Antipyretic drug dosage regimes

Ensure the parent/carer uses the appropriate strength of antipyretic drug and does not exceed the recommended daily dosage or dose frequency. An accurate administration device should be used, such as a calibrated spoon or syringe, and co-administration of other paracetamol or ibuprofen containing preparations should be avoided, to reduce the risk of unintended overdose.

• Oral paracetamol standard doses are guided by age:
  • Age 1 to 2 months: 30–60 mg every 8 hours as required, maximum daily dose to be given in divided doses; maximum 60 mg/kg per day (off-label indication).
  • Age 3 to 5 months: 60 mg. For children aged 3 months and over, doses may be repeated every 4–6 hours if necessary (maximum of 4 doses in 24 hours).
  • Age 6 months to 1 year: 120 mg.
  • Age 2 to 3 years: 180 mg.
  • Age 4 to 5 years: 240 mg.
  • Age 6 to 7 years: 240–250 mg.
  • Age 8 to 9 years: 360–375 mg.
  • Age 10 to 11 years: 480–500 mg.
  • Age 12 to 15 years: 480–750 mg.
  • Age 16 years: 500 mg to 1 gram.
• Oral ibuprofen standard doses are guided by age, over the age of 3 months:
  • Age 1 to 2 months: 5 mg/kg 3–4 times a day (off-label indication under 3 months of age or bodyweight less than 5 kg).
  • Age 3 to 5 months: 50 mg three times a day (maximum daily dose to be given in 3–4 divided doses; maximum 30 mg/kg per day).
  • Age 6 to 11 months: 50 mg three to four times a day (maximum daily dose to be given in 3–4 divided doses; maximum 30 mg/kg per day).
  • Age 1 to 3 years: 100 mg three times a day (maximum daily dose to be given in 3–4 divided doses; maximum 30 mg/kg per day). 
  • Age 4 to 6 years: 150 mg three times a day (maximum daily dose to be given in 3–4 divided doses; maximum 30 mg/kg per day).
  • Age 7 to 9 years: 200 mg three times a day (maximum daily dose to be given in 3–4 divided doses; maximum 30 mg/kg per day; maximum 2.4 g per day).
  • Age 10 to 11 years: 300 mg three times a day (maximum daily dose to be given in 3–4 divided doses; maximum 30 mg/kg per day; maximum 2.4 g per day).
  • Age 12 to 16 years: initially 300–400 mg 3–4 times a day (increased if necessary up to 600 mg 4 times a day; maintenance 200–400 mg 3 times a day may be adequate).

[MHRA, 2014; Rajanayagam, 2015; BNF for Children, 2017; NICE, 2017]

Basis for recommendation

The recommendations on the management of a febrile infant or child are largely based on the National Institute for Health and Care Excellence (NICE) clinical guideline Feverish illness in children: assessment and initial management in children younger than 5 years [NICE, 2017], a Health Technology Assessment Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial [Hay et al, 2009], a Task Force Report of the International League Against Epilepsy (ILAE) Commission of Pediatrics Summary of recommendations for the management of infantile seizures [Wilmshurst, 2015]; two Cochrane systematic reviews Combined and alternating paracetamol and ibuprofen therapy for febrile children [Wong, 2013] and Prophylactic drug management for febrile seizures in children [Offringa, 2017], a retrospective analysis of paracetamol-associated paediatric acute liver failure cases [Rajanayagam, 2015], a questionnaire-based survey of parental and medical knowledge of fever management [Chiappini, 2012], an intention-to-treat analysis of alternating versus monotherapy antipyretic drug regimens [Luo, 2017], an analysis of international guidelines on fever management [Chiappini, 2017], and expert opinion in review articles on fever management [Richardson, 2015; Star, 2015; Narayan, 2017].

• CKS notes that the NICE clinical guideline covers children aged less than 5 years but considers it reasonable to extrapolate the recommendations to cover children up to 16 years of age. This approach is supported by the expert opinion of previous external reviewers of this CKS topic.

Assessing for the risk of serious illness

• The recommendation to use the NICE 'traffic light' system to assess and predict a child's risk of serious illness and the need for further investigation and/or monitoring is based on evidence-based reviews identified by NICE, clinical features in the Yale Observation Scale (a pre-existing scoring system), and the clinical experience of the NICE guideline development group [NICE, 2017].
• The recommendation not to prescribe oral antibiotics if there is no known focus of infection is based on the NICE clinical guideline, which states that inappropriate antibiotic prescribing may be a cause of unnecessary adverse effects and antibiotic resistance. NICE also notes that the majority of well-appearing children with fever without an apparent cause do not have occult bacteraemia and will therefore not benefit from empirical oral antibiotics [NICE, 2017].

