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

Interactions
PK
Renal impairment
References

Metronidazole

Generic name
Metronidazole
Brand name
ATC Code
P01AB01

Pharmacokinetics in children

Elimination half-life in preterm neonates is up to 100 h. Pharmacokinetics in children >8 weeks is almost the same as in adults [SmPC].The following kinetic parameters have been observed [Rubenson 1986, Lau 1992, Suyagh 2011]:

  Cmax
(1x 20 mg/kg IV)		 Tmax (min) t½ (hours) Cl (l/kg/hour) Vd
Premature infants - - 19.7 0.0237 0.756 l/kg
1 day-8 weeks (full-term) 17.7 µg/mL 59 18.4 - -
3.5-10 months 25.3 µg/ml 42.5 7 - -
> 4 yrs - - 7-8 0.057 -

Severely malnourished children have a reduced clearance and a longer half-life (average 0.077 l/kg/hour versus 0.166 l/kg/hour and 10 hours versus 5 hours): study of 10 children aged between 4 and 43 months [Lares-Asseff 1992].

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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

Anaerobic infections
  • Oral
    • < 1 month
      [16]
      • 15 mg/kg/day in 1 - 2 doses.
    • 1 month up to 18 years
      [16]
      • 20 - 30 mg/kg/day in 1 - 3 doses. Max: 2.000 mg/day.
  • Intravenous
    • Postmenstrual age < 26 weeks
      [17]
      • Initial dose: 15 mg/kg/dose, once only.
      • Maintenance dose: 24 hours after the initial dose: 7.5 mg/kg/day in 1 dose
    • Postmenstrual age 26 weeks up to 28 weeks
      [17]
      • Initial dose: 15 mg/kg/dose, once only.
      • Maintenance dose: 24 hours after the initial dose: 10 mg/kg/day in 1 dose
    • Postmenstrual age 28 weeks up to 34 weeks
      [17]
      • Initial dose: 15 mg/kg/dose, once only.
      • Maintenance dose: 12 hours after the initial dose: 15 mg/kg/day in 2 doses.
    • Postmenstrual age 34 weeks up to 38 weeks
      [17]
      • Initial dose: 15 mg/kg/dose, once only.
      • Maintenance dose: 12 hours after the initial dose: 20 mg/kg/day in 2 doses.
    • Term neonate
      [17]
      • Initial dose: 15 mg/kg/dose, once only.
      • Maintenance dose: 12 hours after the initial dose: 20 mg/kg/day in 2 doses.
    • 1 month up to 18 years
      [40]
      • 20 - 30 mg/kg/day in 1 dose. Max: 40mg/kg/day, but not exceeding 1.500 mg/day.

      • Alternatively: 22,5 mg/kg/day in 3 doses, max 500 mg/dose
Perioperative prophylaxis
  • Intravenous
    • < 33 kg
      [29] [30]
      • 15 mg/kg/dose within 1 hour before the procedure; repeat if necessary after 8 hours..
    • ≥ 33 kg
      [29] [30]
      • 500 mg/dose within 1 hour before the procedure; repeat if necessary after 8 hours..
Eradication of H. pylori (triple therapy)
  • Oral
    • 0 years up to 18 years
      [28] [38]
      • 20 - 30 mg/kg/day in 2 doses. Max: 1.000 mg/day.
      • Duration of treatment:

        14 days

      • Triple therapy: metronidazole combined with:
        - amoxicillin 50 mg/kg/day orally in 2 doses. In clarithromycin and metronidazole resistency use high dose amoxicillin: 80-90 mg/kg/day.
        - esomeprazol or omeprazole 1,5-2.5 mg/kg/day orally in 2 doses.

        <insert hyperlinks to drugmonographs>
Organic acid syndrome
  • Oral
    • 1 month up to 18 years
      • 10 - 20 mg/kg/day in 1 dose

      • Treatment by or after consultations with a paediatric specialist (metabolic disorders) who has experience using metronidazole for this indication.

        No studies have been carried out into the use of metronidazole for organic acid disorders in children
Dientamoebiasis
  • Oral
    • 1 month up to 18 years
      [26] [36]
      • 30 mg/kg/day in 3 doses. Max: 1.500 mg/day.
      • Duration of treatment:

        10 days
Giardiasis
  • Oral
    • 1 month up to 18 years
      [19]
      • 50 mg/kg/day in 1 dose. Max: 2.000 mg/day.
      • Duration of treatment:

        Duration of treatment: 3 days

        Alternative treatment regimen: 15-30 mg/kg/day in 3 doses for 7-10 days, max. 1,500 mg/day.
Trichomoniasis
  • Oral
    • 1 month up to 18 years
      [1] [16] [34]
      • 15 - 30 mg/kg/day in 2 - 3 doses. Max: 800 mg/day.
      • Duration of treatment:

        7 days

        Alternative treatment regimen: a one-off dose of 40 mg/kg/day, maximum 2000 mg/dose

      • No studies have been carried out into the use of metronidazole for trichomoniasis in children.

