Ganciclovir-pharmex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GANCICLOVIR-PHARMEX (GANCICLOVIR-PHARMEX)

Composition:

Active substance: ganciclovir;

1 vial contains 500 mg of ganciclovir (as ganciclovir sodium salt).

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physico-chemical characteristics: lyophilized porous mass or powder, white or almost white.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Nucleosides and nucleotides, excluding reverse transcriptase inhibitors. Ganciclovir.

ATC code J05A B06.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Ganciclovir is a synthetic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpesviruses both in vitro and in vivo. Ganciclovir is active against the following human viruses: 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, varicella zoster virus (Varicella zoster), and hepatitis B virus. Clinical studies have been limited to evaluating the efficacy of the drug in patients with cytomegalovirus infection.

In CMV-infected cells, ganciclovir is 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 is primarily dependent on the action of the viral kinase, it occurs predominantly in infected cells.

The antiviral effect of ganciclovir is due to inhibition of viral DNA synthesis by: competitive inhibition of deoxyguanosine triphosphate incorporation into DNA by DNA polymerase; and incorporation of ganciclovir triphosphate into viral DNA, leading to termination or severe limitation of viral DNA elongation.

Antiviral Activity

The in vitro antiviral activity (IC50) of ganciclovir against cytomegalovirus ranges from 0.08 µM (0.02 µg/mL) to 14 µM (3.5 µg/mL).

Clinical Efficacy and Safety

Viral Resistance

The possibility of viral resistance development should be considered in patients who show poor clinical response upon re-evaluation 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 ganciclovir monophosphorylation, 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 are resistant to ganciclovir but may also exhibit cross-resistance to other antiviral agents targeting viral polymerase, and vice versa.

Children

In a prospective study, 36 pediatric patients (aged 6 months to 16 years) with severe immunodeficiency (HIV and CMV infection) received intravenous ganciclovir at a dose of 5 mg/kg/day for 2 days, followed by oral ganciclovir for a mean duration of 32 weeks. Ganciclovir was effective, and the toxicity profile was similar to that 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 children required granulocyte colony-stimulating factor (G-CSF) therapy to maintain an 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, ganciclovir was administered for at least 14 days at a dose of 5 mg/kg intravenously twice daily, followed by CMV prophylactic monitoring using polymerase chain reaction (PCR). CMV risk was considered high in 43 patients and normal in 79. Asymptomatic CMV infection was detected by PCR in 34.4% of patients and occurred more frequently in those at higher risk compared to recipients at normal risk (58.1% vs. 21.8%, p = 0.0001). CMV infection developed in 12 patients (9.8%) (8 in the high-risk group vs. 4 in the normal-risk group, p = 0.03). Acute rejection occurred in 3 patients within 6 months after CMV detection, while rejection preceded CMV infection in 13 patients. No CMV-related deaths occurred. Overall, 38.5% of patients did not receive antiviral therapy 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/dose to 1 g/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 infection was 16% (15 out of 92 patients). Time to onset of CMV infection was comparable between both groups.

In a randomized controlled trial, 100 newborns (age ≤1 month) with symptomatic congenital CMV infection involving the central nervous system (CNS) received ganciclovir 6 mg/kg intravenously every 12 hours for 6 weeks or no treatment. Of the 100 patients enrolled, 42 met all study criteria and had audiometric assessments at baseline and at 6 months of follow-up. Of these, 25 received ganciclovir and 17 received no treatment. Hearing improved or remained normal compared to baseline at 6 months in 21 out of 25 patients receiving ganciclovir versus 10 out of 17 in the control group (84% vs. 59%, p = 0.06). Hearing did not worsen compared to baseline at 6 months in any patient receiving ganciclovir, compared to 7 patients in the control group (p < 0.01). At one year, hearing worsened compared to baseline in 5 out of 24 patients receiving ganciclovir and in 13 out of 19 control group patients (p < 0.01). Neutropenia was observed in 29 out of 46 patients receiving ganciclovir versus 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 of the deaths were related to the study drug.

In a Phase III randomized controlled trial, 100 newborns aged 3 to 33 days (mean age 12 days) with severe symptomatic congenital CMV infection involving the CNS received ganciclovir 6 mg/kg intravenously 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 therapy. 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 of age. Safety was not assessed in this study.

In a retrospective study, the effect of antiviral therapy on delayed-onset hearing loss in infants with congenital CMV infection was evaluated (age range 4–34 months, mean age 10.3 ± 7.8 months, median age 8 months). Of 21 infants with normal hearing at birth, all 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 loss at baseline. Neutropenia was the only reported adverse effect, and no patient required discontinuation of therapy.

