Dose and Administration

For all neonates, including preterm:

1. Oral: 10 mg/kg/dose 6 hourly.⁴
2. Rectal: 20 mg/kg/dose 8 hourly.⁴

Indications

1. Analgesia
2. Pyrexia
3. Post-operative pain relief
4. Irritable or unsettled behaviour following vaccination.

Precautions

1. Known hypersensitivity to paracetamol
2. Moderate or severe pain
3. Use in preterm infants, especially very immature infants
4. Impaired hepatic or kidney function
5. Use in the 1st 24-hours after birth (see "Special Considerations").

Clinical Pharmacology

Paracetamol has analgesic and antipyretic actions but only weak anti-inflammatory properties. The drug inhibits prostaglandin biosynthesis in conditions associated with low levels of cellular peroxides (pain, fever).

Due to metabolic immaturity, neonatal clearance of paracetamol is different from adults. Sulphate conjugation is well developed in a neonate and is the major metabolic pathway for paracetamol clearance. Glucuronidation clearance is not well developed and plays a minor role in paracetamol clearance in neonates. With maturation these clearance pathways for paracetamol change. The usual adult ratio of 2:1 glucuronide to sulphate conjugates of paracetamol is achieved by 12 years of age.⁴

Neonatal gastric pH is almost neutral, and although this favours absorption of paracetamol the stomach is not an optimal entry point to the circulation. ⁴ Paracetamol, therefore, is ideally absorbed from the small intestine where the large surface area, ideal blood flow and permeability favour absorption of the majority of drugs. Absorption from this area, however, depends on gastric emptying which is slow and erratic in a neonate. Slow absorption of paracetamol in infants less than three months has been demonstrated. ⁴

Hepatotoxicity in children from paracetamol ingestion has been demonstrated and there is the potential for this to occur in neonates. ⁴ The enzyme systems P450 CYP2E1, 1A2, 3A4 are responsible for forming paracetamol toxic metabolites. Despite a low activity of P450 CYP 2E1 in neonates, toxic metabolites can still be formed.

Possible Adverse Effects

1. Adverse effects occur rarely, but may include skin rash, fever, thrombocytopenia, leucopenia, neutropenia, pancytopenia, agranulocytosis.
2. Overdosage may lead to severe liver damage and occasionally acute renal tubular necrosis.
3. Hypersensitivity reactions have been reported. These include urticaria, dyspnoea, hypotension, angioedema.

Special Considerations

1. Clinical experience in neonates, especially those preterm, is limited.
2. Caution in the 1st 24 hours for treatment of "pain" related to birth.  Infants who are unsettled should be assessed clinically and not assumed to be in pain secondary to birth.
3. Management of paracetamol overdose and/or toxicity: activated charcoal, acetylcysteine or oral methionine. Contact Starship Emergency Department.
4. Consider a dose of paracetamol prior to administration of vaccines. Repeat doses may be required for hyperthermia and irritability.
5. Note:  Some liquid preparations of paracetamol have high ethanol content.  These should not be used in neonates.