Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489 Greifswald, Germany
Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, nucleosides and nucleotides excluding reverse transcriptase inhibitors
ATC code: J05AB06
Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of herpes viruses both in vitro and in vivo. Sensitive human viruses include human cytomegalovirus (HCMV), herpes-simplex virus-1 and -2 (HSV-1 and HSV-2), human herpes virus -6, -7 and -8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and hepatitis B virus. Clinical studies have been limited to evaluation of efficacy in patients with CMV infection.
In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, UL97. Further phosphorylation occurs by several cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolised intracellularly. This has been shown to occur in HSV- and HCMV-infected cells, with half-lives of 18 and 6-24 hours, respectively, after removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.
The virustatic activity of ganciclovir is a result of the inhibition of viral DNA synthesis by: (1) competitive inhibition of incorporation of deoxyguanosine triphosphate into DNA by DNA polymerase, and (2) incorporation of ganciclovir triphosphate into viral DNA, causing termination of, or very limited, viral DNA elongation.
The in vitro antiviral activity, measured as IC50 of ganciclovir against CMV, is in the range of 0.08 μM (0.02 μg/ml) to 14 μM (3.57 μg/ml).
The possibility of viral resistance should be considered in patients who repeatedly achieve a poor clinical response or experience continuous viral excretion during treatment.
Viral resistance to ganciclovir can arise by selection of mutations in the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or the viral polymerase gene (UL54). Viruses containing mutations in the UL97 gene are resistant to ganciclovir alone, whereas viruses with mutations in the UL54 gene are resistant to ganciclovir but may show cross-resistance to other antivirals that also target viral polymerase.
In a prospective study, 36 severely immunocompromised paediatric patients (6 months-16 years of age) with HIV and CMV infection received intravenous ganciclovir at a dose of 5 mg/kg per day for 2 days followed by oral ganciclovir for a median of 32 weeks. Ganciclovir was effective with a toxicity profile similar to that seen in adults. Ganciclovir was associated with a decrease in the detection of CMV by culture or polymerase chain reaction. Neutropenia was the only severe adverse drug reaction observed during the study and although none of the children required treatment cessation, 4 required granulocyte colony-stimulating factor (G-CSF) treatment to maintain absolute neutrophil counts >400 cells/mm³.
In a retrospective study, 122 paediatric liver transplantation recipients (16 days-18 years of age, median age 2.5 years) received a minimum of 14 days of intravenous ganciclovir 5 mg/kg twice a day followed by pre-emptive CMV PCR monitoring. Forty-three patients were considered high-risk for CMV and 79 were routine-risk. Asymptomatic CMV infection was detected by PCR in 34.4% of subjects and was more likely in high-risk than in routine-risk recipients (58.1% vs. 21.8%, p = 0.0001). Twelve subjects (9.8%) developed CMV disease (8 high-risk vs. 4 routine-risk, p = 0.03). Three subjects developed acute rejection within 6 months of detection of CMV, but CMV was preceded by rejection in 13 subjects. There were no deaths secondary to CMV. A total of 38.5% of subjects were spared antiviral medications beyond their initial postoperative prophylaxis.
In a retrospective analysis, the safety and efficacy of ganciclovir was compared to valganciclovir in 92 paediatric kidney and/or liver transplant patients (7 months -18 years of age, median age 9 years). All children received intravenous ganciclovir 5 mg/kg twice daily for 2 weeks following transplantation. Children treated before 2004 then received oral ganciclovir 30 mg/kg/dose up to 1 g/dose three times daily (n = 41), while children treated after 2004 received valganciclovir up to 900 mg once daily (n = 51). The overall incidence of CMV was 16% (15/92 patients). Time to onset of CMV infection was comparable in both groups.