Pharmacokinetics

Systemic exposure (AUC0–∞) observed in adult liver transplant recipients after a single 1-hour intravenous infusion of ganciclovir at 5 mg/kg 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.

Metabolism

Ganciclovir is minimally metabolized.

Excretion

Ganciclovir is primarily eliminated unchanged by renal excretion via glomerular filtration and active tubular secretion. 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

Intravenously administered ganciclovir exhibits linear pharmacokinetics in the dose range of 1.6–5.0 mg/kg.

Pharmacokinetics in Special Patient Populations

Patients with Renal Impairment

Total ganciclovir clearance is linearly correlated 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. Elimination half-life of ganciclovir is prolonged in patients with renal dysfunction. In patients with severe renal impairment, the half-life is increased nearly 10-fold (for dosage adjustment in patients with renal impairment, see section "Dosage and Administration").

Patients on Hemodialysis

Four-hour hemodialysis reduces plasma ganciclovir concentrations by approximately 50% after both intravenous and oral administration.

With intermittent hemodialysis, ganciclovir clearance ranges from 42 to 92 mL/min, and the half-life during dialysis is 3.3–4.5 hours. The fraction of ganciclovir removed during a single hemodialysis session is 50–63%. With continuous dialysis, ganciclovir clearance 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 transplantation (n = 18) and kidney transplantation (n = 25), analyzed 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 among different age groups were observed, while age, sex, and type of organ transplant were not significant covariates in these populations. Calculated pharmacokinetic parameters by age group are presented in Table 1.

Table 1.

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

	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. When dosing was based on body weight 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 pediatric valganciclovir dosing regimen and provides comparable ganciclovir exposure in children from birth to 16 years of age (see Table 2).

Table 2.

Modelled* AUC_0–24h (μg×h/mL) values of ganciclovir in children receiving ganciclovir at a dose calculated using the formula 3 × BSA × CrCl, administered as a 1-hour infusion.

Parameters	Age < 4 mos.	Age ≥ 4 mos. to ≤ 2 yrs.	Age > 2 to < 6 yrs.	Age ≥ 6 to < 12 yrs.	Age ≥ 12 to ≤ 16 yrs.	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	57.1	58.0	55.1	52.6	51.8	56.4
Min.	24.9	24.3	16.5	23.9	22.6	16.5
Max.	124.1	133.0	105.7	115.2	94.1	133.0
Patients with AUC < 40 μg × hr/mL	89 (11%)	38 (10%)	13 (15%)	23 (24%)	28 (22%)	191 (13%)
Patients with AUC 40–60 μg × hr/mL	398 (51%)	195 (51%)	44 (51%)	41 (43%)	63 (50%)	741 (50%)
Patients with AUC > 60 μg × hr/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. Max. — maximum. Min. — minimum. * Modeling was performed using a validated population pharmacokinetic model in children and demographic data from children who received valganciclovir or ganciclovir treatment in clinical studies (n = 1,473 data records).

Geriatric patients

Studies involving individuals aged 65 years and older have not been conducted.

Clinical characteristics.

Indications

Ganciclovir-Farmex is indicated for adults and adolescents ≥ 12 years of age for:

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

Ganciclovir-Farmex is also indicated for children from birth for:

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

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

Contraindications

Hypersensitivity to ganciclovir, valganciclovir, or to any other component of the medicinal product.

Breastfeeding.

Special precautions

Precautions during preparation of ganciclovir solution

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

Inhalation or direct contact with the powder contained in vials, or direct contact with the reconstituted solution and skin or mucous membranes should be avoided. Ganciclovir solution is alkaline (pH approximately 11). This procedure should be performed wearing polyethylene gloves and protective goggles.

If ganciclovir comes into contact with skin or mucous membranes, the affected area must 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 forms of interaction

Pharmacokinetic interactions

Probenecid. Administration of probenecid with oral ganciclovir results in a statistically significant reduction in renal clearance of ganciclovir, leading in turn to a statistically significant increase in exposure. Similar effects are expected when intravenous ganciclovir and probenecid are administered concomitantly. Therefore, patients receiving both probenecid and ganciclovir should be closely monitored for ganciclovir toxicity.

Didanosine. It has been established that concomitant administration of didanosine and ganciclovir leads to sustained increases in plasma concentrations of didanosine. When ganciclovir is administered intravenously at doses of 5–10 mg/kg/day, the AUC of didanosine increases by 38–67%. No clinically significant changes in ganciclovir concentrations were observed. However, due to increased plasma concentrations of didanosine in the presence of ganciclovir, patients should be closely monitored for didanosine toxicity (see section "Special instructions for use").

