Cimaven®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYMEVENE® (CYMEVENE®)

Composition:

Active substance: ganciclovir;

1 vial contains ganciclovir 500 mg (as ganciclovir sodium salt 543 mg).

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: lyophilisate (solid substance) white to almost white in color.

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. 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 been limited to evaluation of the drug's efficacy 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 mediated 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 an intracellular half-life of approximately 18 hours and 6–24 hours, respectively, after ganciclovir disappears from the extracellular fluid. Since phosphorylation of ganciclovir primarily depends on the viral kinase, it occurs predominantly in infected cells.

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

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 potential for development of viral resistance should be considered in patients who show poor clinical response upon re-treatment or who continue to shed virus 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 with mutations in the UL97 gene are resistant only to ganciclovir, whereas viruses with mutations in UL54 are resistant to ganciclovir and may exhibit cross-resistance to other antiviral agents targeting viral polymerase.

Pediatric

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 a mean duration 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 counts 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 preemptive 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 at high risk compared to those at 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, while rejection preceded CMV infection in 13 patients. No deaths were attributed to CMV infection. 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 at 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 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 either 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 evaluations 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 of 25 ganciclovir-treated patients compared to 10 of 17 in the control group (84% vs. 59%, p = 0.06). No patient receiving ganciclovir experienced hearing deterioration compared to 7 in the control group (p < 0.01). At one year, hearing deterioration occurred in 5 of 24 ganciclovir-treated patients and in 13 of 19 control patients (p < 0.01). Neutropenia was observed in 29 of 46 patients receiving ganciclovir versus 9 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 the study drug.

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 either intravenous ganciclovir 6 mg/kg twice daily for 6 weeks (n = 48) or no antiviral therapy (n = 52). Infants receiving ganciclovir showed improved neurodevelopmental outcomes at 6 and 12 months compared to untreated infants. Although ganciclovir-treated patients had less developmental 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 impact 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 evaluated. Among 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 existing hearing loss at baseline. Neutropenia was the only reported adverse effect, and no patient required treatment discontinuation.

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×hr/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 concentrations may reach 24–67% of plasma levels.

Biotransformation

Ganciclovir is minimally metabolized.

Elimination

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 an 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 over the dose range of 1.6–5.0 mg/kg.

Patients with Renal Impairment

Total ganciclovir clearance correlates linearly with creatinine clearance. Mean systemic clearance in patients with mild, moderate, and severe renal impairment was 2.1, 1, and 0.3 mL/min/kg, respectively. The elimination half-life of ganciclovir is prolonged in patients with renal impairment. 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

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

During intermittent hemodialysis, 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 is 50–63%. Clearance during continuous dialysis is lower (4.0–29.6 mL/min), but a greater percentage of the administered dose is eliminated between doses.

Patients with Hepatic Impairment

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

Pediatric

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, using a population pharmacokinetic model.

Creatinine clearance (CrCl) was identified as a statistically significant covariate for ganciclovir clearance, and patient height was a statistically significant covariate 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).

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 AUC0–∞ on day 1 (n = 10) and A游戏副本0–12 on day 14 (n = 7), was 19.4 ± 7.1 and 24.1 ± 14.6 μg×h/mL, with corresponding Cmax 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 AUC0–∞ on day 1 (n = 7) and AUC0–12h 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 similar ganciclovir exposure levels in children from birth to 16 years of age (see Table 2).

Table 2. Modelled* ganciclovir AUC0–24h (μg × h/mL) values in children receiving ganciclovir at a dose calculated by 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
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 × 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. *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)

Patients of elderly age

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

Clinical characteristics.

Indications.

Cymevene® is indicated for adults and adolescents aged ≥ 12 years for:

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

Cymevene® is also indicated for children from birth for:

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

Official guidelines for appropriate use of antiviral agents should be followed.

Contraindications.

Hypersensitivity to the active substance of Cymevene® (ganciclovir), valganciclovir, or to any of the excipients.

Breastfeeding.

Special precautions.

Warning regarding preparation of ganciclovir solution

Since Cymevene® 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, as well as direct contact with the reconstituted solution and skin or mucous membranes, should be avoided. Cymevene® solution is alkaline (pH approximately 11). Reconstitution 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 forms of interaction.

Pharmacokinetic interactions

Probenecid: coadministration of probenecid with oral ganciclovir resulted in a statistically significant reduction in renal clearance of ganciclovir, leading 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 Cymevene® should be closely monitored for signs of 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 signs of didanosine toxicity (see section "Special warnings and precautions 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 who received ganciclovir and imipenem/cilastatin concomitantly. These agents should be used in combination with Cymevene® only if potential benefits outweigh the risks (see section "Special warnings and precautions for use").

