Pediatric Formulary

Dosages

Side effects in children

Warnings & precautions in children

Contra-indications in children

Interactions

Renal impairment

References

Amoxicillin

Generic name

Amoxicillin

Brand name

ATC Code

J01CA04

Pharmacokinetics in children

In neonates, premature neonates and children, the following kinetic parameters have been found after IV administration (Charles 1997, Huisman-de Boer 1995, Pullen 2006, Pullen 2007, Schaad 1983):

Age	PNA (avg)	n=	t½ (hours)	Cl (l/kg/hour)	Vd (ml/kg)
26-32 weeks GA	3 days	17	6.7 ± 1.7	0.066 ± 0.024	671 ± 117
25-42 (avg. 35) weeks GA	0.8 days	150	5.2 ± 1.9	0.096 ± 0.036	650 ± 130
26-41 (avg. 34) weeks GA	25 days	32	3.0 ± 1.3	0.18 ± 0.10	660 ± 270
2-14.5 years	-	12	1.2 ± 0.06		764 ± 58

The following kinetic parameters have been observed in infants aged over 4 months and in children after oral administration (Ginsburg 1979, Ginsburg 1981, Nelson 1982, Van Niekerk 1985, Schaad 1986):

t½ (hours)	HTmax (hours)	Cl (l/kg/hour)	Vd (l/kg)	Cmax (µg/ml) (15-25 mg/kg)
1.1-1.8	1-1.5	1.16-1.30	1.95-2.17	3.2-8.9

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]

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

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Available formulations

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Dosages

Bacterial infections
Oral 1 month up to 18 years ^{[3] [10] [40]} 50 mg/kg/day in 3 doses. Max: 1.5 g/day. Range: 40-60 mg/kg/day

Severe bacterial infections
Intravenous < 1 week and weight at birth < 2000 g ^{[2] [13]} 50 mg/kg/day in 2 doses. < 1 week and weight at birth ≥ 2000 g ^{[2] [13]} 75 mg/kg/day in 3 doses. 1 week up to 4 weeks and weight at birth < 2000 g ^{[2] [13]} 75 mg/kg/day in 3 doses. 1 week up to 4 weeks and weight at birth ≥ 2000 g ^{[2] [13]} 100 mg/kg/day in 4 doses. 1 month up to 18 years ^{[2] [13]} 100 mg/kg/day in 3 - 4 doses. Max: 12 g/day. Oral Term neonate ^{[3] [10]} 90 mg/kg/day in 3 doses. Max: 3 g/day. 1 month up to 18 years ^{[3] [10]} 90 mg/kg/day in 3 doses. Max: 6 g/day.

Severe bacterial infections

Intravenous
- < 1 week and weight at birth < 2000 g
  ^{[2]
  
  [13]}
  - 50 mg/kg/day in 2 doses.
- < 1 week and weight at birth ≥ 2000 g
  ^{[2]
  
  [13]}
  - 75 mg/kg/day in 3 doses.
- 1 week up to 4 weeks and weight at birth < 2000 g
  ^{[2]
  
  [13]}
  - 75 mg/kg/day in 3 doses.
- 1 week up to 4 weeks and weight at birth ≥ 2000 g
  ^{[2]
  
  [13]}
  - 100 mg/kg/day in 4 doses.
- 1 month up to 18 years
  ^{[2]
  
  [13]}
  - 100 mg/kg/day in 3 - 4 doses. Max: 12 g/day.
Oral
- Term neonate
  ^{[3]
  
  [10]}
  - 90 mg/kg/day in 3 doses. Max: 3 g/day.
- 1 month up to 18 years
  ^{[3]
  
  [10]}
  - 90 mg/kg/day in 3 doses. Max: 6 g/day.

Meningitis
Intravenous < 1 week and weight at birth < 2000 g ^{[6] [7]} 100 mg/kg/day in 2 doses. < 1 week and weight at birth ≥ 2000 g 150 mg/kg/day in 3 doses. 1 week up to 4 weeks and weight at birth < 2000 g ^{[6] [7]} 150 mg/kg/day in 3 doses. 1 week up to 4 weeks and weight at birth ≥ 2000 g ^{[6] [7]} 200 mg/kg/day in 4 doses. 1 month up to 18 years ^[13] 200 mg/kg/day in 3 - 4 doses. Max: 12 g/day.