  • Vaginal
    • Tablet for vaginal use
      • Post menarche 10 years up to 18 years
        [1]
        • 500 mg/day in 1 dose Deep in the vagina, for the night.
        • Duration of treatment:

          10 days

        • No studies have been carried out into the use of metronidazole for trichomoniasis in children.
Microsporidiosis
  • Oral
    • 1 month up to 18 years
      [1]
      • 15 mg/kg/day in 3 doses. Max: 750 mg/day.
      • Duration of treatment:

        Maximum duration of treatment is 21 days.

        If the symptoms return: 5 mg/kg/day until symptoms have gone.

         

      • No studies have been carried out into the use of metronidazole for microsporidiosis in children.
Blastocystosis
  • Oral
    • 1 month up to 18 years
      [1] [27]
      • 50 mg/kg/day in 3 doses. Max: 1.500 mg/day.
      • Duration of treatment:

        10 days

      • No studies have been carried out into the use of metronidazole for blastocystosis in children.
Amoebiasis
  • Oral
    • 1 month up to 18 years
      [34] [35]
      • 35 - 50 mg/kg/day in 3 doses. Max: 2.400 mg/day.
      • Duration of treatment:

        5-10 days

        • Follow-on treatment with clioquinol
        • Treatment after consultation with a paediatrician-infectiologist
Gardnerella vaginalis
  • Oral
    • ≥ 12 years
      [34]
      • 800 - 1.000 mg/day in 2 doses.
      • Duration of treatment:

        5-7 days
        Alternative treatment regimen: one-time dose of 2000 mg

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Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be 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

Abdominal pain, headache, nausea, metal taste sensation, anorexia. Cerebellar dysfunction has been reported in children, with vision disorders, vertigo and ataxia. Sensory or autonomic neuropathy have also been described [Hobson-Webb 2006].

Frequency, type end severity of side effects in children complies to them in adults [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

The risk of peripheral neuropathy occurring as a side effect increases in prolonged use [Hobson-Webb 2006].

Rapid onset of severe hepatotoxicity/acute liver failure after initiation of treatment has been observed in patients with Cockayne-syndrome. In this population Metronidazol should only be used after careful risk-benefit analysis, if no alternatives exist and under close monitoring of liver function parameters.

Infants <13 weeks at risk of developing methemoglobinemia have to consider that 500mg Metronidazol contain up to 2mg nitrite.

In cases of severe hepatic impairment, the daily dosage should be reduced to one third of the usual dosage in a single dose.

The Flagyl suspension contains ethanol (6.4 mg/ml).    Use the tablets if possible in children.

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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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References

