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

Interactions
PK
Renal impairment
References

Aciclovir

Generic name
Aciclovir
Brand name
ATC Code
J05AB01

Pharmacokinetics in children

 

The following pharmacokinetic parameters have been found in a PopPK study in immunocompromised children (1.4 – 18.1 years) (n=120) undergoing prophylaxis or treatment for HSV-VZV infection during hematopoietic stem cell transplant (HSCT) or chemotherapy, after IV administration [6]:Acyclovir is partially metabolized into 9-carboxymethoxymethylguanine, while the remaining portion is excreted unchanged in the urine. Acyclovir is primarily excreted through the kidneys, with 75-80% of the drug eliminated unchanged via glomerular filtration and tubular secretion. The remaining 10-15% is excreted in the urine as 9-carboxymethoxymethylguanine. In adults with normal renal function, the plasma elimination half-life is approximately 2.9 hours [SmPC, Drugbank].

The body weight and renal function influence the clearance of acyclovir; an increased body weight is associated with higher clearance[Abdalla 2020; Zeng 2009; Maximova 2022]

The following kinetic parameters are available for preterm and term neonates [Hintz M 1982, Sampson MR 2014, Blum MR 1984]: 

PMA <30 weeks (n=13) 30 - 35 weeks (n=9) 36-41 weeks (n=6)
Dose 20 mg/kg/Tag 20/40/60 mg/kg/Tag 60 mg/kg/Tag
Cmax (mg/l) 10.3 (4.59-110) 8.83 (5.44-29.8) 12.4 (10.8-86.1)
t½ (h) 10.2 (4.73-13.2) 6.55 (4.28-9.26) 3.0 (1.61-3.69)
Cl (l/h/kg) 0.211 (0.095-0.31) 0.449 (0.302-0.812) 0.59 (0.126-0.77)
Vd (l/kg) 2.88 (0.646-5.30) 4.49 (1.87-10.85) 2.55 (0.293-4.09)

 

Dose 5 mg/kg 10 mg/kg 15 mg/kg
Cmax (µM) 30.0 ± 9.9 61.2 ± 18.3 86.1 ± 23.5
t½ (h) 4.03 ± 1.56 4.07 ± 1.53 3.24 ± 0.69
Cl (ml/min/1.73 m²) 122 ± 51 98 ± 34 108 ± 43
Vd (l/1.73 m²) 30.0 ± 2.0 28.9 ± 11.3 24.1 ± 6.3

The following pharmacokinetic parameters have been found in immunocompromised children (1.4 – 18.1 years) (n=18) with cancer, after IV administration [Eksborg 2002]:

  Mean [median] (range)
Dosis mg/kg [10,5] 4,9-23,3
AUC (µmol/hr/L) 113 (59-224)
AUC (mg/kg) 11.09 (5,33-21,39)
AUC (mg/m2) 0,423 (0,221-0,754)
Cmax (µmol/L) 62,4 (29,2-120,7)
T1/2 (hr) 1,80 (1,20-3,29)

The following pharmacokinetic parameters have been found in a PopPK study in immunocompromised children (1.4 – 18.1 years) (n=120) undergoing prophylaxis or treatment for HSV-VZV infection during hematopoietic stem cell transplant (HSCT) or chemotherapy, after IV administration [Maximova 2022]:

  Mean ± SD
Dose (mg) 334 ±158,2
AUC (mg/hr/L) 26 ± 13,2
Cl (L/hr) 14 ± 5,5
Vd (L) 25,4 ± 8,7
T1/2 (hr) 1,364 ± 0,614

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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

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Dosages

HSV/VSV infection
  • Oral
    • 1 month up to 18 years
      [4] [6]

      • The bioavailability of oral aciclovir is very poor. For oral application, treatment with valaciclovir is therefore preferred.
Herpes simplex infections (normal and deficient immune response), recurrent Varicella zoster infection (normal immune response)
  • Intravenous
    • 3 months up to 12 years
      [5]
      • 30 mg/kg/day in 3 doses.
      • Duration of treatment:

        10 days

    • 12 years up to 18 years
      [5]
      • 15 mg/kg/day in 3 doses.
      • Duration of treatment:

        5 dagen
Herpes simplex encephalitis (normal immune system); primary and recurrent Varicella Zoster infection in immuno-compromised children
Herpes neonatorum
  • Intravenous
Herpes-simplex-Enzephalitis (immunkompetent); primäre/rezidivierende Varicella-Zoster-Infektion (immungeschwächt)
  • Intravenous
    • Premature neonates: Gestational age < 37 weeks
      [8] [25]
      • 60 mg/kg/day in 3 doses.
    • Term neonate
      [8] [10] [16] [35]
      • 60 mg/kg/day in 3 doses.
    • 1 month up to 3 months
      [38]
      • 60 mg/kg/day in 3 doses.
    • 3 months up to 18 years
      [29]
      • 45 mg/kg/day in 3 doses.

