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

Interactions
PK
Renal impairment
References

Paracetamol

Generic name
Paracetamol
Brand name
ATC Code
N02BE01

Pharmacokinetics in children

Paracetamol is metabolized in the liver and excreted with the urine, mainly in the form of the glucuronide and the sulphate conjugate, and approx. 5% unchanged. 

Following intravenous administration of paracetamol to (premature) neonates, the following pharmacokinetic parameters have been found (Allegaert et al 2004, Allegaert et al 2011, van Ganzewinkel 2014.)

  t½ (hours) Cl (l/kg/hour) Vd (l/kg)
Premature neonates 4.6 - 5.9 0.09 - 0.14 0.61 - 0.76
Term neonates 2.9 ± 1 0.17 ± 0.06 0.64 ± 0.25

The clearance values in infants of 3 months and 1 year are 8.8 and 13.6 l/hour/70 kg respectively (84% of the value found in older children). These values are comparable to the value after oral and rectal administration. The half-life of paracetamol in premature infants after rectal administration is therefore greatly extended, from an average of 11 hours in premature infants after gestation of 28-32 weeks to an average of 2.7 hours in full-term neonates [van Lingen et al., Allegaert et al.].

Rectally administered paracetamol is absorbed slowly in children. The median tmax values after a single rectal dose of paracetamol in premature and full-term neonates are 4–5 hours and 1.5 hours respectively (van Lingen et al.). Various studies have also shown that the absorption of paracetamol from suppositories is variable and incomplete. The relative bioavailability of rectal formulations (F rectal/oral) varies from 0.5 in older children to approximately 1 in neonates (Hahn et al., Coulthard et al., Birmingham et al., Anderson et al., Arana et al.). Oral bioavailability of 72% is reported in critically ill children 0-6 years old (Kleiber 2019).

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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

Mild to moderate pain; fever
  • Oral
    • Term neonate
      [8] [9]
      • 10 - 15 mg/kg/dose, as required, max. 3 x daily. Max: 45 mg/kg/day.

      • Note: some liquid dosage forms contain toxic excipients and are therefore not suitable for use in neonates

    • 1 month up to 18 years
      [24] [54] [60] [61] [62] [63] [64] [66]
      • 10 - 15 mg/kg/dose, as required, max. 4x daily. Max: 60mg/kg/day, but not exceeding 4 g/day.
  • Rectal
    • Term neonate and ≥ 3 kg
      [28] [52] [67] [68]
      • 10 - 20 mg/kg/dose, as required, max. 3-4 times daily. Max: 60 mg/kg/day.
    • 1 month up to 18 years and ≥ 3 kg
      [27] [52] [67] [68]
      • 10 - 20 mg/kg/dose, as required 3-4 daily. Max: 60mg/kg/day, but not exceeding 4 g/day.
Pain, acute/post-operative
  • Oral
    • Premature infants Postconceptional age 28 weeks up to 33 weeks
      • 30 mg/kg/day in 3 doses.
      • Duration of treatment:

        Short-term use, maximum of 2-3 days

    • Premature infants Postconceptional age 33 weeks up to 37 weeks
      [8] [10]
      • 45 mg/kg/day in 3 doses.
      • Duration of treatment:

        Shortterm use, maximum 2-3 days

      • Because of the simplicity of the dose recommendation and the lack of scientific evidence towards the effectiveness of an oral loading dose, no loading dose is recommended.

    • Term neonate
      [9]
      • 60 mg/kg/day in 4 doses.
      • Duration of treatment:

        kortdurend gebruik, maximaal 2-3 dagen.
        After the maximum duration, switch to dose recommendation for mild/moderate pain and fever

      • Because of the simplicity of the dose recommendation and the lack of scientific evidence towards the effectiveness of an oral loading dose, no loading dose is recommended.

