Paracetamol

Generic name
Paracetamol
Brand name
ATC Code
N02BE01
Compare …

Paracetamol

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

Interactions
PK
Renal impairment
References

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).

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

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

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.

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)

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

Interactions

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

OTHER ANALGESICS AND ANTIPYRETICS

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

References

  1. Murat I, et al, Tolerance and analgesic efficacy of a new i.v. paracetamol solution in children after inguinal hernia repair, Paediatr Anaesth, 2005, 15, 663-70
  2. Allegaert K, et al, Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates, Eur J Clin Pharmacol, 2004, 60, 191-7
  3. Allegaert K, et al, Not all intravenous paracetamol formulations are created equal, Paediatr Anaesth, 2007, 17, 811-2
  4. Allegaert K, et al, Pharmacokinetics of single dose intravenous propacetamol in neonates: effect of gestational age, Arch Dis Child Fetal Neonatal Ed, 2004, 89, F25-8
  5. Anderson BJ., What we don\'t know about paracetamol in children, Paediatr Anaesth, 1998, 8, 451-60
  6. Anderson BJ, et al, Intravenous neonatal paracetamol dosing: the magic of 10 days, Paediatr Anaesth, 2009, 19, 289-95
  7. Anderson BJ, et al, Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis, Paediatr Anaesth, 2005, 15, 282-92
  8. Anderson BJ, et al, Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis., Anesthesiology, 2002, 96, 1336-45
  9. Anderson BJ, et al, A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children, Br J Clin Pharmacol, 2000, 50, 125-34
  10. Arana A, et al, Treatment with paracetamol in infants, Acta Anaesthesiol Scand. 2001, 2001, 45, 20-9
  11. Bartocci M,, Intravenous paracetamol: the \'Stockholm protocol\' for postoperative analgesia of term and preterm neonates, Paediatr Anaesth, 2007, 17, 1120-1
  12. Birmingham PK, et al, Initial and subsequent dosing of rectal acetaminophen in children: a 24-hour pharmacokinetic study of new dose recommendations, Anesthesiology, 2001, 94, 385-9
  13. Birmingham PK, et al, Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations, Anesthesiology, 1997, 87, 244-52
  14. Coulthard KP, et al, Relative bioavailability and plasma paracetamol profiles of Panadol suppositories in children., J Paediatr Child Health, 1998, 34, 425-31
  15. Hahn TW, et al, Pharmacokinetics of rectal paracetamol after repeated dosing in children, Br J Anaesth, 2000 Oct, 85, 512-9
  16. Hameleers-Snijders P, et al, Risk of acute hepatic insufficiency in children due to chronic accidental overdose of paracetamol., Ned Tijdschr Geneeskd, 2007, 151, 897-900
  17. Kozer E, et al, Repeated supratherapeutic doses of paracetamol in children--a literature review and suggested clinical approach, Acta Paediatr., 2006, 95, 1165-71
  18. Palmer GM, et al, I.V. acetaminophen pharmacokinetics in neonates after multiple doses, Br J Anaesth, 2008, 101, 523-30
  19. Prins SA, et al, Pharmacokinetics and analgesic effects of intravenous propacetamol vs rectal paracetamol in children after major craniofacial surgery, Paediatr Anaesth, 2008, 18, 582-92
  20. Van der Marel CD, et al, Paracetamol and metabolite pharmacokinetics in infants, Eur J Clin Pharmacol, 2003, 59, 243-51
  21. Van Lingen RA, et al, Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates, Arch Dis Child Fetal Neonatal Ed, 1999, 80, F59-63
  22. Van Lingen RA, et al, Multiple-dose pharmacokinetics of rectally administered acetaminophen in term infants, Clin Pharmacol Ther, 1999, 66, 509-15
  23. Wilson-Smith EM, et al, Survey of i.v. paracetamol (acetaminophen) use in neonates and infants under 1 year of age by UK anesthetists, Paediatr Anaesth., 2009, 19, 329-37
  24. Actavis, SPC Pinex (RVG 106712), www.cbg-meb.nl, Geraadpleegd 25/11/13, http://db.cbg-meb.nl/IB-teksten/h106712.pdf
  25. NVA, Richtlijn Postoperatieve pijn, www.anesthesiologie.nl, 2012
  26. van Driest SL et al, Association Between Early Postoperative Acetaminophen Exposure and Acute Kidney Injury in Pediatric Patients Undergoing Cardiac Surgery, JAMA Pediatr, 2018, Jul 1;172(7), 655-663
  27. Ratiopharm, SmPC Paracetamol-ratiopharm® 125 mg / 250 mg / 500 mg / 1000 mg Zäpfchen (3599.98.97/ 3599.97.97/ 3599.99.97/ 3599.96.97), 05/2017
