Posted: 03/23/2012; Arch Dis Child. 2012;97(3):277-278. © 2012 BMJ
Abstract and Introduction
Paracetamol is the most frequently used medicine worldwide. It is usually bought as an over-the-counter medication for use in all ages but is particularly favoured for treatment in infants and children by parents, pharmacists, doctors and nurses. It has an excellent safety profile when used within the recommended dose range and is the first line pharmaceutical treatment in common clinical situations such as elevated temperature in childhood caused by intercurrent infection, and irritability in infancy and childhood following immunisation. It is also used for the relief of pain, for example following mild injury, and for toothache and simple headache. Given that much usage is undertaken by parents and carers without discussion or contact with the medical profession, it is important that prescribing and administration information is clear and simple.
The dosages recommended in the British National Formulary for Children (BNFC) are divided into different age groups and are within the licensed dose recommendations as indicated in the summary of product characteristics agreed with the Medicines and Healthcare products Regulatory Agency (MHRA).
It has been suggested that due to wide variations in children's weight for a given age range, paracetamol may be mis-prescribed if the dosage is based purely on the child's age. Eyers et al in New Zealand have very recently compared age-based prescribing of paracetamol as used in the BNFC with internationally recommended weight-based guidelines.
The authors conclude that children underweight or overweight for their age are at risk of inappropriate paracetamol administration based on the BNFC age-based dosing instructions. To illustrate their point, the authors suggest that a 3-month-old child could have their paracetamol dose chosen either from the 1–3-month or the 3–12-month age range. Therefore, the upper dose could be determined by using the maximum dose in the 3–12-month range (120 mg), and assuming the child's weight was below the 10th centile in the 1–3-month range, an inappropriately high dose could be administered. Similarly, to determine the lower dose the authors used the minimum dose in the 1–3-month age group (30 mg), and assuming the child was on or above the 90th centile in the 3–12-month age group, an inappropriately low dose could be given. Such assumptions would naturally produce upper and lower dose values widely different from each other but leave no scope for pragmatism and administration using common sense on an individual basis.
Does the above matter? Are some children at clinical risk? Are there recorded problems based on the recommended oral paracetamol dosages as appear in the 2011–2012 BNFC? The dosage of every medicine needs very careful scrutiny and it behoves us all to closely consider both safety and efficacy. The dosages of paracetamol in the BNFC are fully in line with the licensed recommendations. Although the total oral dose is important, so too are pharmacokinetic issues such as absorption, metabolism and excretion. In young infants gastric emptying is slow and erratic. Do parents administer paracetamol to infants and children before, during or after feeds and what effect does this have on blood levels and efficacy? Do children with a lower body weight for age respond differently to the same dosage of paracetamol as heavier children of the same age? What data are available to answer these questions? What is the relationship between paracetamol blood levels, its efficacy and its safety? Are the dosages of paracetamol required to treat fever the same as those needed to relieve moderate pain?
We do not have the answers to many of these questions as few studies have been undertaken in children. Paracetamol blood levels of 4–18 mg/l in children have been shown to be efficacious in treating fever, but response is better the higher the fever.
Also, the clinical benefits for a specific paracetamol blood level are much greater when the level is falling rather than rising. The clinical response to paracetamol, therefore, is related not only to the paracetamol blood level but also to the time lag, known as the effect compartment. Thus, there is a considerable confusion about the exact dose required for a given body weight and the relationship of paracetamol blood levels to clinical efficacy. One suggestion to explain the effect compartment is that time is required for paracetamol to pass from the blood compartment into the cerebrospinal fluid (CSF) compartment. It is the CSF level which more closely equates with clinical response to fever as the mechanism directly involves the hypothalamus. With regard to safety, the BNFC is unaware of any reported toxicity incident involving paracetamol used in children within the licensed dose range.
The BNFC is published annually in July. In July 2011, the MHRA published new guideline dosing tables for paracetamol usage in children, developed because of the wide age bands used previously. These tables will appear on products entering the market by the end of 2011. In the meantime, the MHRA states that parents and carers should continue to follow the advice currently on packaging. The old and the new guidelines remain age range-based for simplicity and clarity (see Table 1). However, the age bands are narrower than previously and as the MHRA Director of Vigilance and Risk Management of Medicines stated, "The change is not because of safety concerns but to ensure children get the optimal dose of paracetamol for their age".
As the BNF for adults is updated every 6 months, the most recent edition, BNF 62 published in September 2011, includes the new MHRA recommendations with the narrower age bands. The next BNFC publication in July 2012 will be similarly updated.