Pharmacokinetics in children

Half life however is shorter and clearance higher in children than in adults [SmPC].

The t½, Cl and Vd in neonates vary widely. The t½ varies between 4.9 and 14.6 hours, the Cl varies between 0.53 and 1.72 ml/kg/min and the Vd varies between 0.45 and 0.75 l/kg [Pacifici et al. 2009].

In children from 0-20 months and ≥ 5 kg, a Vd of 0.39 l/kg and a Cmax of 17.6 mg/l were observed [Zakova et al. 2009].

Vd in adolescents is 0,25 l/kg [SmPC].

The following kinetic parameters have been observed [Avent et al. 2002]:

	< 1200 g	1200-2000 g	> 2000 g
t½	10.3 hours	6 hours	5.9 hours
Vd	0.66 l/kg	0.58 l/kg	0.57 l/kg
Cmax	8 mg/l	8.6 mg/l	8.9 mg/l

The clearance of gentamicin is reduced in neonates who suffer hypothermia in hypoxic ischemic encephalopathy (HIE) [Frymoyer et al., Mark et al., Ting et al.]

In neonates during ECMO Vd can be increased to 0,5 - 0,75 l/kg and t1/2 prolonged to 7,6 - 10 h [Buck 2003, Moffett 2018].

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

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Severe infection, Gram-negative microorganisms

Intravenous Premature infants Postnatal age 0 days up to 7 days [8] Duration of pregnancy < 32 weeks: 5 mg/kg/48 hours should be given during 15-30 minutes Duration of pregnancy 32-37 weeks: 5 mg/kg/36 hours should be given during 15-30 minutes Dose depending on the plasma concentration Premature infants Postnatal age 1 week up to 4 weeks 4 mg/kg/day in 1 dose allow to run in over 15-30 minutes. Dose depending on the plasma concentration Term neonate 4 mg/kg/day in 1 dose Run in over 15-30 minutes. Dose depending on the plasma concentration:  The Dutch Association of Hospital Pharmacists (NVZA) recommends doing the first determination before the second administration. If gentamicin is only used empirically, determination of the levels can be omitted. 1 month up to 12 years [10] [21] [22] [23] 7 mg/kg/day in 1 dose Run in over 15-30 minutes.. Dose depending on the plasma concentration: The Dutch Association of Hospital Pharmacists (NVZA) recommends doing the first determination before the second administration. If gentamicin is only used empirically, determination of the levels can be omitted. 12 years up to 18 years [3] [21] [22] [23] 5 mg/kg/day in 1 dose Run in over 15-30 minutes.. In sepsis or critical illness (on ICU)  6-7 mg / kg / day may be needed. Dose depending on the plasma concentration: The Dutch Association of Hospital Pharmacists (NVZA) recommends doing the first determination before the second administration. If gentamicin is only used empirically, determination of the levels can be omitted.

Infection in hypoxic ischemic encephalopathy (HIE), treated with hypothermia
Intravenous Duration of pregnancy ≥ 36 weeks Postnatal age 0 days up to 1 day [11] [12] [13] [14] [15] 5 mg/kg per 36 hours in 1 dose

Plague
Intravenous 1 month up to 18 years [4] 5 - 7 mg/kg/day in 1 dose Duration of treatment: 10 days Intramuscular 1 month up to 18 years [4] 5 - 7 mg/kg/day in 1 dose Duration of treatment: 10 days

Tularemia
Intravenous 1 month up to 18 years [5] 5 - 7.5 mg/kg/day in 3 doses. Duration of treatment: at least 10 days

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Dose reduction: Depending on the levels (see warnings and precautions), interval extension: 24-48 hours

GFR 30-50 ml/min/1.73 m2

Dose reduction: Depending on the levels (see warnings and precautions), interval extension: 48 hours

GFR 10-30 ml/min/1.73 m2

Dose reduction: Depending on the levels (see warnings and precautions), interval extension: 48 hours

GFR < 10 ml/min/1.73 m2

Dose reduction and interval lengthening: Depending on the levels (see warnings and precautions)

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

Ototoxicity and nephrotoxicity

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

Check the renal, hearing and balance functions regularly during the treatment, particularly in the elderly, in young children, neonates and premature infants (determine the creatinine twice a week). In cases of impaired renal function, the possibility of accumulation cannot be excluded, so plasma concentration measurements are indicated.

