclovir, the overall safety profile of the active form is similar in children and adults. Neutropenia occurs more frequently in children, but there is no correlation between neutropenia and infections in children. The higher risk of cytopenias in neonates and infants requires careful monitoring of blood cell counts in these age groups.

Data on the use of valganciclovir or ganciclovir in neonates or infants with HIV/AIDS or symptomatic congenital CMV infection are limited; however, the safety profile corresponds to the known safety profile of valganciclovir/ganciclovir.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Incompatibilities.

Ganciclovir must not be mixed with other medicinal products intended for intravenous administration. Ganciclovir precipitates in solutions containing parabens.

Packaging.

500 mg in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Mefar Ilac San. A.Ş., Turkey /
Mefar Ilac San. A.S., Turkey.

Manufacturer's address and location of operations.

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey /
Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.

Marketing Authorization Holder.

LLC "WORLD MEDICINE", Ukraine /
WORLD MEDICINE, LLC, Ukraine.