Advice on the use of antipyretic drug treatment

• The recommendation to only treat fever if a child is distressed or unwell is based on the expert opinion of the NICE guideline development group, on the basis that relieving a child's distress is the main concern of parents and carers. The guideline development group also stressed the importance of avoiding unnecessary drug treatment in children with a self-limiting viral illness [NICE, 2017].
  • The NICE guideline development group evaluated studies on antipyretic drug treatment with the aim to relieve distress in a febrile child. A change in a child’s level of distress was used as the primary outcome measure in the included studies, and secondary outcomes of change in temperature and time without fever were also used as proxies for distress. NICE noted there was variable quality of the included studies, with considerable heterogeneity in the treatment regimens used in terms of drug dosage and timing of administration. In addition, the study populations varied, especially in relation to age and the underlying condition causing fever.
  • In addition, a systematic review comparing the effectiveness of paracetamol versus ibuprofen in the management of febrile children noted that 'distress' is not well defined in the literature, and parents' perception of distress is subjective and may vary considerably [Narayan, 2017].
• The recommendation not to use aspirin as an antipyretic in children under 16 years of age is based on the fact that aspirin-containing preparations are contraindicated in this age-group due to an associated increased risk of Reye's syndrome. It may be initiated by a specialist in specific circumstances, such as management of Kawasaki disease [BNF for Children, 2017].
• The recommendation not to use prophylactic antipyretic drugs to prevent febrile seizures is based on a Cochrane systematic review of 30 randomized trials (n = 4256) which studied the continuous or intermittent use of prophylactic antipyretic, antiepileptic, or other drugs compared with each other, placebo, or no treatment. It found no evidence for the intermittent use of ibuprofen, diclofenac, or paracetamol compared with placebo in preventing recurrent febrile seizures [Offringa, 2017]. This approach is supported by the ILAE Task Force Report [Wilmshurst, 2015].
• The recommendation not to use a response to antipyretic therapy alone as a means to differentiate between serious and non-serious illness is based on the NICE clinical guideline, which assessed very low-quality evidence from five prospective and three retrospective studies, and concluded that there is no good evidence to support or refute the recommendation, and more research is needed in this area [NICE, 2017].

Advice on initial treatment with either paracetamol or ibuprofen

• The NICE appraisal of the evidence found that both ibuprofen and paracetamol reduce fever and improve some aspects of quality of life [NICE, 2017].
  • Outcomes of improvement in quality of life and temperature reduction were greater with ibuprofen than paracetamol within 4 hours of treatment starting, but there were no differences between the two drugs over the longer term. NICE found one study suggesting that parents could identify some improvement in the child's activity and alertness after the administration of paracetamol, but no improvement in mood, comfort, appetite, or fluid intake. The guideline development group concluded that any differences between the two drugs were not clinically important and either agent is likely to be effective in any individual case. No difference was found in the rate of adverse events reported, and there was no convincing evidence of harm with the short-term use of antipyretic drug treatment at the correct dose.
• A subsequent Cochrane systematic review published after the NICE clinical guideline assessed six randomized controlled trials (RCTs, n = 915) to examine the effects and adverse effects of alternating or combined paracetamol and ibuprofen regimens compared with monotherapy in the management of febrile children [Wong, 2013].
  • It found moderate-quality evidence that compared with a single antipyretic alone, giving combined paracetamol and ibuprofen may result in a lower mean temperature one hour after treatment. The difference in temperature reduction was very small, however (0.27°C at one hour), so this is unlikely to be of clinical significance. If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at four hours, and in fewer children remaining or becoming febrile for at least four hours after treatment. There was no significant difference in fever-associated discomfort between the treatment regimens in one trial.
• This is supported by a subsequent systematic review of eight RCTs comparing the effectiveness of paracetamol versus ibuprofen in the management of febrile children up to 12 years of age [Narayan, 2017].
  • It found six studies showing that both drugs were effective at reducing fever, and ibuprofen monotherapy was slightly, but not significantly, better at reducing fever and fever-associated discomfort in children than paracetamol monotherapy. There were, however, various study limitations including different study designs, age groups, drug doses, frequency of drug administration, and time and route of temperature measurement after antipyretic treatment, which limited direct comparisons between included studies. It concludes that either drug can be used in the management of febrile children as both drugs are equally effective. It notes that ibuprofen may produce a greater temperature reduction over an extended time period due to its longer duration of action.
• Parental preference depending on previous experience has been noted as an important factor affecting the choice of antipyretic drug in the management of febrile children [Chiappini, 2012; Narayan, 2017; NICE, 2017].
• The recommendation to use ibuprofen with caution if a child is dehydrated is extrapolated from expert opinion in the British National Formulary (BNF) [BNF for Children, 2017].