In a randomised, controlled study, 100 neonates (≤1 month of age) with symptomatic congenital CMV disease with CNS involvement received 6 weeks of intravenous ganciclovir 6 mg/kg every 12 hours or no treatment. Of the 100 patients enrolled, 42 met all study criteria and had both baseline and 6-month follow up audiometric evaluations. Of these, 25 received ganciclovir and 17 received no treatment. Twenty-one of 25 ganciclovir recipients had improved hearing or maintained normal hearing from baseline to 6 months compared with 10/17 control patients (84% and 59%, respectively p = 0.06). None of the ganciclovir recipients had worsening hearing from baseline to 6 months, compared with 7 control patients (p < 0.01). By one year after baseline, 5/24 ganciclovir recipients and 13/19 control patients had worsening hearing (p < 0.01). During the course of the study, 29/46 ganciclovir-treated patients had neutropenia, compared with 9/43 control patients (p < 0.1). There were 9 deaths during the study, 3 in the ganciclovir group and 6 in the control group. No deaths were related to study medication.
In a Phase III, randomised, controlled study, 100 neonates (3-33 days of age, median age 12 days) with severe symptomatic congenital CMV with CNS involvement, received either intravenous ganciclovir 6 mg/kg twice daily for 6 weeks (n = 48) or no antiviral treatment (n = 52). Infants who received ganciclovir had improved neurodevelopmental outcomes at 6 and 12 months compared with those who did not receive antiviral treatment. Although ganciclovir recipients had fewer delays and more normal neurological outcomes, most were still behind what would be considered normal development at 6 weeks, 6 months, or 12 months of age. Safety was not assessed in this study.
A retrospective study investigated the effect of antiviral treatment on late-onset hearing loss in infants with congenital CMV infection (4-34 months of age, mean age 10.3±7.8 months, median age 8 months). The study included 21 infants with normal hearing at birth who developed late-onset hearing loss. Antiviral treatment consisted of either:
None of the children required a cochlear implant and hearing loss improved in 83% of ears affected by hearing loss at baseline. Neutropenia was the only side effect reported and it was not necessary to discontinue treatment in any patient.
The systemic exposure (AUC0-∞) reported following dosing with a single 1-hour IV infusion of 5mg/kg ganciclovir in adult liver transplant patients was on average 50.6 µg.h/mL (CV% 40). In this patient population peak plasma concentration (Cmax) was on average 12.2 µg/mL (CV% 24).
The volume of distribution of intravenously administered ganciclovir is correlated to body weight. The steady state volume of distribution has a range of 0.54-0.87 L/kg. Plasma protein binding was 1%-2% over ganciclovir concentrations of 0.5 and 51 μg/mL. Ganciclovir penetrates the cerebrospinal fluid, where concentrations observed reach 24%-67% of the plasma concentrations.
Ganciclovir is not metabolised to a significant extent.
Ganciclovir is predominantly eliminated by renal excretion via glomerular filtration and active tubular secretion of unchanged ganciclovir. In patients with normal renal function, more than 90% of the intravenously administered ganciclovir dose is recovered unchanged in the urine within 24 hours. The mean systemic clearance ranged from 2.64 ± 0.38 mL/min/kg (N = 15) to 4.52 ± 2.79 mL/min/kg (N = 6) and renal clearance ranged from 2.57 ± 0.69 mL/min/kg (N = 15) to 3.48 ± 0.68 mL/min/kg (N = 20), corresponding to 90%-101% of administered ganciclovir. Half-lives in subjects without renal impairment ranged from 2.73 ± 1.29 (N = 6) to 3.98 ± 1.78 hours (N = 8).
Intravenous ganciclovir exhibits linear pharmacokinetics over the range of 1.6-5.0 mg/kg.
The total body clearance of ganciclovir is linearly correlated with creatinine clearance. In patients with mild, moderate, and severe renal impairment, mean systemic clearances of 2.1, 1 and 0.3 mL/min/kg were observed. Patients with renal impairment have an increased elimination half-life. In patients with severe renal impairment elimination half-life was increased by 10-fold (see section 4.2 for dose modifications required in patients with renal impairment).
Haemodialysis reduces plasma concentrations of ganciclovir by about 50% after intravenous administration during a 4-hour haemodialysis session.