Other antiretroviral agents. Cytochrome P450 isoenzymes are not involved in the metabolism of ganciclovir. Therefore, 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 administered in combination with ganciclovir only when potential benefits outweigh the risks (see section "Special instructions for use").

Zidovudine. Both zidovudine and ganciclovir can cause neutropenia and anemia. A pharmacodynamic interaction may occur during concomitant use of these medicinal products. Some patients may tolerate poorly the concomitant treatment with full doses of these agents (see section "Special instructions for use").

Other possible interactions

Increased toxicity may occur when ganciclovir is administered concomitantly with other medicinal products that may have myelosuppressive effects or lead to 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 administered concomitantly with ganciclovir only when the potential benefit of treatment outweighs the risk (see section "Special instructions for use").

Children

Interaction studies have been conducted exclusively in adults.

Special precautions for use.

Cross-sensitivity

Due to the similarity in chemical structure between ganciclovir, acyclovir, and penciclovir, cross-sensitivity reactions with these drugs are possible. Therefore, caution should be exercised when administering ganciclovir to patients with known hypersensitivity to acyclovir or penciclovir (or their inactive prodrugs, valganciclovir or famciclovir, respectively).

Mutagenicity, teratogenicity, carcinogenicity, fertility, and contraception

Before initiating ganciclovir therapy, patients should be informed of the potential risk to the fetus. In animal studies, ganciclovir demonstrated mutagenic, teratogenic, and carcinogenic effects, as well as suppression of fertility. Based on clinical and preclinical data, ganciclovir is likely to cause temporary or irreversible 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 malignancies. Women of reproductive age should be advised to use reliable contraceptive methods during ganciclovir therapy and for 30 days after completion of treatment. 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").

The use of ganciclovir, especially in children, requires extreme caution due to the potential for delayed carcinogenicity and toxic effects on reproductive function. The benefits of therapy should be carefully evaluated in each individual case, with full consideration of the associated risks.

Myelosuppression

Ganciclovir should be used with caution in patients with existing hematological cytopenia or a history of drug-induced hematological cytopenia, as well as in patients receiving radiotherapy.

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow suppression have been observed in patients treated with ganciclovir. Ganciclovir 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 below 8 g/dL (see sections "Dosage and administration" and "Side effects").

Complete blood counts, including platelet counts, should be monitored during treatment. Enhanced hematological monitoring may be necessary for patients with renal impairment, as well as for neonates 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 other myelotoxic agents, and those with renal impairment, daily monitoring is recommended.

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

Renal impairment

Patients with renal impairment are at increased risk of developing toxicity (particularly hematological toxicity). Dose adjustment is required (see sections "Pharmacokinetics in special patient populations" and "Dosage and administration").

Concomitant use with other medicinal products

Seizures have been reported in patients receiving imipenem/cilastatin and ganciclovir. Therefore, ganciclovir should not be administered 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 administration of ganciclovir with didanosine or other agents with myelosuppressive or nephrotoxic effects should be closely monitored, as this may lead to additive toxicity (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

This medicinal product in the 500 mg strength contains 2 mmol (45 mg) of sodium. This should be taken into account for patients on a controlled sodium intake.

Use during pregnancy or breastfeeding.

Fertility

In a small clinical study involving kidney transplant patients who received ganciclovir for cytomegalovirus (CMV) infection prophylaxis for up to 200 days, valganciclovir/ganciclovir was shown to affect spermatogenesis, resulting in reduced sperm concentration and motility, as assessed after completion of treatment. This effect was reversible. Approximately 6 months after discontinuation of ganciclovir, mean sperm concentration and motility returned to levels comparable to those observed in untreated control groups.

In animal studies, ganciclovir caused fertility impairment in male and female mice and suppressed spermatogenesis, leading to testicular atrophy in mice, rats, and dogs at clinically relevant doses.

Based on clinical and preclinical data, ganciclovir is likely to cause temporary or irreversible 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, it is known that ganciclovir rapidly crosses the placental barrier. Animal studies have shown reproductive toxicity and teratogenic effects with ganciclovir administration. Therefore, ganciclovir should not be used during pregnancy except when the clinical need for treatment outweighs the potential teratogenic risk to the fetus.

Contraception

Women of reproductive age should be advised to use effective contraceptive methods during treatment and for at least 30 days after completion of 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.

Breastfeeding

It is unknown whether ganciclovir is excreted in human breast milk; however, ganciclovir may pass into breast milk and cause serious adverse reactions in the infant. Animal data indicate that ganciclovir is excreted in milk during lactation in rats. Therefore, breastfeeding should be discontinued during ganciclovir therapy.