Zidovudine: both zidovudine and ganciclovir may cause neutropenia and anemia. A pharmacodynamic interaction may occur during concomitant use of these medicinal products. Some patients may poorly tolerate combination therapy with full doses of these agents (see section "Special warnings and precautions for use").

Other possible interactions

Increased toxicity may occur when ganciclovir is administered concomitantly with other medicinal products 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, hydroxyurea); nucleosides (e.g., zidovudine, stavudine, didanosine); nucleotide analogues (e.g., tenofovir, adefovir). Therefore, these medicinal products should be administered concomitantly with ganciclovir only if the expected benefit outweighs the risk (see section "Special warnings and precautions for use").

Children

Interaction studies have been conducted exclusively in adults.

Special precautions for use.

Cross-sensitivity

Due to the similarity of the chemical structure of ganciclovir, acyclovir, and penciclovir, cross-sensitivity reactions between these medicinal products are possible. Therefore, caution should be exercised when prescribing Cymevene® to patients with known hypersensitivity to acyclovir or penciclovir (or their prodrugs, valganciclovir or famciclovir, respectively).

Mutagenicity, teratogenicity, carcinogenicity, fertility, and contraception

Before initiating ganciclovir therapy, patients should be informed about 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 study results, it is considered likely that ganciclovir may 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 ganciclovir treatment and for 30 days after treatment ends. Men are recommended to use barrier contraception during treatment and for at least 90 days after completion of therapy, 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 treatment should be carefully evaluated in each individual case, with a clear assessment of risks. Appropriate treatment guidelines should be followed.

Myelosuppression

Cymeven**®** should be used with caution in patients with 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, and bone marrow function suppression have been observed in patients treated with ganciclovir. Cymeven**®** should not be administered if the absolute neutrophil count is less than 500 cells/μL, platelet count is less than 25,000/μL, or hemoglobin level is less than 8 g/dL (see sections "Dosage and administration" and "Side effects").

During treatment, complete blood counts including platelet counts should be monitored. 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 levels (<1,000 neutrophils/μL), those who experienced leukopenia during prior therapy with other myelotoxic agents, and patients 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 therapy (see sections "Dosage and administration" and "Side effects").

Renal function impairment

Patients with impaired renal function have an increased risk of toxicity (particularly hematological toxicity). Dose adjustment of the drug is required (see sections "Dosage and administration" and "Pharmacokinetics in special patient groups").

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 of therapy outweigh the possible risks (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant administration of ganciclovir and didanosine or drugs with myelosuppressive 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

This medicinal product in the 500 mg strength 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 CMV infection prophylaxis for up to 200 days, an effect of valganciclovir/ganciclovir on spermatogenesis was demonstrated, with decreased 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 observed 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 the results of clinical and preclinical studies, it is considered likely that ganciclovir may 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. In animal studies, ganciclovir administration was associated with reproductive toxicity and teratogenicity. Therefore, ganciclovir should not be used during pregnancy except in cases of clinical necessity when the benefit to the woman outweighs the potential teratogenic risk to the fetus.

Contraception in men and women

Women of childbearing potential should be advised to use effective contraceptive methods during treatment and for at least 30 days after treatment ends, 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 ends, unless it has been established that the female partner has no risk of pregnancy.

Breastfeeding

It is unknown whether ganciclovir passes into human breast milk, but it cannot be excluded that ganciclovir may be excreted in breast milk and cause serious adverse reactions in the infant. Data from animal studies show that ganciclovir is excreted in milk during lactation in rats. Therefore, breastfeeding should be discontinued during ganciclovir treatment.

Ability to affect reaction speed when driving vehicles or operating machinery.

Ganciclovir may have a significant effect on the ability to drive vehicles or operate machinery (see section "Side effects").

Method of Administration and Dosage

The solution obtained by reconstituting the sterile lyophilisate of Cymeven**®** 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 Cymeven**®** 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 Cymeven**®** solution.

Treatment of CMV Infection

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

• Induction therapy: 5 mg/kg administered as an intravenous infusion over 1 hour every 12 hours (10 mg/kg/day) for 14–21 days.
• Maintenance therapy: For patients who have not regained immune function and thus remain at risk of relapse, maintenance therapy may be initiated — 5 mg/kg administered as an intravenous infusion over 1 hour 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 by the physician. Current treatment guidelines should be taken into account.
• Treatment of progressing disease: Any patient experiencing progression of CMV infection either during maintenance therapy or after discontinuation of ganciclovir may be re-treated according to the induction therapy regimen.

Children from birth to 12 years of age

Available information on the use of the drug in children is presented in the section "Pharmacological Properties"; however, no dosage recommendations can be provided at this time.