Target levels in neonates and children [Dutch Association of Hospital Pharmacists – Therapeutic drug monitoring of gentamicin]:
Neonates:
Peak level: 8-12 mg/l (in infections with microorganisms for which the MIC is < 1 mg/l)
Trough level: < 0.5-1 mg/l

Children aged > 1 month
Peak level: 15-20 mg/l
Trough level: < 0.5-1 mg/l

Use caution in pediatric patients on ECMO-therapy: the pharmacokinetics of aminoglykosides might change [Buck 2003, Moffett 2018].

Interactions

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

• ANTIINFECTIVES FOR SYSTEMIC USE
• ANTIBACTERIALS FOR SYSTEMIC USE

AMINOGLYCOSIDE ANTIBACTERIALS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

Other aminoglycosides
	Amikacin Related Medicines Menu">	J01GB06

References

1. Hartwig NC, et al, Vademecum pediatrische antimicrobiele therapie, 2005
2. Ratiopharm Nederland BV, SPC Gentamicine (RVG 56478), www.cbg-meb.nl, Geraadpleegd 06 aug 2010, http://db.cbg-meb.nl/IB-teksten/h56478.pdf
3. Centrafarm BV, SPC Gentamicine (RVG 57571) 20-05-2014, www.geneesmiddeleninformatiebank.nl, Geraadpleegd 28 okt 2015
4. LCI, Richtlijn Pest, 10-12-2013
5. LCI, Richtlijn Tularemie, mei 2017
6. Pacifici GM. , Clinical pharmacokinetics of aminoglycosides in the neonate: a review., Eur J Clin Pharmacol., 2009, Apr;65(4):, 419-27
7. Zakova M et al., Dose derivation of once-daily dosing guidelines for gentamicin in critically ill pediatric patients. , Ther Drug Monit. , 2014, Jun;36(3):, 288-94
8. Avent ML et al., Gentamicin and tobramycin in neonates: comparison of a new extended dosing interval regimen with a traditional multiple daily dosing regimen. , Am J Perinatol., 2002, Nov;19(8):, 413-20
9. Coenradie S et al. , TDM Gentamicine, www.tdm-monografie.org, 08-07-2015
10. Medellín-Garibay SE et al, Population pharmacokinetics of gentamicin and dosing optimization for infants, Antimicrob Agents Chemother, 2015, Jan;59(1), 482-9
11. Bijleveld YA et al. , Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia., Br J Clin Pharmacol., 2016 , Jun;81(6), 1067-77
12. Frymoyer A et al. , Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia., Pharmacotherapy. , 2013 , Jul;33(7):, 718-26
13. Frymoyer A et al. , Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia., J Perinatol. , 2013 , Oct;33(10):, 778-82
14. Mark LF et al. , Gentamicin pharmacokinetics in neonates undergoing therapeutic hypothermia., Ther Drug Monit. , 2013 , Apr;35(2):, 217-22
15. Ting JY et al. , Pharmacokinetics of gentamicin in newborns with moderate-to-severe hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia., Indian J Pediatr. , 2015 , Feb;82(2):, 119-25
16. Buck, ML, et al., Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates, Clin Pharmacokin, Clin Pharmacokin, 42(5), 403-17
17. Merck, SmPC Refobacin 10 mg Amp. (14374), https://www.univadis.at/, 03/2018
18. Cohen, P, et al., Gentamicin pharmacokinetics in neonates undergoing extracorporal membrane oxygenation, Pediatr Infect Dis J, 1990, 9, 562–566
19. Moffett, BS, et al., Population Pharmacokinetic Analysis of Gentamicin in Pediatric Extracorporeal Membrane Oxygenation, Ther Drug Monit, 2018, 40(5), 581-588
20. Touw, DJ, et al., Therapeutic drug monitoring of aminoglycosides in neonates, Clin Pharmacokin, 2009, 48(2), 71-88
21. Bialkowski S, et al, Gentamicin Pharmacokinetics and Monitoring in Pediatric Patients with Febrile Neutropenia. , Ther Drug Monit., 2018, 38(6), 693-98
22. Inparajah M, et al , Once-daily gentamicin dosing in children with febrile neutropenia resulting from antineoplastic therapy., Pharmacotherapy., 2010, 30(1), 43-51
23. McDade EJ, et al, Once-daily gentamicin dosing in pediatric patients without cystic fibrosis., Pharmacotherapy. , 2010, 30(3), 248-53

Changes

Therapeutic Drug Monitoring

Overdose