Pharmacokinetics in children

The kinetic parameters for amoxicillin and clavulanic acid (90 mg/kg/day (14:1) in 2 doses) in children aged 8 months – 11 years are as follows:
Cmax: 15.7 ± 7.7 mcg/ml and 1.7 ± 0.9 mcg/ml respectively (average (SD))
Cl/F: 0.9 ± 0.4 l/hour/kg and 1.1 ± 1.1 l/hour/kg respectively (average (SD))
Tmax: 2.0 (1.0 – 4.0) hours and 1.1 (1.0 – 4.0) hours respectively (median (range))
T½: 1.4 ± 0.3 hours and 1.1 ± 0.3 hours respectively (average (SD))

The Paediatric Antimicrobial Therapy vademecum of the ErasmusMC/Sophia Hospital gives the following half-lives in neonates:
< 1 week, < 2 kg: amoxicillin 6 – 8 hours, clavulanic acid 2 – 4 hours.
< 1 week, > 2 kg: amoxicillin 2 – 4 hours, clavulanic acid 2 hours.
1 – 4 weeks, > 2 kg: amoxicillin 2 hours.

In a pooled popPK study by Keij et al. 2023, absorption of amoxicillin in neonates was estimated to be delayed. Tmax was estimated to be 9 hours. This would lead to a gradually increase in plasma concentration and justify twice daily dosing. Clearance (L/h/kg) in neonates born after 30 weeks’ gestation was found to increase with postnatal age (PNA day 10, 1.25-fold; PNA day 20, 1.43-fold vs PNA day 3). Oral bioavailability was estimated to be 87%. [Keij 2023]
 

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

CAUTION:
Route of administration not applicable 0 years up to 18 years All dosing recommendations below are based on the amoxicillin component. Dosing of the clavulanic acid component depends on the product follows.Respect the indicated maximum doses for clavulanic acid.

Bacterial infections
Oral 1 month up to 18 years [2] [3] [4] [5] [6] [7] [8] [20] [21] Amoxicillin/clavulanic acid 8:1 50/6.25 mg/kg/day in 3 doses. Max: 1500/187.5mg/day. Range: 40/5 - 60/7.5 mg/kg/day amoxicillin/clavulanic acid Amoxicillin/clavulanic acid 4:1 50/12.5 mg/kg/day in 3 doses. Max: 1500/375mg/day. Range: 40/10-60/15 mg/kg/day amoxicillin/clavulanic acid

Severe bacterial infections

Intravenous < 1 week and weight at birth < 2000 g [1] Amoxicillin/clavulanic acid 10:1 : 50 / 5 mg/kg/day in 2 doses < 1 week and weight at birth ≥ 2000 g [1] Amoxicillin/clavulanic acid 10:1 : 75 / 7,5 mg/kg/day in 3 doses 1 week up to 4 weeks and weight at birth < 2000 g [1] Amoxicillin/clavulanic acid 10:1 : 75 / 7,5 mg/kg/day in 3 doses 1 week up to 4 weeks and weight at birth ≥ 2000 g [1] Amoxicillin/clavulanic acid 10:1  100/10 mg/kg/day in 3 doses 1 month up to 18 years [19] Amoxicillin/clavulanic acid 10:1  100/10 mg/kg/day in 3 doses, max 12.000 mg / 600 mg per day If maximum dosage of clavulanic acid interferes with higher dosages for amoxicillin: consider alternating amoxicillin+ clavulanic acid with amoxicillin alone (alternately). Oral 1 month up to 18 years [21] Amoxicillin/clavulanic acid 8:1  : 80/10 – 90/11,25 mg/kg/day in 3 doses. Max: 6000 mg/375 mg per day. Amoxicillin/clavulanic acid 4:1   80/20– 90/22,5mg/kg/day in 3 doses . Max: 6000 mg/ 375 mg per day. If maximum dosage of clavulanic acid interferes with higher dosages for amoxicillin: consider alternating amoxicillin+ clavulanic acid with amoxicillin alone (alternately).

Surgical prophylaxis in procedures < 1 hour
Intravenous ≥ 40 kg Amoxicilline/clavulaanzuur 10:1  1000/100-2000/200 mg/dosis

Surgical prophylaxis in procedures > 1 hour
Intravenous ≥ 40 kg Amoxicillin/clavulanic acid 10:1 1000/100-2000/200 mg/dose. Max repeat 3 times in 24 hours.