    • 6 months up to 18 years
      [8] [9] [10] [25] [26]
      • 90 mg/kg/day in 4 doses. Max: 4 g/day. Max single dose: 1 g/dose.
      • Duration of treatment:

        Shortterm use, maximal 2-3 days. After the maximum duration, switch to dose recommendation for mild/moderate pain and fever

      • Because of the simplicity of the dose recommendations and the lack of scientific evidence for the effectiveness of an oral loading dose, no loading dosage is recommended.

    • 1 month up to 6 months
      [8] [9]
      • 60 mg/kg/day in 4 doses.
      • Duration of treatment:

        Shortterm use, maximal 2-3 days. After the maximum duration, decrease dose to 10 mg/kg/dose PRN, max 40 mg/kg/day.

      • Because of the simplicity of the dose recommendations and the lack of scientific evidence for the effectiveness of an oral loading dose, no loading dosage is recommended.

  • Rectal
    • Premature infants Postconceptional age 28 weeks up to 32 weeks and ≥ 1.5 kg
      [21]
      • Initial dose: 20 mg/kg/dose, once only.
      • Maintenance dose: 40 mg/kg/day in 2 doses.
      • Duration of treatment:

        Shortterm use, maximal 2-3 days

    • Premature infants Postconceptional age 32 weeks up to 36 weeks
      [21] [25]
      • Initial dose: 30 mg/kg/dose, once only.
      • Maintenance dose: 40 mg/kg/day in 2 doses.
      • Duration of treatment:

        Shortterm use, maximal 2-3 days

    • Premature Postconceptional age 36 weeks up to 37 weeks
      [8] [10] [25]
      • Initial dose: 30 mg/kg/dose, once only.
      • Maintenance dose: 60 mg/kg/day in 3 doses.
      • Duration of treatment:

        Shortterm use, maximal 2-3 days

    • Term neonate
      [8] [10] [22] [25]
      • Initial dose: 30 mg/kg/dose, once only.
      • Maintenance dose: 60 mg/kg/day in 3 doses.
      • Duration of treatment:

        Shortterm use, maximal 2-3 days. After the maximum duration, switch to dose recommendation for mild/moderate pain and fever at lower end of dosing range.

    • 1 month up to 18 years
      [8] [10] [13] [19] [25] [26]
      • Initial dose: 40 mg/kg/dose, once only. Max single dose: 1 g/dose.
      • Maintenance dose: 90 mg/kg/day in 3 - 4 doses. Max: 4 g/day. Max single dose: 1 g/dose.
      • Duration of treatment:

        Shortterm use, maximal 2-3 days. After the maximum duration, switch to dose recommendation for mild/moderate pain and fever

  • Intravenous
    • Premature infants Postmenstrual age < 32 weeks
      [55] [57] [59]
      • Initial dose: 12 mg/kg/dose, once only.
      • Maintenance dose: 24 mg/kg/day in 4 doses.
        • The intravenous paracetamol solution is administered as a 15-minute intravenous infusion.
        • The minimum interval between the 2 doses is 4 hours and the maximum number of doses per day is 4. 
    • Premature infants Postmenstrual age 32 weeks up to 44 weeks
      [55] [56] [59]
      • Initial dose: 20 mg/kg/dose, once only.
      • Maintenance dose: 40 mg/kg/day in 4 doses.
        • The intravenous paracetamol solution is administered as a 15-minute intravenous infusion.
        • The minimum interval between 2 doses is 4 hours and the maximum number of doses administered per day is 4.
    • Term neonate
      [56] [58] [59] [65]
      • Initial dose: 20 mg/kg/dose, once only.
      • Maintenance dose: 40 mg/kg/day in 4 doses.
        • The intravenous paracetamol solution is administered as a 15-minute intravenous infusion.
        • The minimum interval between doses must be 4 hours. The maximum number of doses administered per day is 4.
    • 1 month up to 18 years
      [26] [55] [58]
      • Initial dose: 20 mg/kg/dose, once only. Max single dose: 1 g/dose.
      • Maintenance dose: 60 mg/kg/day in 4 doses. Max: 4 g/day. Max single dose: 1 g/dose.
        • The intravenous paracetamol solution is administered as a 15-minute intravenous infusion.
        • The minimum interval between doses must be 4 hours. The maximum number of doses administered per day is 4.
Chronic pain
  • Oral
    • 1 month up to 18 years
      [69]
      • 60 mg/kg/day in 3 - 4 doses. Max: 3 g/day. Max single dose: 1 g/dose.