Advice on switching from paracetamol to ibuprofen or vice versa

• The recommendation to consider switching antipyretic treatment is based on the expert opinion of the NICE guideline development group, which found evidence that both ibuprofen and paracetamol reduce fever and improve some aspects of quality of life [NICE, 2017]. This approach is also pragmatic, based on what CKS considers to be good clinical practice, if monotherapy with one antipyretic agent has not reduced a child's distress or discomfort.
• The NICE clinical guideline stresses that paracetamol and ibuprofen should not be used simultaneously.
  • Evidence showed little difference between paracetamol and ibuprofen given alone or simultaneously to reduce temperature. The guideline development group recognised that some of the evidence showed a small benefit in reducing temperature when both drugs were given together compared with paracetamol monotherapy, but no evidence of a reduction in distress or discomfort, which was the primary outcome. Each antipyretic drug is known to be effective as a single agent, and the potential for confusion and drug administration errors is increased by using more than one drug.
• A subsequent Cochrane systematic review published after the NICE clinical guideline assessed six RCTs (n = 915) to examine the effects and adverse effects of alternating or combined paracetamol and ibuprofen regimens compared with monotherapy in the management of febrile children. There was no significant difference in fever-associated discomfort between the treatment regimens in one trial [Wong, 2013].

Considering alternating ibuprofen and paracetamol if monotherapy is ineffective

• The recommendation to consider alternating ibuprofen and paracetamol is based on limited evidence in the NICE clinical guideline which showed a greater improvement in quality of life and temperature reduction outcomes when these agents were alternated compared with either treatment alone. The guideline development group considered alternating drugs to be a reasonable option if monotherapy has been unsuccessful, but advised that this should only be used while the child appears distressed [NICE, 2017].
• A subsequent Cochrane systematic review published after the NICE clinical guideline assessed six RCTs (n = 915) to examine the effects and adverse effects of alternating or combined paracetamol and ibuprofen regimens compared with monotherapy in the management of febrile children [Wong, 2013].
  • It found low-quality evidence that alternating treatment may result in a lower mean temperature one hour after the second dose and may also result in fewer children remaining or becoming febrile for up to three hours after it is given. In addition, one trial assessing child discomfort found mean scores were lower with alternating therapy, despite fewer doses of antipyretic being given overall.
  • One small trial comparing alternating therapy with combined therapy found very low-quality evidence of no statistically significant differences in mean temperature or the number of febrile children at one, four or six hours between the different regimens. Overall, there was some evidence that both alternating and combined antipyretic therapy may be more effective at reducing temperatures than monotherapy alone. It concluded that there is insufficient evidence to know which of combined or alternating therapy might be more beneficial.
• A Chinese open-label RCT using an intention-to-treat analysis based in tertiary care (n = 471) assessed alternating paracetamol and ibuprofen compared with drug monotherapy [Luo, 2017]:
  • It found no significant clinical or statistical difference in mean discomfort scores or temperature during the 24-hour treatment period in all febrile children across the three groups, but did note that alternating antipyretic therapy can reduce the proportion of children with refractory fever. It concluded that two or more cycles of alternating antipyretic therapy may have little to no clinical benefit if febrile children do not respond to one cycle of alternating therapy. Study limitations included non-compliance with the drug dosage regimen in all three treatment groups.