Meningitis

Intravenous
- < 1 week and weight at birth < 2000 g
  ^{[6]
  
  [7]}
  - 100 mg/kg/day in 2 doses.
- < 1 week and weight at birth ≥ 2000 g
  - 150 mg/kg/day in 3 doses.
- 1 week up to 4 weeks and weight at birth < 2000 g
  ^{[6]
  
  [7]}
  - 150 mg/kg/day in 3 doses.
- 1 week up to 4 weeks and weight at birth ≥ 2000 g
  ^{[6]
  
  [7]}
  - 200 mg/kg/day in 4 doses.
- 1 month up to 18 years
  ^[13]
  - 200 mg/kg/day in 3 - 4 doses. Max: 12 g/day.

Eradication of H. pylori (triple therapy)
Oral 1 month up to 18 years ^{[11] [41]} 50 mg/kg/day in 2 doses. Max: 2 g/day. Duration of treatment: 14 days In clarithromycin and metronidazole resistency: use high dose amoxicilline: 80-90 mg/kg/day, max 6 g/day Triple therapy: amoxicillin combined with: - clarithromycin 20-30 mg/kg/day, max 1 g/dag orally in 2 doses OR alternatively metronidazole 20-30 mg/kg/day in 2 doses, max 1 g/dag - esomeprazole or omeprazole 1,5 - 2,5 mg/kg/day orally in 2 doses

Eradication of H. pylori (triple therapy)

Oral
- 1 month up to 18 years
  ^{[11]
  
  [41]}
  - 50 mg/kg/day in 2 doses. Max: 2 g/day.
  - Duration of treatment:
    14 days
  - In clarithromycin and metronidazole resistency: use high dose amoxicilline: 80-90 mg/kg/day, max 6 g/day
    
    Triple therapy: amoxicillin combined with:
    - clarithromycin 20-30 mg/kg/day, max 1 g/dag orally in 2 doses OR alternatively metronidazole 20-30 mg/kg/day in 2 doses, max 1 g/dag
    - esomeprazole or omeprazole 1,5 - 2,5 mg/kg/day orally in 2 doses

Endocarditis prophylaxis (including in the oral cavity, upper respiratory tract, urogenital tract and digestive tract)
Oral 1 month up to 18 years ^{[15] [16]} 30-60 minutes before the treatment: 50 mg/kg/dose, once only. Max single dose: 2 g/dose. Endocarditis prophylaxis in hypersensitivity to penicillin or treatment with penicillin in the 7 days before the procedure: - for procedures in the oral cavity and upper respiratory tract: clindamycin (for the dosage, refer to the monograph on clindamycin) - for procedures in the urogenital tract and digestive tract: vancomycin (for the dosage, refer to the monograph on vancomycin) Intravenous 1 month up to 18 years ^[4] 30-60 minutes before the treatment: 50 mg/kg/dose, once only. Max single dose: 2 g/dose. Endocarditis prophylaxis in hypersensitivity to penicillin or treatment with penicillin in the 7 days before the procedure: - for procedures in the oral cavity and upper respiratory tract: clindamycin (for the dosage, refer to the monograph on clindamycin) - for procedures in the urogenital tract and digestive tract: vancomycin (for the dosage, refer to the monograph on vancomycin)

Endocarditis prophylaxis (including in the oral cavity, upper respiratory tract, urogenital tract and digestive tract)

Oral
- 1 month up to 18 years
  ^{[15]
  