      • In chronic pain, consultation with a pain specialist is recommended.

  • Rectal
    • 1 month up to 18 years
      [69]
      • 60 mg/kg/day in 3 - 4 doses. Max: 3 g/day. Max single dose: 1 g/dose.

      • In chronic pain, consultation with a pain specialist is recommended

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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

Hepatotoxicity caused by toxic metabolites. (in children > 140 mg/kg bodyweight)

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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

Prolonged or frequent use of paracetamol is not recommended. Caution is needed in premature infants with hyperbilirubinaemia. Accumulation may occur after repeated rectal administration in premature infants. Paracetamol is metabolized by sulphation (particularly in children and especially in infants), glucuronidation and oxidative pathways. The reactive radical N-acetyl parabenzoquinone-imine (NAPQI) is formed via the oxidative pathway. NAPQI is then conjugated by glutathione to cysteine and mercapturic acid metabolites. In cases of overdose, a larger portion of the paracetamol is metabolized via the oxidative pathway and more NAPQI is formed. If only 30% of the glutathione is present in its unbound form, NAPQI can cause acute liver cell necrosis. Repeated doses of 90 mg/kg/day or more may be toxic to the liver in children. Even repeated doses of 60-90 mg/kg/day can lead to toxic symptoms in some children (reduced glutathione reserves). In cases of symptoms of drowsiness and/or patients with a disease that is associated with dehydration and fasting who regularly take paracetamol for several consecutive days, paracetamol intoxication should be considered. Toxicity can also occur in certain conditions in which glucuronidation has been compromised. Checks are recommended that no other medicinal products containing paracetamol and/or propacetamol are being administered. Some paracetamol preparations contain aspartame and caution is recommended in patients with phenylketonuria.

Caution errors in the dosing of the infusion fluid resulting from confusion between milligrams (mg) and millilitres (ml) can result in accidental overdoses and death

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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

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  3. Allegaert K, et al, Not all intravenous paracetamol formulations are created equal, Paediatr Anaesth, 2007, 17, 811-2
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  7. Anderson BJ, et al, Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis, Paediatr Anaesth, 2005, 15, 282-92
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  10. Arana A, et al, Treatment with paracetamol in infants, Acta Anaesthesiol Scand. 2001, 2001, 45, 20-9
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  28. Ratiopharm, SmPC Paracetamol-ratiopharm® 75 mg Zäpfchen (82785.00.00), 11/2016
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  41. Ratiopharm, SmPC Paracetamol-ratiopharm® 1000 mg Tabletten (81886.00.00), 10/2017
  42. Ratiopharm, SmPC Paracetamol-ratiopharm® 500 mgTabletten (3599.99.98), 05/2017
  43. Actavis Deutschland , SmPC Paracetamol apo-rot 500 mg Filmtabletten (80538.00.00), 01/2017
  44. bene Arzneimittel , SmPC ben-u-ron® 1000 mg Tabletten (64647.00.00 (apothekenpflichtig) // 75195.00.00 (verschreibungspflichtig)), 03/2014 // 01/2015
  45. Ratiopharm, SmPC Paracetamol-ratiopharm® 500 mg Brausetabletten (32290.00.00), 05/2017
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  48. bene Arzneimittel , SmPC ben-u-ron® 125 mg, Zäpfchen (6012055.00.00), 12/2014
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  67. Karo Pharma AS , SmpC Paracet 60/125/250/500/1g stikkpiller (0000-07753) 08-04-2022, www.legemiddelsok.no
  68. Healthypharm B.V, SmPC Kinderparacetamol HTP zetpil 60/120/240mg (RVG 32144, 24202 en 24203) 10-05-2022, www.geneesmiddeleninformatiebank.nl
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