RCH logo

Pharmacy

Valganciclovir and Ganciclovir Medication Guideline

  • Valganciclovir and Ganciclovir Medication Guideline for cytomegalovirus infection in paediatric immunosuppressed patients

    Introduction  

    Ganciclovir and valganciclovir are antiviral agents primarily indicated for treatment and prevention therapy of detected cytomegalovirus (CMV) infections in immunosuppressed patients. Patients including children treated with chemotherapy and/or haemopoietic stem cell transplants (HSCT) have compromised immune function and are associated with significant increased risk of CMV infection. Treatment is necessary if CMV viral load is detected as it is associated with significant morbidity and mortality in immunocompromised patients. (4, 6, 7) 

    Aim 

    To provide guidance on the dosing of ganciclovir and valganciclovir in immunocompromised children.

    Definition of terms 

    Table 1 

    CMV   Cytomegalovirus  
    HSCT   Haemopoietic stem cell transplant 
    CrCl   Creatinine clearance  
    BSA  Body Surface Area 
    GCSF  Granulocyte colony stimulating factor 


    Indication 

    For the treatment and prevention therapy of detected cytomegalovirus (CMV) infection in immunocompromised children and/or HSCT recipients.   

    Dose

    Ganciclovir  

    Intravenous ganciclovir is indicated in initial treatment of CMV infection. Aciclovir should be withheld or discontinued whilst on ganciclovir. 

    Table 2 


    Ganciclovir  Dose  Duration 

    INDUCTION 

    (>1 month of age): 

    		 5 mg/kg intravenous every 12 hours.*# 

    Dependent on severity of the disease.  

    Typically, 14 - 21 days, followed by maintenance therapy.   

    MAINTENANCE 

    (>1 month of age): 

    		 5 mg/kg intravenous every 24 hours* 

    Individual patient decision.  

    Consider duration and degree of immunosuppression.  

    *Dose adjustment required in renal impairment (see table 3) 

    # Dose may be increased to 7.5 mg/kg every 12 hours if inadequate response.  

    Ganciclovir is a cytotoxic agent, an oncology pharmacist must be contacted to arrange timely compounding and supply of ganciclovir.  At the RCH, please contact 52526 (weekdays) or oncology pharmacist on call via switch if after hours or on weekends. 

    Dose adjustment in renal impairment  


    Ganciclovir is excreted, unmodified in the urine and clearance is directly correlated to glomerular filtration rate. Dose adjustment is therefore required in renal impairment. Contact the ward pharmacist for further details or if a patient has been transitioned to renal replacement therapy (RTT)   

    Table 3: Ganciclovir renal adjustment dosing recommendations

     
    Age  CrCl*  Induction dose  Maintenance dose 

     

     

    > 1 month to 18 years 

    		 >70mL/min 

    5 mg/kg every 12h 

    		 5 mg/kg every 24h 
    50-69 mL/min 

    2.5 mg/kg every 12h 

    		 5 mg/kg every 24h 
    25-49 mL/min  2.5 mg/kg every 24h  1.25 mg/kg every 24h 
    10-24mL/min  1.25 mg/kg every 24h 

    0.625 mg/kg every 24h 
    <10 mL/min  1.25 mg/kg 3 x a week after haemodialysis  0.625 mg/kg 3 x a week after haemodialysis# 

    *CrCl = using Schwartz Creatinine Clearance or Cockcroft and Gault (if >16 years) 

    # Refer to pharmacist if not on haemodialysis.  

    Dose adjustment in hepatic impairment: 

    No dose adjustment recommended.  

    Valganciclovir 

    Valganciclovir is the oral prodrug of ganciclovir. It is indicated for treatment and prophylaxis of CMV infection after appropriate response to intravenous ganciclovir induction.  Initiate only when patient is tolerating an enteral diet. Aciclovir should be withheld or discontinued whilst on valganciclovir.  


    Table 4 

    Valganciclovir 

    Dose (mg) 

    Duration 

    INDUCTION 

    (>1 month of age): 

     

    7 x BSA x CrCl* oral every 12 hours  

                        Max 900mg/dose 

    Dependent on severity of the disease.  

