Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Ganciclovir

Generic name
Ganciclovir
Brand name
ATC Code
J05AB06

Pharmacokinetics in children

Following pharmacokinetic parameters were observed in neonates  (Acosta 2007, Kimberlin 2008,Trang 1993):

IV Ganciclovir 
12 mg/kg/day in 2 doses		 Mean
(single dose)		 Mean
Steady state		 Median
(range)
Cmax (mg/l) 7.0 ± 0.5 4.36-12.91 4.48-6.56 (0.7-93.02)
Tmax (h) - 1.2-1.43 1-1.08 (0.23-2.92)
t½ (h) 2.4 2.31-2.71 2.23-2.91 (1.69-3.9)
Cl (ml/min/kg) 3.55 ± 0.35 4.70-7.93 3.74-6.83 (0.49-40.44)
Vd (l/kg) 0.75 ± 0.06 1.04-1.58  0.85-1.31 (0.14-5.91)

Following pharmacokinetic parameters were observed in children after kidney (n=25) and liver (n=18) transplantation (3 months - 16 years) after intravenous administration of 200 mg/m2 Ganciclovir [SmPC]:

  < 6 years (n=17)
 6 - 12 years (n=9)
 12 - 6 years (n=17)
CL(l/h) 4,23 (2,11–7,92) 4,03 (1,88–7,8) 7,53 (2,89–16,8) 
Cmax (μg/ml) 12,1 (9,17–15) 13,3 (4,73–15) 12,4 (4,57–30,8)
Vd, steady states (l)   8,06 (3,35–16,6) 22,1 (14,6–30,1) 37,9 (16,5–57,2)
AUC0-24h (μg/hr/ml) 24,3 (14,1–38,9) 40,4 (17,7-48,6) 37,6 (19,2–80,2)

Data are presented as median (minimum - maximum).

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dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

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Available formulations

No information is present at this moment.

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Dosages

(Congenital) CMV infection
  • Intravenous
    • Premature neonates: Gestational age < 37 weeks
      • 12 mg/kg/day in 2 doses.

      • Adjust dose based on effect (CMV viral loads) and/or ganciclovir plasma concentrations.

    • Full-term neonates Gestational age ≥ 37 weeks
      • 12 mg/kg/day in 2 doses.

      • Adjust dose based on effect (CMV viral loads) and/or ganciclovir plasma concentrations.
Preemptive therapy of CMV in organ and stem cell transplants
  • Intravenous
    • 1 month up to 18 years
      • 10 mg/kg/day in 2 doses.

      • Adjust dose based on effect (CMV viral loads) and/or ganciclovir plasma concentrations.

    • 1 month up to 18 years
      [6] [16] [23] [27]
      • 10 mg/kg/day in 2 doses.

      • Adjust dose based on effect (CMV viral loads) and/or ganciclovir plasma concentrations.
Prophylaxis of CMV in organ and stem cell transplants
Treatment of CMV infection after organ and stem cell transplantation
  • Intravenous
    • 1 month up to 18 years
      [13] [14] [26] [29]
      • Initial dose: 15 mg/kg/day in 2 doses. If needed, increase to 20 mg/kg/day in 2 doses.
        • Adjust dose based on effect (CMV viral loads) and/or ganciclovir plasma concentrations.
        • In augmented renal clearance (> 130 ml/min), a dose of 20 – 25 mg/kg/day in 2 doses is needed to attain the AUC target

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Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2
50 percentage of single dose and dosing interval : 12 uur Depending on the level, interval extension: 24-48 hours
Eerste gift 100 % van de normale keerdosering
GFR 30-50 ml/min/1.73 m2
50 percentage of single dose and dosing interval : 24 uur Dose reduction depending on the concentrations (see warnings and precautions), Interval extension: 48 hours
Eerste gift 100 % van de normale keerdosering
GFR 10-30 ml/min/1.73 m2
25 percentage of single dose and dosing interval : 24 uur Dose reduction depending on the concentrations (see warnings and precautions), Interval extension: 48 hours
Eerste gift 100 % van de normale keerdosering
GFR < 10 ml/min/1.73 m2
25 percentage of single dose and dosing interval : 48 uur Dose reduction depending on the levels (see warnings and precautions), interval extension: 48-96 hours
Eerste gift 100 % van de normale keerdosering
Clinical consequences

Myelosuppressie is een dosisbeperkende bijwerking; trombocytopenie komt bij 5- 20% van de patiënten voor; neutropenie komt voor bij 15-40% van de patiënten en kan optreden na ong. 10 dagen, in het bijzonder bij doseringen hoger dan 15 mg/kg lich.gewicht per dag.