Infections (without clinical suspicion of meningitis) caused by microorganisms susceptible at increased exposure ('I')

Oral 1 month up to 18 years [38] [39] Amoxicillin/clavulanic acid 8:1   60/7,5– 90/11,25 mg/kg/day in 3 doses. Max: 6000 mg/375 mg per day. Amoxicillin/clavulanic acid 4:1   60/15– 90/22,5mg/kg/day in 3 doses. Max: 6000 mg/ 375 mg per day.   If maximum dosage of clavulanic acid interferes with higher dosages for amoxicillin: consider alternating amoxicillin+ clavulanic acid with amoxicillin alone (alternately). Intravenous 1 month up to 18 years [38] [39] Amoxicillin/clavulanic acid 10:1  100/10 mg/kg/day in 3 doses max 12.000 mg/ 600 mg/day. If maximum dosage of clavulanic acid interferes with higher dosages for amoxicillin: consider alternating amoxicillin+ clavulanic acid with amoxicillin alone (alternately).

Suspected neonatal bacterial infection (in the absence of positive culture)

Oral Gestational age ≥ 34 weeks [40] [41] After initial treatment with IV antibiotics: Amoxicillin/clavulanic acid 4:1: 60/15 mg/kg/day in 2 doses Amoxicillin/clavulanic acid 8:1: 60/7.5 mg/kg/day in 2 doses Intravenous Gestational age 34 weeks up to 41 weeks [40] Postnatal age 0-7 days: amoxicillin/clavulanic acid 10:1 :  50/5 mg/kg/day in 2 doses Postnatal age 8-28 days: amoxicillin/clavulanic acid 10:1:  75/7,5 mg/kg/day in 3 doses

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Adjustment is not required

GFR 30-50 ml/min/1.73 m2

Adjustment is not required

GFR 10-30 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 12 uur

GFR < 10 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 24 uur

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

Gastrointestinal problems such as nausea, vomiting, diarrhoea, dyspepsia and abdominal pain, allergic reaction, exanthema, abnormalities of the blood count such as agranulocytosis and thrombocytopenia in high doses. Also rash and allergic reactions.

Hepatic reactions were rarely observed in children [SmPC].

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

The amoxicillin-clavulanic acid ratios in the various preparations vary. This should be taken into account, above all because of the fact that the severity of the gastrointestinal side effects is clearly related to the quantity of clavulanic acid (> 10 mg/kg/day results in more gastrointestinal side effects).

Caution is needed in administration to infants whose mothers are allergic to penicillin and patients on a sodium-restricted diet if high parenteral doses are being used. Superficial discoloration of the teeth (in particular with the suspensions); this can generally be removed by brushing the teeth. If severe diarrhoea occurs, the diagnosis of pseudomembranous colitis should be considered.
The drops and suspensions contain aspartame and should therefore be used with caution in children with phenylketonuria. Augmentin sachets do not contain aspartame.

Cases of nephrotoxicity have been seen after using amoxicillin.

Hepatic adverse reactions occur very rarely in children and may be related to prolonged (>2 weeks) or repeated treatment; the symptoms usually develop during or shortly after the treatment, but sometimes only after a few weeks to 3 months.

Interactions

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

Penicillins with extended spectrum
	Amoxicillin Related Medicines Menu">	J01CA04
	Ampicillin Related Medicines Menu">	J01CA01

Beta-lactamase sensitive penicillins
	Benzathine benzylpenicillin Related Medicines Menu">	J01CE08
	Benzylpenicillin Related Medicines Menu">	J01CE01
	Phenoxymethylpenicillin Related Medicines Menu">	J01CE02

Beta-lactamase resistant penicillins
	Kloksacillin Related Medicines Menu">	J01CF02

Combinations of penicillins, incl. beta-lactamase inhibitors
	Piperacillin (as the sodium salt) / tazobactam (as the sodium salt) Related Medicines Menu">	J01CR05