  [16]}
  - 30-60 minutes before the treatment: 50 mg/kg/dose, once only. Max single dose: 2 g/dose.
  - Endocarditis prophylaxis in hypersensitivity to penicillin or treatment with penicillin in the 7 days before the procedure:
    - for procedures in the oral cavity and upper respiratory tract: clindamycin (for the dosage, refer to the monograph on clindamycin)
    - for procedures in the urogenital tract and digestive tract: vancomycin (for the dosage, refer to the monograph on vancomycin)
Intravenous
- 1 month up to 18 years
  ^[4]
  - 30-60 minutes before the treatment: 50 mg/kg/dose, once only. Max single dose: 2 g/dose.
  - Endocarditis prophylaxis in hypersensitivity to penicillin or treatment with penicillin in the 7 days before the procedure:
    - for procedures in the oral cavity and upper respiratory tract: clindamycin (for the dosage, refer to the monograph on clindamycin)
    - for procedures in the urogenital tract and digestive tract: vancomycin (for the dosage, refer to the monograph on vancomycin)

Early localized and disseminated Lyme disease, with the exception of meningitis and Lyme carditis
Oral 1 month up to 18 years ^[9] 50 mg/kg/day in 3 doses. Max: 1.5 g/day. Duration of treatment: 14 days Lyme arthritis: 30 days

Prophylaxis after exposure to anthrax
Oral 1 month up to 18 years ^[12] 80 mg/kg/day in 3 doses. Max: 1.5 g/day. Duration of treatment: 60 days

Infections (without clinical suspicion of meningitis) caused by microorganisms susceptible at increased exposure ('I')
Oral 1 month up to 18 years and < 40 kg ^{[42] [43]} 80 - 90 mg/kg/day in 3 doses. Max: 3 g/day. 1 month up to 18 years and ≥ 40 kg ^{[42] [43]} 1.5 - 3 g/day in 3 doses. increase dose if needed up to max 6 g /day. Intravenous 1 month up to 18 years ^{[42] [43]} 200 mg/kg/day in 3 - 4 doses. Max: 12 g/day.

Suspected neonatal bacterial infection (in the absence of positive culture)
Oral Postnatal age 0-28 days Gestational age ≥ 34 weeks ^[46] After initial treatment with i.v. antibiotics: 60 mg/kg/day in 2 doses. Intravenous Gestational age 25 weeks up to 28 weeks ^[46] Postnatal age 0-7 days: 20 mg/kg/day in 2 doses Postnatal age 8-28 days: 30 mg/kg/day in 3 doses Gestational age 28 weeks up to 32 weeks ^[46] Postnatal age 0-7 days: 30 mg/kg/day in 2 doses Postnatal age 8-28 days: 50 mg/kg/day in 3 doses Gestational age 32 weeks up to 41 weeks ^[46] Postnatal age 0-7 days: 50 mg/kg/day in 2 doses Postnatal age 8-28 days: 75 mg/kg/day in 3 doses

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

Oral
- Postnatal age 0-28 days Gestational age ≥ 34 weeks
  ^[46]
  - After initial treatment with i.v. antibiotics: 60 mg/kg/day in 2 doses.
Intravenous
- Gestational age 25 weeks up to 28 weeks
  ^[46]
  - - Postnatal age 0-7 days: 20 mg/kg/day in 2 doses
    - Postnatal age 8-28 days: 30 mg/kg/day in 3 doses
- Gestational age 28 weeks up to 32 weeks
  ^[46]
  - - Postnatal age 0-7 days: 30 mg/kg/day in 2 doses
    - Postnatal age 8-28 days: 50 mg/kg/day in 3 doses
- Gestational age 32 weeks up to 41 weeks
  ^[46]
  - - Postnatal age 0-7 days: 50 mg/kg/day in 2 doses
    - Postnatal age 8-28 days: 75 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

Adjustment is not required

GFR 30-50 ml/min/1.73 m2

Adjustment is not required

GFR 10-30 ml/min/1.73 m2

Adjustment is not required

GFR < 10 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 12 up to 24 uur

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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

Superficial tooth discoloration was observed in children using dispersible tablets and oral suspensions. Adequate oral hygiene can help to avoid tooth discolotrations as brushing usually removes them [SmPC].

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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

In cases of long-term use, application in premature children or during the neonatal period, check the renal and hepatic function regularly and have regular haematological tests carried out.
Cases of nephrotoxicity have been described after using amoxicillin.