Using a drug treatment diary if alternating antipyretic drugs

• The recommendation to use a drug treatment diary is largely based on expert opinion in a Health Technology Assessment [Hay et al, 2009]. CKS also considers this to be a pragmatic approach, based on good clinical practice when two different drug dosages and intervals are used.
  • Although none of the primary or secondary outcomes focused on the accuracy of drug dosing, the authors recommended that if two medicines are used then all dose times should be recorded carefully to avoid accidentally exceeding the maximum recommended dose [Hay et al, 2009].
• The recommendation to minimize the risk of medication errors is also based on literature which highlights the potential for severe adverse effects if antipyretic drugs are not taken correctly.
  • Expert opinion in an editorial article highlights various reasons for medication errors involving paracetamol including different paracetamol formulations available to prescribe and buy over-the-counter, which may lead to unintentional drug overdose. It highlights the need to reduce the risk by healthcare professionals specifying paracetamol dose, frequency, and formulation to caregivers of children [Star, 2015].
  • Similarly, an analysis of international fever management guidelines (which graded the NICE clinical guideline favourably) cites studies reporting wrong drug doses or insufficient time intervals between drug doses, which may delay any underlying diagnosis and increase the risk of antipyretic drug overdose [Chiappini, 2017].
  • An Australian and New Zealand retrospective analysis (2002–2012) found that paracetamol overdose secondary to medication errors was the leading cause of paracetamol-associated paediatric acute liver failure presenting to transplant services [Rajanayagam, 2015].
  • An Italian questionnaire-based survey of parents and paediatricians' fever management of pre-school children (n = 388 parents and 480 paediatricians) found poor awareness of the risk of antipyretic misuse, and one-third of parents were unaware of the dangers of using doses of antipyretics above the recommended prescribed levels. The study notes the risk of bias inherent in a self-reported questionnaire survey [Chiappini, 2012].

Basis for recommendation

The recommendations on the management of a febrile infant or child are largely based on the National Institute for Health and Care Excellence (NICE) clinical guidelines Feverish illness in children: assessment and initial management in children younger than 5 years [NICE, 2017], the Public Health England (PHE) publication Health Protection in schools and other childcare facilities [UKHSA, 2023], and expert opinion in review articles on fever management [Richardson, 2015; Lim, 2018].

• CKS notes that the NICE clinical guideline covers children aged less than 5 years but considers it reasonable to extrapolate the recommendations to cover children up to 16 years of age. This approach is supported by the expert opinion of previous external reviewers of this CKS topic.

Advice on sources of information and support

• The recommendation on providing information and support for parents and carers is based on the NICE clinical guideline, and is what CKS considers to be good clinical practice.

Advice on self-care strategies

• The recommendation on the signs of dehydration is based on a NICE Delphi survey and the clinical experience of the guideline development group, which identified specific clinical signs that were sensitive for identifying dehydration but would not need specialist skills to detect.
• The recommendations on fluid intake and the need to increase fluids if there are signs of dehydration are based on a NICE Delphi survey as there was a lack of evidence from clinical studies.
• The recommendations to dress a febrile child appropriately are based on limited evidence identified by NICE and consensus opinion of the guideline development group, which felt the main aim of fever management was to reduce the distress of the child.
  • One study compared undressing a child with the use of paracetamol and tepid sponging and concluded that undressing alone had little effect on body temperature.
• The NICE clinical guideline notes that physical interventions to reduce body temperature do not treat the underlying cause of fever, and there is a lack of evidence to support these measures from clinical studies.
  • It notes that tepid sponging does not reduce core body temperature, just the part of the body being sponged. It concluded that tepid sponging offers no significant benefit over antipyretic drugs alone. In addition, it is time-consuming, may cause distress to the child, and resultant vasoconstriction may cause a paradoxical increase in temperature and metabolism.
  • This is supported by a small South Korean meta-analysis of 14 studies on the effect of tepid sponging for febrile children (using different water temperatures and durations of application). This showed no significant effect of tepid massage on temperature reduction, and higher rates of adverse effects such as chills and shivering due to peripheral vasoconstriction and discomfort, compared with other fever management strategies [Lim, 2018].
  • In addition, a review article found no evidence for physical methods of cooling such as undressing or fanning. It noted that tepid sponging may produce a short-lived reduction in body temperature, but undesirable adverse effects such as shivering and crying make this method counterproductive [Richardson, 2015].
• The recommendation to check a febrile child regularly including at night is based on a NICE Delphi survey, which found no evidence on the optimal frequency of checking a child.
• The recommendations on keeping a febrile child away from nursery or school are based on the PHE publication [UKHSA, 2023] and a NICE Delphi survey.

Providing safety-netting advice

• The recommendations on safety-netting are based on the NICE clinical guideline, which aimed to allow parents/carers to take appropriate action if their child deteriorates or does not recover as expected. The NICE guideline development group noted a lack of evidence from clinical studies, and therefore conducted a Delphi survey of specific indicators.