Prevention of CMV Infection via Preemptive Therapy

Adults and adolescents aged ≥ 12 years with normal renal function

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

Children from birth to 12 years of age

Current data on the use of the drug in children are 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 administered as an intravenous infusion over 1 hour 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; current treatment guidelines should be considered.

Children from birth to ≤ 16 years of age

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

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

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

If the creatinine clearance 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.

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. Patients aged 16 years and older should receive the adult-recommended dosage.

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

It is recommended to regularly monitor serum creatinine levels, as well as the patient’s height and body weight, and adjust the dose 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 using the formula 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 preemptive 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 Cymeven® 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 instructions" prior to initiation of therapy).

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

Elderly patients.

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

Children.

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

Route of administration.

Caution!

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.

Cymeven® is a lyophilized powder for solution for infusion. After reconstitution, Cymeven® is a solution ranging from colorless to light yellow, practically free of 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. Do not use bacteriostatic water for injection containing parabens (parahydroxybenzoates), as they are incompatible with Cymeven®.
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 particulates before dilution with a compatible diluent. The color of the reconstituted Cymeven® solution may range from colorless to light yellow.

Preparation of the final diluted infusion solution.

The required volume, calculated according to the patient’s body weight, is withdrawn from the vial and further diluted in 100 mL of an appropriate infusion solution. Infusion solutions with a concentration higher than 10 mg/mL are not recommended. The following infusion solutions are compatible with Cymeven®: 0.9% sodium chloride solution, 5% dextrose solution, Ringer’s solution, and lactated Ringer’s solution. Cymeven® must not be mixed with other products intended for intravenous administration.

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

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 Cymeven® should be used immediately. Otherwise, the duration and conditions of storage prior to use are the responsibility of the user. In such cases, storage 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 instructions", "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 was observed:

• Hematological toxicity: myelosuppression, including pancytopenia, leukopenia, neutropenia, granulocytopenia, bone marrow aplasia;
• 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; thus, hemodialysis may be used to reduce plasma levels in patients who have received an overdose (see section "Pharmacokinetics").

Patients with renal impairment: overdose of ganciclovir is expected to increase nephrotoxicity in patients with renal impairment (see section "Special instructions").

Children: specific information is lacking.

Adverse Reactions

Note: Valganciclovir is an inactive prodrug of ganciclovir, and adverse reactions associated with valganciclovir use are expected to occur with ganciclovir use. Oral ganciclovir is no longer marketed, but adverse reactions reported during its use are also expected in patients receiving intravenous ganciclovir. Therefore, the list below includes adverse reactions observed during intravenous or oral administration of ganciclovir or valganciclovir.

The most serious and common adverse reactions observed in patients treated with ganciclovir/valganciclovir 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). Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 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 certain differences in the frequency of some 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 – candidiasis, 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 nutritional 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, convulsions, 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, abdominal distension, oral ulcers, pancreatitis.

Hepatobiliary disorders: common – increased blood alkaline phosphatase and AST [aspartate aminotransferase], liver function abnormalities, increased 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 cramps.

Renal and urinary disorders: common – decreased creatinine clearance, renal dysfunction, increased blood creatinine; uncommon – hematuria, renal failure.

Reproductive system and breast disorders: uncommon – male infertility.

General disorders and administration site conditions: very common – asthenia, fatigue; common – pain, chills, malaise, asthenia, 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 within the first or second week of induction therapy and after a cumulative dose ≤ 200 mg/kg. Cell counts usually return to normal within 2–5 days after discontinuation or dose reduction (see section "Special instructions").

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

Thrombocytopenia. Patients with low baseline platelet counts (< 100,000/μL) are at increased risk of developing thrombocytopenia. Patients with iatrogenic immunosuppression due to immunosuppressive therapy have a higher risk of thrombocytopenia compared to AIDS patients (see section "Special instructions"). Severe thrombocytopenia may be associated with life-threatening hemorrhage.

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

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

Injection site reactions. Injection site reactions are common in patients receiving ganciclovir. Cymevene® should be administered according to the recommendations in the section "Method of administration and dosage" to minimize the risk of local tissue irritation.

Pediatric 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 pediatric patients. 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 suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued 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.

Keep out of reach and sight of children. Store at a temperature not exceeding 30 °C.

Incompatibilities.

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

Packaging.

500 mg of lyophilisate in a 10 mL colorless glass vial. 1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

1. CHEPLAPHARM Arzneimittel GmbH
2. Prestige Promotion Verkaufsförderung und Werbeservice GmbH

Manufacturer's address and place of business.

1. Ziegelhof 23-24, Greifswald, Mecklenburg-Vorpommern, 17489, Germany
2. Borsigstrasse 2, Alzenau, Bavaria, 63755, Germany