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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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Penicillins with extended spectrum
	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
	Amoxicillin + clavulanic acid Related Medicines Menu">	J01CR02
	Piperacillin (as the sodium salt) / tazobactam (as the sodium salt) Related Medicines Menu">	J01CR05

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References

Canafax DM et al, Amoxicillin middle ear fluid penetration and pk in children with acute otitis media, Paediatr Infect Dis J, 1998, 17, 149-56
Hartwig NG, et al, Vademecum Pediatrische Antimicrobiële Therapie, 2005
Astellas Pharma Europe B.V., SPC Flemoxin Solutab (RVG 12546) 28-7-2016, www.geneesmiddeleninformatiebank.nl
Endocarditis Profylaxe Commissie Nederlandse Hartstichting, Preventie bacteriele endocarditis, Herziening augustus 2008
PCH. , SPC Amoxicilline suspensie , www.cbg-meb.nl , 6-8-2012
Pullen J, et al, Amoxicillin pharmacokinetics in (preterm) infants aged 10 to 52 days: effect of postnatal age, Ther Drug Monit., 2007, 29, 376-80
Pullen J, et al, Population pharmacokinetics and dosing of amoxicillin in (pre)term neonates, Ther Drug Monit., 2006, 28, 226-31
Sánchez Navarro A., New formulations of amoxicillin/clavulanic acid: a pharmacokinetic and pharmacodynamic review, Clin Pharmacokinet, 2005, 44, 1097-115
CBO, Richlijn Lymeziekte, www.cbo.nl, 2013, 132-160
EMA, Amoxicilline: Public Assessment Report for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, www.hma.eu, Geraadpleegd 13 juni 2012, http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Paediatric_Regulation/Assessment_Reports/Article_45_work-sharing/Amoxicillin_2010_07_45PaedPAR.pdf
NVK, Richtlijn Helicobacter Pylori-infectie bij kinderen van 0-18 jaar, 2012
LCI. , Richtlijn Antrax., 2002
Centrafarm, SmPC Amoxicilline injectie (RVG 57326) 15-02-2023, www.geneesmiddeleninformatiebank.nl
Mrvos R et al, Amoxicillin renal toxicity: how often does it occur?, Pediatr Emerg Care, 2013 , May;29(5):, 641-3
Verduijn MM et al, NHG-Behandelrichtlijn endocarditis profylaxe, www.nhg.org, 2016
Habib G et al, ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC), Eur Heart J, 2015 Nov 21, 36(44), 3075-128
Charles BG et al. , Population pharmacokinetics of intravenous amoxicillin in very low birth weight infants., J Pharm Sci. , 1997 , Nov;86(11), 1288-92
Huisman-de Boer JJ et al., Amoxicillin pharmacokinetics in preterm infants with gestational ages of less than 32 weeks., Antimicrob Agents Chemother., 1995 , Feb;39(2), 431-4
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
Ginsburg CM et al., Comparative pharmacokinetics of amoxicillin and ampicillin in infants and children, Pediatrics. , 1979 , Nov;64(5), 627-31
Ginsburg CM et al. , Comparative pharmacokinetics of cyclacillin and amoxicillin in infants and children., Antimicrob Agents Chemother., 1981 , Jun;19(6):, 1086-8
Nelson JD et al. , Pharmacokinetics of potassium clavulanate in combination with amoxicillin in pediatric patients. , Antimicrob Agents Chemother., 1982 , Apr;21(4), 681-2
van Niekerk CH et al. , Pharmacokinetic study of a pediatric formulation of amoxycillin and clavulanic acid in children., Eur J Clin Pharmacol , 1985;, 29, 235-9
Schaad UB et al. , Pharmacokinetics of a syrup formulation of amoxycillin-potassium clavulanate in children. , J Antimicrob Chemother., 1986 , Mar;17(3), 341-5