Bij neutropenie normaliseert het aantal cellen gewoonlijk binnen 2-5 dagen na staken van het geneesmiddel of verminderen van de dosis.

Bij overdosering is tevens hematurie gemeld. Zo nodig dialyseren en hydrateren.

Aanpassen van de dosering beïnvloedt de dalspiegel. Als de dalspiegel niet voldoende hoog is, is de antivirale werking mogelijk niet voldoende; dit kan resistentie tot gevolg hebben.

Patients on dialysis

HD: 1ste gift normale keerdosis, vervolgens 25% van normale keerdosis na elke dialyse, op geleide spiegel

CVVH: 1ste gift normale keerdosis, vervolgens 50% van normale keerdosis en interval tussen twee doseringen: 24 uur, op geleide spiegel

PD: gebruik vermijden

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The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Neutropenia, nausea, vomiting, diarrhoea, anorexia, headaches, fever, confusion.

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The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Therapeutic drug monotoring
There is no agreement yet on whether to routinely perform TDM due to the lack of PK/PD data. According to the NVZA, the evidence level for performing TDM is 4 (Level 4: do not perform routine TDM. Consider performing TDM selectively only in special cases, for example, to investigate toxicity, ineffectiveness/compliance or the effect of pharmacokinetic interactions) [NVZA monograph ganciclovir].

TDM in special populations with unpredictable PK/PD profiles, i.e. patients with unstable renal function, younger children, or patients with suspected resistance may be considered [Li 2023]. Despite the uncertainty surrounding the benefits of TDM in general, it may provide some guidance in these cases.

Neutropenia can occur, particularly when high dosages are used. After reducing the dose or discontinuing the therapy, the cell counts usually normalize within 2-5 days. Check the blood count; adjust dose or stop the treatment if applicable. Potentially carcinogenic and teratogenic.

Determine the creatinine twice weekly. Substantial inter-patient and intra-patient variability of GCV levels has been noted after kidney transplants. Pharmacokinetic monitoring of GCV and valganciclovir therapy in both preventive and therapeutic treatment of CMV disease after transplantation is justifiable.

Level determinations are only needed for intravenous ganciclovir or oral valganciclovir if the renal function is impaired or if there is any doubt about the effectiveness or side effects
Allow to run in during 1 hour.
T=1.5 (= peak): 2.5-12.5 mg/l
T=0 (= trough): 0.2-1 mg/l

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Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

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Nucleosides and nucleotides excl. reverse transcriptase inhibitors
J05AB01
J05AB12
J05AB16
J05AB04
J05AB11
J05AB14
Phosphonic acid derivatives
J05AD01
Protease inhibitors
J05AE08
J05AE10
J05AE07
J05AE02
J05AE04
J05AE03
J05AE01
Nucleoside and nucleotide reverse transcriptase inhibitors
J05AF06
J05AF02
J05AF09
J05AF10
J05AF05
J05AF04
J05AF07
J05AF13
J05AF13
J05AF01
Non-nucleoside reverse transcriptase inhibitors
J05AG06
J05AG03
J05AG04
J05AG01
J05AG05
Neuraminidase inhibitors
J05AH02
J05AH01
Antivirals for treatment of HIV infections, combinations
J05AR02
J05AR20
J05AR13
J05AR25
J05AR18
J05AR19
J05AR03
J05AR09
J05AR10
Other antivirals
J05AX28
J05AX12
J05AX07
J05AX09
J05AX08
J05AX24
ANTIVIRALS FOR TREATMENT OF HIV INFECTIONS, COMBINATIONS
J05AR02
J05AR20
J05AR13
J05AR25
J05AR18
J05AR19
J05AR03
J05AR09
J05AR10
Integrase inhibitors
J05AJ04
Antivirals for treatment of HCV infections
J05AP54
J05AP57
J05AP51
J05AP08
J05AP55