    Typically, 14- 21 days, followed by maintenance therapy.   

    MAINTENANCE 

    (>1 month of age): 

     

    7 x BSA x CrCl* oral every 24 hours  

                       Max 900mg/dose 

     

    Individual patient decision.  

    Consider duration and degree of immunosuppression.  

    *Schwartz creatinine clearance or Cockcroft and Gault (if >16 years) 

    Note: If creatinine clearance is >150 mL/min/1.73 m2 use 150 mL/min/1.73 m2 value  

    Valganciclovir presentation:  

    • Tablets: 450 mg   
    • Oral solution: 50 mg/mL  

    Doses in tablet and liquid form should be rounded to the nearest 25 mg.  

    Use tablets if the calculated dose is within 10% of the available tablet form.   

    For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet should be prescribed.   

    Dose adjustment in renal impairment

    As with ganciclovir, valganciclovir requires dose adjustment in renal impairment. 

    Table 5: Valganciclovir renal adjustment dosing recommendations 
    Age  CrCl*  Induction dose  Maintenance dose 

     

     

    > 1 month to 18 years 

    		 ≥60 mL/min  Normal dosing  Normal dosing 
    40-59 mL/min 

    50% of the standard dose given 12 hourly 

    		 50% of the standard dose given 24 hourly 
    25-39 mL/min 

    50% of the standard dose given 24 hourly 

    		 50% of the standard dose given 48 hourly 
    10-24mL/min  50% of the standard dose given 48 hourly  50% of the standard dose given twice weekly 
    <10 mL/min 

    Avoid#  

    Consider ganciclovir  

    Avoid#  

    Consider ganciclovir 

    *CrCl = using Schwartz Creatinine Clearance or Cockcroft and Gault (if >16 years) 

    # Refer to pharmacist if not on haemodialysis.  

    Dose adjustment in hepatic impairment: 


    No dose adjustment recommended.  


    Monitoring requirements


    • CMV blood viral load
      • Weekly whilst in induction therapy 
    • FBC, LFTs, serum creatinine   
    • Height and body weight
      • Dose adjust appropriately  
    • CMV retinitis: refer to ophthalmology for eye examination on commencing intravenous ganciclovir and continue monitoring as per viral load 

    Administration

    Ganciclovir 

  • Avoid rapid administration.  

    •  Valganciclovir:  

    • Cytotoxic precautions should be followed.  
    • Parents should be counselled to use gloves to handle the tablets and to use oral syringes to measure the oral solution.  
    • Whenever possible, doses should be taken with food.  
    • Do not crush or chew tablets.  

    Ganciclovir Therapeutic Drug Monitoring

    Monitoring of treatment by determining the area under the concentration-time curve should be performed in those with active CMV infection to ensure the therapeutic target is achieved. Ganciclovir therapeutic drug monitoring should only be calculated by staff experienced in medication monitoring.  Two samples are required to be collected (see below).  Samples should be collected within the first week of treatment and measured weekly until the target is achieved.  Further monitoring is only required if there is a dose adjustment, there is a >20% change in body weight or the renal function changes by 0.5 x baseline.  

    Samples are processed in Queensland and are sent weekly by the RCH lab on Wednesdays.  

    Timing of samples required:

    • Peak: 1 to 4 hours after completion of ganciclovir dose 
    • Trough: 30 minutes to 1-hour pre ganciclovir dose 

    Note: Both samples are required for AUC calculation. Specimen container options:  Send sample in a serum-gel' tube, minimum volume 2mL, preferred volume 5mL. https://www.rch.org.au/specimen-collection/Ganciclovir_Level/

    • To reduce the risk of contamination when collecting blood samples draw back and discard 5 mL of blood, before taking sample. 

    Calculating AUC for ganciclovir and valganciclovir:  

    Only staff experienced in ganciclovir AUC calculation should carry out monitoring and dose adjustments. Use the following AUC online calculator: Use the following AUC online calculator: kidscalc.org.

