Paracetamol use in infants and young children

Paracetamol is one of the most commonly administered medicines in children​[1,2]​. In a similar way to ibuprofen, its benefits as an analgesic and antipyretic, as well as its short-term safety profile, are widely known by both parents and healthcare professionals​[3]​. It is available for purchase as a general sales list medicine across the UK and is recommended alongside other over-the-counter (OTC) analgesics as a first-line treatment for fever and discomfort in young children​[4,5]​.  

Febrile illness is very common in preschool children, with 20–40% of parents presenting to healthcare professionals, including community pharmacies, with children experiencing symptoms of cough, cold, earache and fever each year​[6]​.

Paracetamol is a safe medicine, when used at the right time and dose; however, safety concerns have been raised owing to its overuse by anxious parents attempting to reduce fever, reports of acute hepatotoxicity caused by accidental overdose or ingestion, and the possible link between paracetamol use in infancy and the development of asthma​[2,7,8]​.  

It is therefore essential that pharmacists educate parents and carers on the appropriate evidence-based use of all OTC analgesics, including information on their mechanism of action and administration, which are important in reducing errors and any risk of adverse effects.

Mechanism of action and pharmacokinetics

Despite the prevalent use of paracetamol for many decades, its full mechanism of action is still unknown​[9]​. There is evidence that it works via several central mechanisms, including effects on prostaglandin production, and across serotonergic, opioid, nitric oxide and cannabinoid pathways​[9]​. Its analgesic and antipyretic effects occur through the inhibition of prostaglandin production centrally; however, unlike non-steroidal anti-inflammatory drugs it has little anti-inflammatory effect​[9]​.

Absorption

Oral formulations have a high bioavailability, with 70–90% of the dose absorbed​[10]​. The time for peak serum levels post-oral administration is similar for both children and adults, and is dependent on the speed of gastric emptying​[1]​. Food delays absorption; therefore, it can be given on an empty stomach to achieve a quicker onset of action​[1]​. It is well absorbed by the rectal route; however, this has a lower bioavailability than oral absorption​[1]​.  

Distribution

Paracetamol is widely and quickly distributed in the body, and rapidly crosses the blood-brain barrier to exert its central analgesic effect​[1]​. Distribution is greatest in preterm infants, before reducing with maturity until reaching the same levels as adults at around one year of age​[1]​.   

Metabolism

Paracetamol is metabolised in the liver, predominantly by glucuronidation and sulfation to non-toxic conjugates that are renally excreted​[9]​. The glucuronidation pathway is not fully developed at birth and may take up to two years to mature; therefore, the majority of paracetamol is metabolised in infants by the sulfation pathway and a small amount is oxidised via the cytochrome P450 (CYP) system to form the highly toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI)​[9,11]​. NAPQI is then conjugated with glutathione and renally excreted. CYP enzymes are less developed in neonates and young children, resulting in smaller amounts of NAPQI formation[1]. However, where glutathione levels may be lower (e.g. in malnutrition), or insufficient, a paracetamol overdose could cause higher levels of NAPQI, resulting in acute hepatotoxicity​[1,9]​.

Elimination

The elimination half-life of paracetamol is longer in neonates than older children and is reflected in the frequency of recommended dosing (see Table)​[9,12]​. Regardless of age, in all patients with a reduced estimated glomerular filtration rate, frequency of doses should be capped at every six hours, owing to delays in the elimination of glucuronidation and sulfation conjugates​[12]​.

Hepatotoxicity concerns

Paracetamol-induced hepatotoxicity is rare in infants and children when used at recommended doses​[9]​. It has been suggested that neonates have an unexpected, conferred protection from hepatotoxicity owing to paracetamol, even when given in large therapeutic excess, potentially explained by their increased ability to produce glutathione rapidly and slow oxidative metabolism​[13]​. Several studies have highlighted medication errors by carers, parents and healthcare professionals that have resulted in the development of acute liver failure in children after receiving an overdose of paracetamol​[14–16]​.

A review of VigiBase reports (n=200) of suspected fatal adverse drug reactions to paracetamol in children aged under 5 years found that 30% were associated with medication errors (e.g. accidental overdose by a parent, carer or healthcare professional, accidental ingestion by the child and incorrect drug administration)​[15]​. Rajanayagam et al. retrospectively analysed 14 cases of paediatric acute liver failure that were associated with paracetamol overdose; 12 of the children were aged under 5 years​[16]​. The review highlighted common administration errors linked to parental accidental overdose, resulting in hepatotoxicity (see Box 1)​[16]​.  

Some medications may increase the risk of paracetamol hepatotoxicity, including those that induce liver enzymes (e.g. in children taking medicines for epilepsy or tuberculosis)​[17]​. Medicines that induce liver enzymes (e.g. phenobarbital, phenytoin) may also reduce the effectiveness of paracetamol​[18]​.

Confirming appropriateness

Before recommending any OTC medicine for any indication, it is essential that pharmacists and their teams assess the child for risk of life-threatening and serious illnesses, including meningitis and sepsis. This assessment may not include a physical examination, owing to scope of practice, and is therefore based on an interpretation of symptoms rather than physical signs​[6]​. As physical signs of serious illness in infants and young children are difficult to assess and recognise, the National Institute for Health and Care Excellence traffic light system can help when triaging patients, but should be used with professional judgment when deciding an appropriate course of action (see Figure)​[6]​.

Paracetamol may mask a fever owing to other underlying causes, such as systemic bacterial or viral infection; therefore, parents/carers should not delay in seeking medical advice​[19]​. Online or telephone appointments for unwell children with amber or red features, and infants aged under three months, should only be offered to triage referral for medical review and physical assessment​[20]​. For infants aged under three months, there should be a low threshold for referral for medical review, especially where there is parental anxiety​[6]​.

Use of paracetamol

Paracetamol is safe to give to most children; lower doses may be required for those who are small for their age, or who have liver or kidney disease​[12]​. It can be used in children from two months of age for fever related to immunisations, and from the age of three months for fever and pain​[6,12]​. In addition, ibuprofen may be used in children aged over three months for the management of fever​[6]​. In an otherwise well child, if one antipyretic is not effective it can be switched to another. Alternating agents can be recommended if distress persists or occurs before the next dose is due. Both agents should not be given for fever simultaneously​[5]​.

Paracetamol is available orally in two strengths of liquid: 120mg/5ml for children aged <6 years and 250mg/5ml for children >6 years​[12]​. It is also available as melt-tab and rectal formulations; therefore, it is important to ensure the correct strength has been selected​[12]​. The Table shows the recommended doses for paracetamol oral suspension for children​[18]​.

Intravenous paracetamol is available for hospital use for the management of severe pain and may also be used in some neonatal units ‘off label’ to close a patent ductus arteriosis in premature babies​[12,21]​.

Immunisation

Fever is a common side effect associated with vaccination, particularly the meningitis B vaccine, peaking at 6 hours post-vaccination​[22]​. It is usually gone after 48 hours. Paracetamol is currently recommended for post-immunisation fever following the meningitis B vaccination; dosing advice differs when used following other routine vaccinations — parents can be advised to administer up to three doses, which may differ from the advice provided on the product information. Further important counselling points can be found in Box 2​[23]​.

General advice

By understanding the evidence-base underpinning guideline recommendations and the quality of clinical data, pharmacists and their teams can provide appropriate, practical advice and support to parents and carers regarding paracetamol administration and appropriate dosing (see Box 3).