Ability to affect reaction speed when driving or operating machinery.

Ganciclovir may significantly impair reaction speed when driving or operating machinery (see section "Side effects").

Method of Administration and Dosage

The solution obtained by reconstituting the sterile powder is intended for intravenous use only, preferably administered via 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 drug may cause severe tissue irritation due to the high pH (9–11) of the Ganciclovir-Farmeks solution.

Recommended doses, frequency, or infusion rates must not be exceeded.

Treatment of CMV Infection

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

Initial (induction) therapy: 5 mg/kg administered as a 1-hour intravenous infusion twice daily (every 12 hours, 10 mg/kg/day) for 14–21 days.

Maintenance therapy: For patients with persistent immunosuppression and ongoing risk of CMV retinitis recurrence, maintenance therapy may be administered as 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.

Treatment of progressive disease: Any patient experiencing progression of CMV infection either during maintenance therapy or after discontinuation of ganciclovir may be re-treated using the induction regimen.

Children from birth to 12 years of age

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

Prevention of CMV Infection via Preemptive Therapy

Adults and adolescents aged ≥ 12 years with normal renal function

Induction regimen: 5 mg/kg as a 1-hour intravenous infusion every 12 hours (10 mg/kg/day) for 7–14 days.

Maintenance regimen: 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.

Children from birth to 12 years of age

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

Prevention of CMV Infection via Universal Prophylaxis

Adults and adolescents aged 16 years and older: 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 prophylaxis should be determined based on the risk of CMV infection.

Children from birth to ≤ 16 years

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

The recommended single daily dose of ganciclovir administered as a 1-hour intravenous infusion should be calculated based on BSA determined using the Mosteller formula and CrCl calculated using the Schwartz formula. The 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 Mosteller BSA and Schwartz CrCl below).

If the CrCl calculated using 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.

k = 0.33 for patients < 1 year of age with low body weight at 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 dosing recommendations should be applied.

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

It is recommended to regularly monitor serum creatinine levels, patient height, and body weight, and adjust the dose as necessary.

Special Dosage Recommendations

Patients with Renal Impairment

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

Patients aged 12 years and older with renal impairment receiving preemptive therapy or CMV infection treatment at a body weight-based dose should have their ganciclovir dose adjusted according to CrCl as shown in Table 3.

Table 3
Dose Adjustment for Patients with Renal Impairment

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, CrCl = 72 × 0.011 × serum creatinine [µmol/L]

For women, CrCl = 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, marked neutropenia, anemia, thrombocytopenia, and pancytopenia (see section "Special precautions" before initiation of therapy)

If significant decreases in blood cell counts occur during ganciclovir treatment, consider treatment with hematopoietic growth factors and/or interruption of therapy (see sections "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, ganciclovir should be administered with strict regard to renal function (see section "Pharmacological properties").

Children

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

Administration

Attention!

Ganciclovir should 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.

Intramuscular or subcutaneous injection must not be used, 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 must not be exceeded.

Ganciclovir-Farmex is a lyophilisate (powder) for solution for infusion. After reconstitution, the medicinal product Ganciclovir-Farmex is a solution ranging from colorless to pale yellow, with almost no visible particles.

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

Preparation of reconstituted concentrate

Reconstitution should be performed under aseptic conditions.

1. Remove the cap to access the center of the rubber stopper. Draw 10 mL of water for injection into a syringe and slowly transfer it into the vial through the center of the rubber stopper. Bacteriostatic water for injection containing parabens (parahydroxybenzoates) must not be used, as it is incompatible with the medicinal product Ganciclovir-Farmex.
2. Gently shake the vial to ensure complete wetting of the lyophilisate.
3. Gently rotate the vial in circular motions for several minutes to obtain a fully reconstituted solution.
4. Carefully inspect the reconstituted solution for mechanical particles before dilution with a compatible diluent. The reconstituted solution of the medicinal product Ganciclovir-Farmex may range from colorless to pale yellow.

Preparation of 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 ganciclovir: 0.9% sodium chloride solution; 5% dextrose solution; Ringer's solution; and lactated Ringer's solution. Ganciclovir-Farmex must not be mixed with other intravenous medicinal products.

The diluted solution must not be administered intravenously for longer than 1 hour, as specified in the section "Administration" above.

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 stored in a refrigerator 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 medicinal product Ganciclovir-Farmex should be used immediately; otherwise, the duration and conditions of storage prior to use are the responsibility of the user. The shelf life must not exceed 24 hours at 2–8°C if 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

There is limited experience in treating children under 12 years of age (see sections "Pharmacological properties", "Indications", "Interaction with other medicinal products and other forms of interaction", "Special precautions", "Dosage and administration", "Overdose", and "Adverse reactions").