    The following data is required: 

    Dose records – enter the three doses given prior to measurement of ganciclovir levels:

    • Date and time of doses in complete 24-hour format (e.g. 18:36 rather than 6:36pm)
    • Dose
    • Infusion time  

    Ganciclovir sampling information - enter the results of the two ganciclovir levels (peak and trough):

    • Date and time of samples taken
    • Two ganciclovir levels (mg/L) 

    Weight and Renal function

    • Most recent weight (kg) 
    • Serum creatinine level (umol/L) 

    Note: Please exit the calculator when not in use. 

    Target treatment AUC: 

    AUC: 40 to 100 mg/L*h

    Dose Adjustments  

    Dose adjustments should be made based on linear dose adjustments i.e. 

    Adjusted total daily dose = Target AUC (i.e. 50 mg/L*h) / Calculated AUC x Total daily dose received 

    Note: Do not exceed doses of 7.5mg/kg/dose without prior discussion with the Infectious Diseases team or ward pharmacist.

    If a dose adjustment has been made, repeat TDM monitoring 48 hours after dose adjustment. 

    Conversion between ganciclovir and valganciclovir  

    Use dosing calculations above to transition between intravenous and oral.  

    Note: oral valganciclovir 900 mg twice a day is equivalent to ganciclovir 5 mg/kg intravenous 12 hourly in adult literature.  

    Medication Interactions 

    Medication  

    Interaction description  

    Action 
    Imipenem-cilastatin  Seizure risk of imipenem increased.   Avoid combination unless benefit outweighs risk.  
    Mycophenolate mofetil   Combination increases risk of neutropenia   Monitor FBC 
    Nephrotoxic agents e.g., ciclosporin, tacrolimus, aminoglycosides, and amphotericin (including liposomal)  Increased risk of nephrotoxicity and reduced clearance of ganciclovir thus increased myelosuppression.   Monitor renal function and blood cell count  
    Trimethoprim and sulfamethoxazole (Treatment dosing)  Both are myelosuppressive and nephrotoxic   Monitor renal function and blood cell count 

    Adverse Reactions 

    Gastrointestinal: Abdominal pain, diarrhoea, vomiting, raised LFTs, hepatitis  

    Haematological: Bone marrow suppression (consider granulocyte-colony stimulating factors if necessary) 

    Renal: Raised creatine, nephrotoxicity (dose adjustment required)  

    Reproductive: Spermatogenesis and infertility (animal data) 

    Other: Confusion, fever, rigors, and peripheral neuropathy.  

    Preparation 

    Intravenous ganciclovir should not be prepared by nursing staff on the ward due to its hazardous profile. It is prepared using cytotoxic compounding techniques in ae sterile cytotoxic manufacturing facility. Valganciclovir powder for oral liquid must also be prepared by reconstitution in pharmacy.  

    Precautions 

    Bone marrow suppression.  

    • Neutropenia ( <0.5x 109 cells/L) 
    • Thrombocytopaenia (platelet count <25 x 109 cells/L), or  
    • Anaemia (haemoglobin <80 g/L). 

    Administration  

    • Intravenous: Ganciclovir has a low pH. Monitor site for phlebitis and avoid rapid infusion. Avoid direct contact with solution. Cytotoxic precautions should be used on the handling of ganciclovir.  
    • Tablets and oral solution: Avoid direct contact with solution or broken/crushed tablets with skin or mucous membranes. Cytotoxic precautions should be used on the handling of valganciclovir.  
    • If direct contact  with skin or mucous membranes occurs, refer to: Policies and Procedures : Hazardous Medicines – Management of spills and accidental personal exposure (rch.org.au)  

    Fertility 

    Ganciclovir and valganciclovir are reported to cause teratogenic and oncogenic effects in animal studies.  Oral contraception in sexually active adolescent patients is recommended with use.   

    Resistance testing  

    Refer to Infectious Diseases team if resistance is suspected for testing and management.  

    Compatibility 

    Fluid compatibility: refer to Paediatric Injection Guideline. 

    Medication compatibility: refer to Australian Injectable Drugs Handbook  

    Storage and Handling

    • Ganciclovir and valganciclovir should be handled with cytotoxic precautions.  
    • The tablets should not be broken or crushed.  
    • The storage requirements for prepared IV doses of ganciclovir may vary, refer to the product label for storage instructions.