During intermittent haemodialysis, estimates for the clearance of ganciclovir ranged from 42-92 mL/min, resulting in intra-dialytic half-lives of 3.3-4.5 hours. The fraction of ganciclovir removed during a single dialysis session varied from 50% to 63%. Estimates of ganciclovir clearance for continuous dialysis were lower (4.0-29.6 mL/min) but resulted in greater removal of ganciclovir over a dose interval.
The safety and efficacy of Cymevene have not been studied in patients with hepatic impairment. Hepatic impairment should not affect the pharmacokinetics of ganciclovir since it is excreted renally and, therefore, no specific dose recommendation is made (see section 4.2).
The pharmacokinetics of IV ganciclovir (administered as 200 mg/m² dose) were investigated across two studies in paediatric liver (n=18) and renal (n=25) transplant patients aged 3 months to 16 years and evaluated using a population pharmacokinetic model. Creatinine clearance (CrCL) was identified as statistically significant covariate for ganciclovir clearance and height of the patient as statistically significant covariate for ganciclovir clearance, steady state volume and peripheral volume of distribution. When CrCL and height were included in the model, the apparent differences in ganciclovir PK across various age groups was accounted for and neither age, gender, nor types of organ transplant were significant covariates in these populations. Table 1 gives the estimated pharmacokinetic parameters by age group.
Table 1 Pharmacokinetic parameters after ganciclovir IV given by BSA (200mg/m²) in renal and liver solid organ transplant patients expressed as medians (minimum-maximum).
| < 6 years n=17 | 6 to <12 years n=9 | ≥12 to <16 years n=17 | |
|---|---|---|---|
| CL(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) |
Furthermore, the pharmacokinetics of intravenous ganciclovir given according to the dosing regimen approved for adults (5mg/kg IV infusion administered over 1 hour) were studied in a small group of infants and children with normal renal function and aged 9 months-12 years (n=10, average 3.1 years). Exposure as measured by mean AUC0-∞ on Day 1 (n=10) and AUC0-12 on Day 14 (n=7) were 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. A trend towards lower exposures in younger paediatric patients was observed with body weight based dosing used in this study. In paediatric patients up to 5 years of age the average values for 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.
The ganciclovir IV dosing regimen based on BSA and renal function (3x BSA x CrCLS), derived from the paediatric dosing algorithm with valganciclovir, leads to similar ganciclovir exposures in the paediatric population from birth to 16 years of age (see Table 2).
Table 2 Simulated* Ganciclovir AUC0-24h (μg • h/mL) for paediatric patients treated with ganciclovir dose (mg) of 3xBSAxCrCLS given as 1 hour infusion.
| < 4 months | ≥ 4 months to ≤ 2 years | > 2 to < 6 years | ≥ 6 to < 12 years | ≥ 12 to ≤ 16 years | All Patients | |
|---|---|---|---|---|---|---|
| No. patients simulated | 781 | 384 | 86 | 96 | 126 | 1473 |
| 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 AUC <40 μg•h/mL | 89 (11%) | 38 (10%) | 13 (15%) | 23 (24%) | 28 (22%) | 191 (13%) |
| Patients AUC 40-60 μg•h/mL | 398 (51%) | 195 (51%) | 44 (51%) | 41 (43%) | 63 (50%) | 741 (50%) |
| Patients 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; max = maximum; min = minimum.
* Simulations were performed using a validated paediatric population PK model and demographic data from paediatric patients receiving valganciclovir or ganciclovir treatment in clinical studies (n=1473 data records)
No studies have been conducted in adults older than 65 years of age (see section 4.2).
Ganciclovir was mutagenic in mouse lymphoma cells and clastogenic in mammalian cells. Such results are consistent with the positive mouse carcinogenicity study with ganciclovir. Ganciclovir is a potential carcinogen.
Ganciclovir causes impaired fertility and teratogenicity in animals. Based upon animal studies where inhibition of spermatogenesis was induced at ganciclovir systemic exposures below therapeutic levels, it is considered likely that ganciclovir causes inhibition of human spermatogenesis.
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