References

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2. Consensus of professional society as reflected in , Vademecum pediatrische antimicrobiële therapie by Hartwig NC, et al, 2005
3. Brook I, et al, Eradication of Streptococcus pneumoniae in the nasopharyngeal flora of children with acute otitis media after amoxicillin-clavulanate therapy., Antimicrob Agents Chemother., 2004, 48, 1419-21
4. Claret Teruel G, et al, Oral therapy for urinary tract infections in infants aged 3 to 12 months., Eur J Clin Microbiol Infect Dis., 2008, 27, 887-9
5. Dowell SF, et al, Acute otitis media - management and surveillance in an era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group., Pediatr Infect Dis J, 1999, 18, 1-9
6. Dunne MW, et al, Randomized, double-blind study of the clinical efficacy of 3 days of azithromycin compared with co-amoxiclav for the treatment of acute otitis media., J Antimicrob Chemother, 2003, 52, 469-72
7. El-Hennawi DM, et al, Management of clinically diagnosed subacute rhinosinusitis in children under the age of two years: a randomized, controlled study., J Laryngol Otol., 2006, 120, 845-8
8. Garbutt JM, et al, A randomized, placebo-controlled trial of antimicrobial treatment for children with clinically diagnosed acute sinusitis., Pediatrics., 2001, 107, 619-25
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10. Hedrick JA, et al, Cefprozil versus high-dose amoxicillin/clavulanate in children with acute otitis media., Clin Ther., 2001, 23, 193-204
11. Jones AE, et al, Pharmacokinetics of intravenous amoxycillin and potassium clavulanate in seriously ill children., J Antimicrob Chemother, 1990, Feb;25(2), 269-74
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14. Reed MD, The clinical pharmacology of amoxicillin and clavulanic acid, Pediatr Infect Dis J, 1998, Oct;17(10), 957-62
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16. Schaad UB, et al, Single-dose pharmacokinetics of intravenous clavulanic acid with amoxicillin in pediatric patients, Antimicrob Agents Chemother, 1983, Feb;23(2), 252-5
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19. GSK. . , Prescribing information Augmentin ES-600, NDA 050755/S-016, S-018
20. Fresenius Kabi Nederland B.V, SmPC Amoxicilline-clavulaanzuur injectie (RVG 112796) 21-11-2018, www.geneesmiddeleninformatiebank.nl
21. GlaxoSmithKline BV, SmPC Augmentin suspensie (RVG 14740) 07-07-2020, www.geneesmiddeleninformatiebank.nl
22. G.L. Pharma, SmPC Xiclav duo 457 mg/5 ml Trockensaft (1–25400), https://www.univadis.at/, 08/2017
23. Hexal, SmPC AmoxClav HEXAL® i. v. 1000/200 mg (61444.00.00), 09/2017
24. 1 A Pharma , SmPC AmoxiClav 875/125 - 1 A Pharma® (49308.00.00), 09/2017
25. InfectoPharm, SmPC InfectoSupramox Saft 400 mg/57 mg/5 ml (84313.00.00), 09/2017
26. GlaxoSmithKline, SmPC Augmentan® Tropfen (7351.01.00), 10/2017
27. Hikma Pharma , SmPC AmoxiClav Hikma i.v. 1,2 g und 2,2 g (57757.00.00/ 57758.00.00), 09/2012
28. Hexal, SmPC AmoxClav HEXAL® i. v. 500/100 mg (61443.00.00), 09/2017
29. 1 A Pharma , SmPC AmoxiClav 500/125 - 1 A Pharma® (43975.00.01), 09/2017
30. GlaxoSmithKline, SmPC Augmentan 500 mg/125 mg Filmtabletten (92660.00.00), 10/2017
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33. STADAPHARM, SmPC Amoxi-Clavulan STADA® 875/125 mg Filmtabletten (51639.00.00), 09/2017
34. GlaxoSmithKline, SmPC Augmentan Kindersaft (35944.00.00), 09/2017
35. GlaxoSmithKline, SmPC Augmentan forte Trockensaft 50 mg/12,5 mg pro ml (7351.00.00), 09/2017
36. AbZ-Pharma , SmPC Amoxiclav-CT Trockensaft (39313.00.01/ 39313.01.01), 07/2015
37. Micro Labs , SmPC Amoxicillin/Clavulansäure-Micro Labs Pulver zur Herstellung einer Suspension zum Einnehmen (95117.00.00/ 95118.00.00), 09/2017
38. European Committee on Antimicrobial Susceptibility Testing - EUCAST, Clinical breakpoints - breakpoints and guidance, https://www.eucast.org/clinical_breakpoints, Jan 2, 2023
39. Dutch Working Party on Antibiotic Policy (SWAB) - Special Interest Group Pediatrics, Expert opinion on high dosing for infections caused by microorganisms susceptible to increased doses., Dec 6, 2022
40. Keij FM, et al. , Oral and Intravenous Amoxicillin Dosing Recommendations in Neonates: A Pooled Population Pharmacokinetic Study, Clin Infect Dis, 2023, Nov 30;77(11), 1595-1603
41. Keij FM, et al., Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates <....>, Lancet Child Adolesc Health., 2022, 6(11), 799-809
42. Hoberman A, et al., Equivalent efficacy and reduced occurrence of diarrhea from a new formulation of amoxicillin/clavulanate potassium (Augmentin®) for treatment of acute otitis media in children, The Pediatric Infectious Disease Journal, 1997, 16(5), 463 - 470

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