    Links  

    Hazardous Medicines – Management of spills and accidental personal exposure   

    Hazardous Medicines – The safe handling of  


    References 


    1. Antibiotic Therapeutic Guidelines [internet]. 2021. Therapeutic Guidelines Limited; West Melbourne, Australia; [Accessed 4th April 2022]   
    2. IBM Micromedix solutions [internet] IBM Watson Heath; Greenwood Village, USA; 2021 [c 2021].  
    3. Lexicomp [internet].  2021. Ganciclovir (systemic):Paediatric drug information. Wikters Kluwer Health, Inc; Riverwoods, USA;  [Accessed 4th April 2022]  
    4. AMH Children’s Dosing Companion [internet]. Australian Medicines Handbook Pty Ltd; Adelaide, Australia; [Accessed 4th April 2022] .  
    5. Paediatric Formulary Committee. 2021. BNF for Children: 2021-2022. London: BMJ Group Pharmaceutical Press; [Accessed 4th April 2022] . 
    6. Bontant T, et al. 2014. Survey of CMV management in pediatric allogeneic HSCT programs, on behalf of the inborn errors, infectious diseases and pediatric diseases working parties of EBMT. Bone Marrow Transplant.  Feb;49(2):276-9. 
    7. Stockmann C, Roberts JK, Knackstedt ED, Spigarelli MG, Sherwin CM. 2015. Clinical pharmacokinetics and pharmacodynamics of ganciclovir and valganciclovir in children with cytomegalovirus infection. Expert Opin Drug Metab Toxicol.;11(2):205-219. 
    8. Duval X, Lemaitre F, Pertuisel S, Probert J, Gandemer V, Verdier MC, Tron C. 2021.The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report. BMC Infect Dis. Nov 8;21(1):1143.
    9. Franck B, et al, 2021. Population pharmacokinetics of ganciclovir and valganciclovir in paediatric solid organ and stem cell transplant recipients. Br J Clin Pharmacol. Aug;87(8):3105-3114 
    10. Jorga, K., Reigner, B., Chavanne, C., Alvaro, G., & Frey, N. 2019. Pediatric Dosing of Ganciclovir and Valganciclovir: How Model-Based Simulations Can Prevent Underexposure and Potential Treatment Failure. CPT: pharmacometrics & systems pharmacology, 8(3), 167–176.
    11. Villeneuve D, Brothers A, Harvey E, et al. 2013. Valganciclovir dosing using area under the curve calculations in pediatric solid organ transplant recipients. Pediatr Transplant 17(1):80-5 
    12. Kimon, Z.2022. Ganciclovir and valganciclovir: An overview. Lexicomp [internet]. Wikters Kluwer Health, Inc; Riverwoods, USA;  [Accessed 4th April 2022] 
    13. MIMS Australia. 2022. Ganciclovir. In MIMS Online. [Accessed 4th April 2022] 
    14. MIMS Australia. 2022. Valganciclovir. In MIMS Online. [Accessed 4th April 2022] 
    15. UK Renal Pharmacy Group. The Renal Drug Database [internet]. CRC Press. [Accessed 16th May 2022] 
    16. Kang D, Bae KS, Houk BE, Savic RM, Karlsson MO. Standard Error of Empirical Bayes Estimate in NONMEM® VI. Korean J Physiol Pharmacol. 2012;16(2):97-106. 

    Revision and approval history 

    Author  Reviewer  Effective Date  Review Date 
    Heather Weerdenburg 
    Senior Clinical Paediatric Oncology PharmacistAmanda GweeInfectious Diseases Physician     		 Paediatric Intensive Care Pharmacist Improvement Manager - Medication Safety Medication Safety Committee   13/6/2024 13/6/2027 

     

    Disclaimer

    RCH Medication guidelines are targeted at clinicians only. Health information for patients and families is available through Kids Health Info.

    The authors of these guidelines have made considerable efforts to ensure the information upon which they are based is accurate and up to date. Users of these guidelines are strongly recommended to confirm that the information contained within them, especially drug doses, is correct by way of independent sources. The authors accept no responsibility for any inaccuracies, information perceived as misleading, or the success or failure of any treatment regimen detailed in the guidelines.