Overdose

Symptoms

Cases of ganciclovir overdose (some with fatal outcomes) have been reported during clinical trials and post-marketing use. Most reports were not associated with any adverse reactions or included one or more of the adverse reactions listed below:

• Hematological toxicity: myelosuppression, including pancytopenia, leukopenia, neutropenia, granulocytopenia, bone marrow failure;
• Hepatotoxicity: hepatitis, liver function abnormalities;
• Nephrotoxicity: 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 by hemodialysis; therefore, hemodialysis may be used to reduce plasma levels in patients who have received an excessive dose (see section "Pharmacokinetics").

Special patient groups

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

Children: Specific information is lacking.

Side effects

Overall safety profile

Note: Valganciclovir is an inactive form (prodrug) of ganciclovir, and side effects associated with valganciclovir administration are expected to occur with ganciclovir use. Ganciclovir for oral administration is no longer manufactured; however, side effects 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 listed below was determined based on pooled data from a group of HIV-infected patients (n = 1704) receiving maintenance therapy with ganciclovir or valganciclovir. Exceptions are agranulocytosis, granulocytopenia, and anaphylactic reaction—their frequency data were obtained from post-marketing experience. Adverse reactions are listed by organ system according to MedDRA [Medical Dictionary for Regulatory Activities], and their frequency is categorized as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000).

The overall safety profile of ganciclovir/valganciclovir is comparable between HIV-infected patients and organ transplant recipients, except that retinal detachment has been reported only in HIV-infected patients with CMV retinitis. However, there are certain differences in the frequency of some reactions. Intravenous ganciclovir administration is associated with a lower risk of diarrhea compared to oral valganciclovir. Fever, candidal infections, 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 commonly observed in organ transplant recipients.

Infections and infestations: very common—candidal 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—elevated alkaline phosphatase and AST [aspartate aminotransferase] levels in blood, hepatic dysfunction, elevated ALT [alanine aminotransferase] levels.

Skin and subcutaneous tissue disorders: very common—dermatitis; common—night sweats, pruritus, rash, alopecia; uncommon—dry skin, urticaria.

Musculoskeletal and connective tissue disorders: common—muscle pain, joint pain, back pain, muscle spasms.

Renal and urinary disorders: common—decreased creatinine clearance, renal dysfunction, elevated blood creatinine levels; uncommon—hematuria, renal failure.

Reproductive system disorders: uncommon—male infertility.

General disorders: very common—malaise, weakness; common—pain, chills, discomfort, asthenia, injection site reactions; uncommon—chest pain.

* Frequency data for these adverse reactions were obtained from post-marketing experience; frequency for all other adverse reactions was determined from clinical trial data.

Description of selected adverse reactions

Neutropenia. The risk of developing neutropenia cannot be predicted based on pre-treatment neutrophil counts. Neutropenia usually occurs during the first or second week of induction therapy and after administration of a cumulative dose ≤ 200 mg/kg. Cell counts usually return to normal within 2–5 days after discontinuation of the drug or dose reduction (see section "Special instructions").

Severe neutropenia. Severe neutropenia was more frequently reported in HIV-infected patients (14%) receiving maintenance therapy with valganciclovir, oral or intravenous ganciclovir (n = 1704) than in 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, whereas 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 treatment with immunosuppressive drugs have a higher risk of thrombocytopenia than patients with AIDS (see section "Special instructions"). Severe thrombocytopenia may be associated with potentially life-threatening bleeding.

Seizures. Seizures have been observed in patients receiving concomitant imipenem-cilastatin and ganciclovir (see sections "Interaction with other medicinal products and other forms of interaction" and "Special instructions").

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. Ganciclovir should be administered according to the recommendations provided in the section "Method of administration and dosage" to minimize the risk of local tissue irritation.

Children

Formal safety studies of ganciclovir use in children aged ≤ 12 years have not been conducted. However, based on experience with valganciclovir, the inactive form (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 cytopenia in neonates and infants requires careful monitoring of blood cell counts in these age groups.

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

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. 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 the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities.

Ganciclovir must not be mixed with other intravenous drugs. Ganciclovir precipitates in solutions containing parabens.

Packaging.

500 mg in a vial, 1 vial in a blister pack, 1 blister pack in a cardboard carton.

Prescription status. Prescription only.

Manufacturer.

LLC "FARMEKS GROUP".

Manufacturer's location and address of place of business.

100 Shevchenka Street, city of Boryspil, Kyiv region, 08301, Ukraine