  1. Hartwig NC, et al, Vademecum pediatrische antimicrobiele therapie, 2005
  2. Lamp KC, et al, Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials, Clin Pharmacokinet, 1999 , May;36(5), 353-73
  3. Lau AH, et al, Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives, Clin Pharmacokinet, 1992, Nov;23(5), 328-64
  4. Jager-Roman E, et al, Pharmacokinetics and tissue distribution of metronidazole in the new born infant, J Pediatr, 1982, Apr;100(4), 651-4
  5. Lares-Asseff I, et al, Pharmacokinetics of metronidazole in severely malnourished and nutritionally rehabilitated children, Clin Pharmacol Ther, 1992, Jan;51(1), 42-50
  6. Rubidge CJ, et al, Treatment of children with acute amoebic dysentery. Comparative trial of metronidazole against a combination of dehydroemetine, tetracycline, and diloxanide furoate, Arch Dis Child, 1970, Apr;45(240), 196-7
  7. Dinleyici EC, et al, Clinical efficacy of Saccharomyces boulardii and metronidazole compared to metronidazole alone in children with acute bloody diarrhea caused by amebiasis: a prospective, randomized, open label study, Am J Trop Med Hyg, 2009, Jun;80(6):, 953-5
  8. Moazam F, et al, Amebic liver abscess: spare the knife but save the child, J Pediatr Surg, 1998, Jan;33(1), 119-22
  9. Kurt O, et al, A comparison of metronidazole and single-dose ornidazole for the treatment of dientamoebiasis, Clin Microbiol Infect, 2008, Jun;14(6), 601-4
  10. Gardner TB, et al, Treatment of giardiasis., Clin Microbiol Rev, 2001 , Jan;14(1), 114-28
  11. Ortiz JJ, et al, Randomized clinical study of nitazoxanide compared to metronidazole in the treatment of symptomatic giardiasis in children from Northern Peru, Aliment Pharmacol Ther, 2001, Sep;15(9), 1409-15
  12. Bulut BU, et al, Alternative treatment protocols in giardiasis: a pilot study, Scand J Infect Dis, 1996, 28(5), 493-5
  13. Sadjjadi SM, et al, Comparative clinical trial of mebendazole and metronidazole in giardiasis of children, J Trop Pediatr, 2001, Jun;47(3), 176-8
  14. Falagas ME, et al, Late incidence of cancer after metronidazole use: a matched metronidazole user/nonuser study, Clin Infect Dis, 1998, Feb;26(2), 384-8
  15. Oldenburg B, et al, Metronidazole. , Pediatr Clin North Am, 1983, Feb;30(1), 71-5
  16. Sanofi BV, SmPC Flagyl suspensie (RVG 10322) 14-06-2023, www.geneesmiddelinformatiebank.nl
  17. Suyagh M et al , Metronidazole population pharmacokinetics in preterm neonates using dried blood-spot sampling, Pediatrics, 2011, Feb;127(2), e367-74
  18. Bontems P et al, Sequential therapy versus tailored triple therapies for Helicobacter pylori infection in children, J Pediatr Gastroenterol Nutr, 2011, Dec;53(6), 646-50
  19. Granados CE et al, Drugs for treating giardiasis, Cochrane Database Syst Rev, 2012, Dec 12;12:, CD007787
  20. Hobson-Webb LD et al, Metronidazole: newly recognized cause of autonomic neuropathy, J Child Neurol, 2006, May;21(5), 429-31
  21. Kafadar I et al, A rare adverse effect of metronidazole: nervous system symptoms. , Pediatr Emerg Care, 2013, Jun;29(6), 751-2
  22. Koletzko S et al, Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children, J Pediatr Gastroenterol Nutr, 2011, Aug;53(2):, 230-43
  23. Kuriyama A et al, Metronidazole-induced central nervous system toxicity: a systematic review., Clin Neuropharmacol, 2011, Nov-Dec;34(6), 241-7
  24. Pant C et al, Clostridium difficile infection in children: a comprehensive review, Curr Med Res Opin, 2013, Aug;29(8), 967-84
  25. Rademaker CMA et al, Geneesmiddelen-Formularium voor kinderen. , 2007
  26. Belo JN et al. , NHG-Standaard acute diarree (derde herziening)., Huisarts Wet, 2014, 57(9), 462-71
  27. SWAB. , SWAB richtlijn antimicrobiële therapie voor acute infectieuze diarree. , www.swabid.nl
  28. Numans ME et al. , NHG-Standaard Maagklachten (Derde herziening). , Huisarts Wet , 2013, 56, 26-35
  29. Lau WY et al. , Cefoxitin versus gentamicin and metronidazole in prevention of post-appendicectomy sepsis: a randomized, prospective trial., J Antimicrob Chemother. , 1986 , Nov;18(5), 613-9
  30. Söderquist-Elinder C et al. , Prophylactic antibiotics in uncomplicated appendicitis during childhood--a prospective randomised study., Eur J Pediatr Surg. , 1995 , Oct;5(5), 282-5
  31. Rubenson A et al. , Single dose prophylaxis with metronidazole in infants during abdominal surgery: a pharmacokinetic study., Eur J Clin Pharmacol. , 1986, 29(5), 625-8
  32. Ratiopharm, SmPC Metronidazol-ratiopharm 400 mg Tabletten (40871.00.00), 05/2018
  33. Hexal, SmPC Metronidazol HEXAL® 400 mg Tabletten (36917.00.00), 12/2016
  34. G. L. pharma, SmPC Anaerobex Ftbl. (16494), https://www.univadis.at/, 10/2017
  35. Wuerz, T, et al., A review of amoebic liver abscess for clinicians in a nonendemic setting, Can J Gastroenterol, 2012, 26(10), 729-33
  36. Schure, JMAT, et al., Symptoms and treatment of Dientamoeba fragilis infection in children, a retrospective study, Pediatr Innfect Dis J, 2013, 32, 148–150
  37. Fresenius Kabi, SmPC Metronidazol Kabi 5% Infusionslsg. (1-18218), https://www.univadis.at/, 06/2017
  38. Jones N, et al, Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016), JPGN, 2107, 64, 991
  39. ZorgInstituut Nederland, Farmacotherapeutisch Kompas (Eigenschappen, Contra-Indicaties, Bijwerkingen, Waarschuwingen en Voorzorgen), Geraadpleegd 05 nov 2014
  40. B. Braun Melsungen AG, SmPC Metronidazol B. Braun 5 mg/ml oplossing voor infusie (RVG 12087) 24-05-2023, www.geneesmiddelinformatiebank.nl

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Changes

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