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Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2
No dose adjustment needed.
GFR 30-50 ml/min/1.73 m2
100 percentage of single dose and dosing interval : 12 uur
GFR 10-30 ml/min/1.73 m2
100 percentage of single dose and dosing interval : 24 uur
GFR < 10 ml/min/1.73 m2
50 percentage of single dose and dosing interval : 24 uur Generalized recommendations cannot be given. Discuss with the paediatric nephrologist.
Clinical consequences

Risk of neurological reactions, including hallucinations, convulsions and coma. Increase of urea and creatinine concentrations, followed by renal failure; in this case, the infusion time should be extended.

Adjusting the dose influences the trough level. If the trough level is not high enough, the antiviral effect may not be sufficient; this can lead to resistance.

Patients on dialysis

Hemodialysis: 50% of normal single dose and interval between doses: 24 hours. Administer on dialysis days after dialysis

CVVH: 100% of the normal dose and interval between two doses: 24 hours, based on drugconcentration levels.

 

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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

In neonates: watch for neutropenia (in about 20%; usually resolves spontenously during use or after discontinuation) and reduction in renal function (nephrotoxic in about 6%).

Anecdotal reports have described neurotoxicity and nephrotoxicity in children older than 3 months receiving doses of 60 mg/kg/day. Issues of neurotoxicity with higher doses of acyclovir have not been observed in neonates and infants under 3 months of age [Kimberlin 2013].

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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

  • Determination of the blood count every two weeks.
  • In high doses or in infusions, monitor the fluid balance, particularly in cases of renal function disorder.
  • Dose adjustment is needed for renal function disorders.
  • In neonates on high doses of aciclovir, neutropenia and nephrotoxicity must be monitored as these occur in 20% and 6% of cases respectively.
  • Determine the creatinine twice weekly. For oral application, valaciclovir is preferred.
  • In obese children, dosing based on IBW is preferred (max. dose of 800 mg)[Ross 2015; NHS 2021]

 

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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
J05AB04
J05AB11
J05AB14
Protease inhibitors
J05AE10
J05AE03
Nucleoside and nucleotide reverse transcriptase inhibitors
J05AF10
J05AF05
J05AF01
Non-nucleoside reverse transcriptase inhibitors
J05AG01
Neuraminidase inhibitors
J05AH02
Antivirals for treatment of HIV infections, combinations
J05AR02
J05AR10
Other antivirals
J05AX12
J05AX08
ANTIVIRALS FOR TREATMENT OF HIV INFECTIONS, COMBINATIONS
J05AR02
J05AR10
Antivirals for treatment of HCV infections
J05AP57
J05AP08
J05AP55

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References

  1. AVOXA, ABDA-Datenbank Interaktionen (BRD) Aciclovir, accessed 2018-07-12
  2. Hartwig NC, et al, Vademecum pediatrische antimicrobiele therapie, 2005
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  4. Nadal D, et al, An investigation of the steady-state pharmacokinetics of oral valacyclovir in immunocompromised children, J Infect Dis, 2002, Oct 15;186 Suppl 1, S123-30
  5. Eksborg S, et al, Pharmacokinetics of acyclovir in immunocompromized children with leukopenia and mucositis after chemotherapy: can intravenous acyclovir be substituted by oral valacyclovir?, Med Pediatr Oncol., 2002, 38, 240-6
  6. GlaxoSmithKline BV, SPC Zovirax IV (RVG 09696) 09-09-2022, www.geneesmiddeleninformatiebank.nl
  7. de Miranda P, et al, Pharmacokinetics of acyclovir after intravenous and oral administration, J Antimicrob Chemother, 1983, Sep;12 Suppl B, 29-37
  8. Hintz M, et al, Neonatal acyclovir pharmacokinetics in patients with herpes virus infections., Am J Med, 1982, Jul 20;73(1A), 210-4
  9. Kimberlin DW, et al, Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections, Pediatrics, 2001, Aug;108(2), 230-8.
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  20. Shepp DH, et al, Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine, N Engl J Med, 1986, Jan 23;314(4), 208-12.
  21. Prober CG, et al, Acyclovir therapy of chickenpox in immunosuppressed children--a collaborative study., J Pediatr., 1982, Oct;101(4):622-5, 622-5
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  23. Balfour HH, Jr., Intravenous acyclovir therapy for varicella in immunocompromised children, J Pediatr, 1984, Jan;104(1), 134-6
  24. HJC de Vries et al, Richtlijn SOA voor de tweede lijn, Nederlandse Vereniging voor Dermatologie en Venereologie (NVDV). , www.huidarts.info, 2012, 114
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  28. Hexal, SmPC Acic® Tabletten (30775.00.00), 02/2017
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Changes

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