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References

  1. Hartwig NC, et al, Vademecum pediatrische antimicrobiele therapie, 2005
  2. Kimberlin DW et al., Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial., J.Pediatr, 2003, 143, 16-25
  3. Vethamuthu J, et al, Unexpectedly high inter- and intrapatient variability of ganciclovir levels in children, Pediatr Transplant, 2007, 11, 301-5
  4. Trang JM, et al, Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Grou, Clin Pharmacol Ther, 1993, Jan;53(1), 15-21.
  5. Kimberlin DW, et al, Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease, J Infect Dis, 2008, Mar 15;197(6), 836-45
  6. Zhang D, et al, Pharmacokinetics of ganciclovir in pediatric renal transplant recipients, Pediatr Nephrol, 2003, Sep;18(9, 943-8
  7. Zhao W, et al, Population pharmacokinetics of ganciclovir following administration of valganciclovir in paediatric renal transplant patients, Clin Pharmacokinet, 2009, 48(5), 321-8
  8. Acosta EP, et al, Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation, Clin Pharmacol Ther, 2007, Jun;81(6), 867-72
  9. Frenkel LM,, Oral ganciclovir in children: pharmacokinetics, safety, tolerance, and antiviral effects. The Pediatric AIDS Clinical Trials Group, J Infect Dis, 2000, Dec;182(6), 1616-24
  10. Oliver SE, et al, Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system, J Clin Virol, 2009, Dec;46 Suppl 4, S22-6
  11. Schleiss MR., Antiviral therapy of congenital cytomegalovirus infection, Semin Pediatr Infect Dis, 2005, Jan;16(1), 50-9
  12. Whitley RJ, et al, Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group, J Infect Dis, 1997, May;175(5), 1080-6
  13. Nigro G, et al, Ganciclovir therapy for symptomatic congenital cytomegalovirus infection in infants: a two-regimen experience, J Pediatr, 1994, Feb;124(2, 318-22
  14. Nigro G,, Ganciclovir therapy for cytomegalovirus-associated liver disease in immunocompetent or immunocompromised children, Arch Virol, 1997, 142(3), 573-80
  15. Spivey JF, et al, Safety and efficacy of prolonged cytomegalovirus prophylaxis with intravenous ganciclovir in pediatric and young adult lung transplant recipients., Pediatr Transplant., 2007, May;11(3), 312-8
  16. Gerna G, et al, Prophylaxis followed by preemptive therapy versus preemptive therapy for prevention of human cytomegalovirus disease in pediatric patients undergoing liver transplantation, Transplantation, 2008, Jul 15;86(1), 163-6
  17. Danziger-Isakov LA, et al, Variability in standard care for cytomegalovirus prevention and detection in pediatric lung transplantation: survey of eight pediatric lung transplant programs, Pediatr Transplant., 2003, Dec;7(6), 469-73.
  18. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie, Expert opinie, 28 maart 2018
  19. Hexal, SmPC Ganciclovir HEXAL 500 mg Pulver für ein Konzentrat zur Herstellung einer Infusionslösung (89276.00.00), 04/2014
  20. Roche, SmPC Cymeven® i.v. 500 mg Pulver für ein Konzentrat zur Herstellung einer Infusionslösung (14837.00.00, 04/2018
  21. Cheplapharm, SmPC Cymevene 500 mg Tr.sbst. z. Inf.ber. (1-19235), https://www.univadis.at/, 02/2019
  22. Cheplapharm Arzneimittel GmbH. Last updated 11-05-2023., SmPC Cymevene 500 mg poeder voor concentraat voor oplossing voor infusie. (RVG 13007) 11-05-2023, www.geneesmiddeleninformatiebank.nl
  23. Launay, E., et al., Pharmacokinetic profile of valganciclovir in pediatric transplant recipients. , The Pediatric infectious disease journal,, 2012, 31(4), 405–407
  24. Nederlandse Vereniging voor ZiekenhuisApothekers (NVZA), TDM monografie ganciclovir, https://tdm-monografie.org/ganciclovir/, 12 okt 2020
  25. Jorga K, et al., Pediatric Dosing of Ganciclovir and Valganciclovir: How Model-Based Simulations Can Prevent Underexposure and Potential Treatment Failure., CPT Pharmacometrics Syst Pharmacol., 2019, Mar;8(3), 167-176
  26. Nguyen, T. et al, Population Pharmacokinetics of Intravenous Ganciclovir and Oral Valganciclovir in a Pediatric Population To Optimize Dosing Regimens., Antimicrobial agents and chemotherapy,, 2021, 65(3), e02254-20
  27. Franck, B, et al., Population pharmacokinetics of ganciclovir and valganciclovir in paediatric solid organ and stem cell transplant recipients., British journal of clinical pharmacology,, 2021, 87(8), 3105–3114
  28. Li, Q. Y., et al, Optimizing ganciclovir and valganciclovir dosing regimens in pediatric patients with cytomegalovirus infection: a spotlight on therapeutic drug monitoring., Expert review of clinical pharmacology,, 2023, 16(8), 727–739
  29. Li S, et al, Population Pharmacokinetics and Dose Optimization of Ganciclovir in Critically Ill Children., Front. Pharmacol., 2021, 11, 614164
  30. Trang JM, et al, Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Grou, Clin Pharmacol Ther, 1993, Jan;53(1), 15-21.
  31. Launay, E., et al., Pharmacokinetic profile of valganciclovir in pediatric transplant recipients., The Pediatric infectious disease journal,, 2012, 31(4), 405–407

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Changes

Changes