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

Interactions
PK
Renal impairment
References

Amphotericin B (parenteral, inhalation)

Generic name
Amphotericin B (parenteral, inhalation)
Brand name
ATC Code
J02AA01

Pharmacokinetics in children

CONVENTIONAL AMFOTERICINE B:

  Vd (L/kg) T1/2 (hours) Clearance ml/min/kg (Benson et al., 1989)
Premature neonates(GA: 27,4 ± 5 weeks): - 14.8 hours (range 5 - 82)  -
4 mnd-18 years 0,23-1,91 
(Benson et al 1989, Koren et al 1988)		 - -
4 mnd-14 years - 18,1 ± 6,6 hours (range  11,9 tot 40,3 ) (Benson et al., 1989) -
8-9 years - - 0,57 ± 0,15
10-14 years - - 0,24 ± 0,02

Premature babies (GA: 27.4 ± 5 weeks): high inter-individual variability in pharmacokinetics;
Central nervous system penetration: cerebrospinal fluid concentration was 40-90% of serum concentration (Baley et al., 1990)

T1 / 2:
The data in the literature is sometimes contradictory.

There is some evidence that amphotericin B has a deep peripheral compartment in children (as well as adults). This would mean a longer terminal half-life. Steady state was not reached even after 7 to 18 days (Koren et al., 1988).

LIPOSOMAL AMPHOTERICIN B
Following administration of 2.5-10 mg / kg Ambisome to children aged 1-17 years, the following kinetic parameters have been found:
Cmax: 15-68 µg / ml
Cl: 38-60 ml / kg / hour; Clsteady state: 13 ml / kg / hour
t½: 10 hours

 

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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

Systemic mycosis: conventional amphotericine B
  • Intravenous
    • Term neonate
      [6] [7] [8] [9]
      • 1 mg/kg/day in 1 dose. Max: 1.5 mg/kg/day.
    • 1 month up to 18 years
      [1] [2]
        • 0,25 - 1 mg/kg/d in 1 dose; max. 1,5 mg/kg/d. The daily dose of 1mg/kg/d can be increased to 1,5mg/kg/d every other day in patients with severe infections. Infusion time: 2-6 h
        • Therapy needs to be started with 0,25 mg/kg/d and dosing inreased carefully
        • Nath et al. (2011) determined that Amphotericin B exposure giving a reference dose of 1 mg/kg is relatively lower in younger children with lower weight (danger of underdosing) in comparison to older, heavier ones (danger of overdosing)
Systemic mycoses
  • Intravenous
    • 0 years up to 18 years
      [13] [14] [15]
      • Amfotericine liposomal of lipid formulations: 3 - 5 mg/kg/day in 1 dose

      • The Abelcet manufacturer recommends a test dose of 0.1 mg / kg, max 1 mg. There is no scientific basis for this. Nor does it provide a reliable prediction for tolerance.

        Doses above 5,5 mg/kg/day are not proven to be more effective compared with lower doses, but may lead to increased toxicity. Cumulative doses above 10 gram should therefore be avoided. (SmPC Abelcet)
Visceral leishmaniasis
  • Intravenous
    • 1 month up to 18 years
      [13]
      • Liposomal or lipid formulation:  3 - 4 mg/kg/day in 1 dose for 10 days.

      • Alternative: 1-1.5 mg / kg / day in 1 dose for 21 days.

        In case of permanent immunocompromised status, secondary prophylaxis is indicated to prevent recurrence. Consult with an expert regarding the type, dose and interval of the secondary prophylaxis.
Pulmonary/respiratory mycoses
  • Inhalation
    • 1 month up to 18 years
      [12]
      • Liposomal formulation:  50 mg/dose once a week.

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Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2
adjustment not necessary
GFR 30-50 ml/min/1.73 m2
adjustment not necessary
GFR 10-30 ml/min/1.73 m2
Conventional Amphotericin B is contraindicated in severe kidney insufficiency. Liposomal or lipid formulations as well as collodidal dispersions of amphotericin B may be administerred without the need for dose adjustment
GFR < 10 ml/min/1.73 m2
A general recommendation is not provided

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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 children, the side effect profile is similar to that of adults.

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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

CONVENTIONAL AMPHOTERICIN B

The first dose should be applied under clinical observation.

Antipyretics such as Paracetamol and/or antihistaminics such as Diphenydramin or low dose corticosteroids can reduce acute side effects of conventional Amphotericin B which ocurred in patients before.

Sodium-supplementation before applying conventional Amphotericin B can reduce nephrotoxicity. Studies show that a high sodium intake of >4mEq/kg/d in perterms in advance to Amphotericin B therapy has proven to be protective [Holler 2004, Turcu 2009, Lannos 1991]. Cave: incompatibility of Amphotericin B solution with sodium-chloride solution! 

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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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Triazole and tetrazole derivatives
J02AC01
J02AC02
J02AC03
Other antimycotics for systemic use
J02AX06
J02AX04
J02AX01
J02AX05

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References

  1. Cheplapharm, SmPC Amphotericin B 50 mg Plv. z. Herst. e. Inf.lsg. (14538), https://www.univadis.at/, 01/2019
  2. Nath, CE, et al., Population pharmacokinetics of amphotericin B in children with malignant diseases, Br J Clin Pharmacol, 2001, 52(6), 671-80
  3. Lannos, A, et al., Effet of salt supplementation on amphotericin B nephrotoxicity, Kidney Int, 1991, 40(2), 302-8
  4. Turcu, R, et al., Influence of sodium intake on amphotericin B-inducednephrotoxicity among extremely premature infants, Pediatr Nephrol, 2009, 24, 497–505
  5. Holler, B, et al., Effects of fluid and electrolyte management on amphotericin B-induced nephrotoxicity among extremely low birth weight infants, Pediatrics, 2004, 113(6), 608-16
  6. Starke, JR, et al., Pharmacokinetics of amphotericin B in infants and children, J Infect Dis, 1987, 155(4), 766-74
  7. Warris, A, et al., ESCMID-ECMM guideline: diagnosis and management of invasive aspergillosis in neonates and children, https://www.escmid.org/escmid_publications/medical_guidelines/escmid_medical_guidelines/, 2019
  8. Hope, WW, et al., ESCMID guiedline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp., https://www.escmid.org/escmid_publications/medical_guidelines/escmid_medical_guidelines/, 2012
  9. Koren, G, et al., Pharmacikinetics and adverse effects of amphotericin B in infants and children, J Pediatr, 1988, 113(3), 559-63
  10. Benson, JM, et al., Pharmacokinetics of amphotericin B in children, Antimicrob Agents Chemother, 1989, 33(11), 1989-93
  11. Baley, JE, et al., Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates, https://www.univadis.at/, 1990, 116(5), 791-7
  12. Hartwig NC et al, Vademecum pediatrische antimicrobiele therapie, 2005
  13. Gilead Sciences International Limited, SmPC Ambisome (RVG 15610) 10 dec 2019, www.geneesmiddeleninformatiebank.nl
  14. Cephalon Ltd, SPC Abelcet (RVG 20850) 17-09-2018, www.geneesmiddeleninformatiebank.nl
  15. Pane ZD et al, Therapeutic strategies for invasive fungal infections in neonatal and pediatric patients: an update, Expert Opin Pharmacother, 2015, Apr;16(5), 693-10

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Changes

Changes