  28. Ratiopharm, SmPC Paracetamol-ratiopharm® 75 mg Zäpfchen (82785.00.00), 11/2016
  29. bene Arzneimittel , SmPC ben-u-ron® 1000 mg Zäpfchen (6012055.03.00), 12/2014
  30. B. Braun Melsungen , SmPC Paracetamol B. Braun 10 mg/ml Infusionslösung (83987.00.00), 09/2016
  31. Hexal, SmPC Paracetamol HEXAL® 10 mg/ml Infusionslösung (84549.00.00), 02/2017
  32. Rubie Pharm Vertriebs , SmPC Rubiemol® Saft (16893.00.00), 03/2006
  33. Ratiopharm, SmPC Paracetamol-ratiopharm®Lösung (5727.00.00), 06/2017
  34. ALIUD PHARMA® , SmPC Paracetamol AL Saft (15134.00.00), 05/2014
  35. MacDonald, M.G., et al., Propylene glycol: increased incidence of seizures in low birth weight infants, Pediatrics, 1987, 79(4), 622-5
  36. Glasgow, A.M., et al., Hyperosmolality in small infants due to propylene glycol, Pediatrics, 1983, 72(3), 353-5
  37. Arulanantham, K. and M. Genel, Central nervous system toxicity associated with ingestion of propylene glycol, J Pediatr, 1978, 93(3), 515-6.
  38. STADA, SmPC Grippostad® Heißgetränk (3000363.00.00), 05/2014
  39. bene Arzneimittel , ben-u-ron® direkt Erdbeer/Vanille 500 mg Granulat in Beuteln (80471.00.00), 05/2015
  40. bene Arzneimittel , SmPC ben-u-ron® direkt Erdbeer/Vanille 250 mg Granulat in Beuteln (80470.00.00), 05/2015
  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
  46. ALIUD PHARMA® , SmPC Paracetamol AL Zäpfchen (54409.00.00/ 54409.01.00/ 54409.02.00/ 54409.03.00), 05/2014
  47. bene Arzneimittel , SmPC ben-u-ron® 250 mg, Zäpfchen (6012055.01.00), 12/2014
  48. bene Arzneimittel , SmPC ben-u-ron® 125 mg, Zäpfchen (6012055.00.00), 12/2014
  49. bene Arzneimittel , SmPC ben-u-ron 500 mg Hartkapseln (2697.00.00), 12/2014
  50. bene Arzneimittel , SmPC ben-u-ron ® 500 mg Tabletten (6012032.00.00 (apothekenpflichtig) // 76984.00.00 (verschreibungspflichtig)), 12/2014
  51. Fresenius Kabi Deutschland , SmPC Paracetamol Kabi 10 mg/ml Infusionslösung (78789.00.00), 05/2013
  52. bene Arzneimittel , SmPC ben-u-ron® 75 mg Zäpfchen (51011.00.00), 01/2015
  53. Ionfarma , SmPC APIREDOL 100mg/ml Tropfen zum Einnehmen (76119.00.00)
  54. bene Arzneimittel , SmPC ben-u-ron® Saft (6012144.00.00), 12/2014
  55. Wang, C., et al, Population pharmacokinetics of paracetamol across the human age-range from (pre)term neonates, infants, children to adults, J Clin Pharmacol, 2014, 54(6), 619-29
  56. Allegaert, K.et al, The pharmacokinetics of intravenous paracetamol in neonates: size matters most, Arch Dis Child, 2011, 96(6), 575-80
  57. van Ganzewinkel, C., et al, Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants., Acta Paediatr, 2014, 103(6), 612-7
  58. Baarslag, M.A. et al, Clinically effective implementation of intravenous paracetamol as primary analgesia after major surgery in neonates and young infants., Arch Dis Child, 2018, 103(12), 1168-116
  59. Mian, P. et al, Intravenous Paracetamol Dosing Guidelines for Pain Management in (pre)term Neonates Using the Paediatric Study Decision Tree., Curr Pharm Des, 2017, 23(38), 5839-5849
  60. Bayer B.V., SmPC Finimal (RVG 06448) 01-07-2019, www.geneesmiddeleninformatiebank.nl
  61. Evolan Pharma AB, SmPC Paracetamol Norfri 24mg/ml mikstur, oppløsning (17-11859) 10-06-2022, www.legemiddelsok.no
  62. Karo Pharma AS , SmPC Paracet 250 mg smeltetablett med banansmak (2002-00074) 23-03-2022, www.legemiddelsok.no
  63. Aurobindo Pharma B.V., SmPC Paracetamol Sanias met aardbeiensmaak 24 mg/ml drank (RVG 106712) 25-06-2022, www.geneesmiddeleninformatiebank.nl
  64. Healthypharm B.V, Paracetamol liquid caps 500 mg (RVG 126506) 16-05-2022, www.geneesmiddeleninformatiebank.nl
  65. Allegaert, K., et al., Hepatic tolerance of repeated intravenous paracetamol administration in neonates, Paediatr Anaesth, 2008, 18(5), 388-92
  66. AbZ-Pharma GmbH, SmPC Paracetamol AbZ 500 mg Tabletten (3599.99.98) , www.fachinfo.de, 12-2021
  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
  69. Cooper, T.E., et al.,, Paracetamol (acetaminophen) for chronic non-cancer pain in children and adolescents, Cochrane Database Syst Rev, 2017, 8, CD012539
  70. Anderson, B.J., et al., Perioperative pharmacodynamics of acetaminophen analgesia in children, Anesthesiology, 1999, 90(2), 411-21
  71. Hopkins, C.S., et al., Pharmacokinetics of paracetamol after cardiac surgery., Arch Dis Child, 1990, 65(9), 971-6
  72. Kleiber, N., et al.,, Enteral Acetaminophen Bioavailability in Pediatric Intensive Care Patients Determined With an Oral Microtracer and Pharmacokinetic Modeling to Optimize Dosing, Crit Care Med, 2019, 47(12), e975-e983

Changes

Therapeutic Drug Monitoring


Overdose