Ratiopharm, SmPC Amoxicillin-ratiopharm® 500 mg / 750 mg / 1000 mg (1883.00.00/1883.01.00/1883.02.00), 09/2017
Ratiopharm, SmPC amoxicillin-ratiopharm Amoxicillin-ratiopharm® 500 mg / 750 mg / 1000 mg Filmtabletten (1883.00.00/1883.01.00/1883.02.00), 09/2017
Heumann, SmPC Amoxicillin 500/750/1000 Heumann (8281.00.00, 8281.01.00, 8281.02.00), 10/2017
1A-Pharma, SmPC Amoxi 500 - Amoxi 750 - Amoxi 1000 - 1 A Pharma® (2467.02.00/ 34561.01.00/ 32376.00.00), 09/2017
Micro Labs , SmPC Amoxicillin Micro Labs 250 mg 500 mg 750 mg 1000 mg Filmtabletten ( 94792.00.00/ 94793.00.00/94794.00.00 /94795.00.00 ), 09/2017
Heumann, SmPC Amoxicillin Heumann 500 mg/5 ml Pulver zur Herstellung einer Suspension zum Einnehmen (25639.00.00), 01/2014
ALIUD PHARMA®, SmPC Amoxicillin AL TS (14031.00.00), 03/2018
ratiopharm, SmPC Amoxicillin-ratiopharm 250 mg/5 ml TS / 500 mg/5 ml TS ( 1883.02.01/ 25642.00.00), 01/2018
INFECTOPHARM, SmPC INFECTOMOX 250 Saft/500 Saft/750 Saft (24657.00.01/ 24657.01.01/ 6727386.00.00), 02/2018
Hexal, SmPC AmoxiHEXAL Saft, AmoxiHEXAL Saft forte (7786.00.00, 25644.00.00), 09/2017
AbZ-Pharma, SmPC Amoxi-CT 1000 mg Brausetabletten (32930.00.00), 07/2014
Heumann Pharma, SmPC Amoxicillin 500/750/1000 Heumann (8281.00.00, 8281.01.00, 8281.02.00), 10/2017
AbZ-Pharma, SmPC Amoxicillin AbZ 500 mg Filmtabletten Amoxicillin AbZ 750 mg Filmtabletten Amoxicillin AbZ 1000 mg Filmtabletten (5574.00.02, 6737.01.00, 32715.00.00), 09/2017
1A-Pharma, SmPC Amoxi 500 - 1 A Pharma 500 mg Filmtabletten Amoxi 750 - 1 A Pharma 750 mg Filmtabletten Amoxi 1000 - 1 A Pharma 1000 mg Filmtabletten (2467.02.00), 09/2017
G.L. Pharma, SmPC Amoxilan 250 mg 5 ml Trockensaft (1-20613) 08-2017
Sandoz, SmPC Ospamox 250 mg/5 ml Plv. f. orale Susp. (17663), https://www.univadis.at/, 10/2017
Jones N, et al, Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016), JPGN, 2017, 64, 991-1003
European Committee on Antimicrobial Susceptibility Testing - EUCAST, Clinical breakpoints - breakpoints and guidance, https://www.eucast.org/clinical_breakpoints, Jan2, 2023
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
Keij FM, et al. , Oral antibiotics for neonatal infections: a systematic review and meta-analysis., J Antimicrob Chemother., 2019, 74(11):, 3150-61
Mir F, et al. , Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trial., Lancet Glob Health, 2017, 5(2):, e177-e85
Keij FM, et al. . 2023., Oral and Intravenous Amoxicillin Dosing Recommendations in Neonates: A Pooled Population Pharmacokinetic Study. , Clin Infect Dis, 2023, Nov 30;77(11), 1595-1603
Mir F, et al., Serum amoxicillin levels in young infants (0-59 days) with sepsis treated with oral amoxicillin., Arch Dis Child, 2020, 105(12), 1208-14
Keij FM, et al., RAIN study: a protocol for a randomised controlled trial evaluating efficacy, safety and cost-effectiveness of intravenous-to-oral antibiotic switch therapy in neonates with a probable bacterial infection., BMJ Open, 2019, 9(7), e026688
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

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Amoxicillin

Amoxicillin

Pharmacokinetics in children

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

Available formulations

Dosages

Renal impaiment in children > 3 months

GFR 50-80 ml/min/1.73 m2

GFR 30-50 ml/min/1.73 m2

GFR 10-30 ml/min/1.73 m2

GFR < 10 ml/min/1.73 m2

Side effects in children

Contra-indications

Warnings & precautions in children

Interactions

References

Changes

Changes