A call for advocacy: Standardized concentration and weight-based dosing of acetaminophen may enhance the therapeutic benefit and reduce the risk for harm

Fever is one of the more common reasons that parents seek medical attention for their children, representing an estimated one-third of the primary complaints of paediatric patients. Furthermore, fever is a secondary complaint for an even larger proportion of patients, prompting numerous office calls and visits. While fever is defined as a rectal temperature >38.2°C in children >1 month of age, approximately one-half of parents consider a temperature <38°C to be a fever and 25% of caregivers would give antipyretics for temperatures <37.8°C (1). As many as 50% of parents administer incorrect doses of antipyretics and approximately 15% give supratherapeutic doses of acetaminophen. Caregivers who understand correctly which temperatures constitute fever and that dosing should be based on weight rather than age or the level of the fever are much less likely to give an incorrect dose (2).

Parents and health care workers often incorrectly assume that there is urgency to bring a fever down. The primary reason to administer antipyretics is to make the child more comfortable because febrile children experience altered activity and sleep patterns in addition to a decreased oral intake (3). Antipyretics also provide analgesia, which may enhance their overall clinical effect. Acetaminophen doses of 10 mg/kg to 15 mg/kg given every 4 h to 6 h orally are generally considered to be safe and effective, and the onset of an antipyretic effect is usually reported to be within 30 min to 60 min (4). However, a recent pharmacokinetics study presented in abstract form by Abourbih et al (5) challenged this dosing. The authors investigated the potential for the weight-based dose recommended by the manufacturer to attain concentrations reported to produce an antipyretic effect (10 μg/mL to 20 μg/mL) in the two- to three-year-old age group. They reported that a 10 mg/kg dose is ineffective at achieving an antipyretic blood concentration of acetaminophen, while a dose of 15 mg/kg would be effective only if the upper range of a given pharmacokinetic constant (Ka) is used for the calculations. The pharmacokinetic constants used to predict acetaminophen concentrations in children remain imprecise because they have been derived based on a small number of children. Thus, the recommended age-based dose for the two- to three-year-old age group of 160 mg found in most commercially available products is predicted to be effective only in patients weighing <10.9 kg (5).

Although alternative dosing regimens, including a higher loading dose, have been suggested, no consistent evidence has indicated that such a dose, administered either orally (30 mg/kg) or rectally (40 mg/kg), improves antipyretic efficacy. The higher rectal dose is often used in intraoperative conditions but cannot be recommended for use in routine clinical care. The use of higher loading doses in clinical practice would contribute to the potential for dosing confusion and hepatotoxicity. Although hepatotoxicity associated with acetaminophen at recommended doses has rarely been reported, the potential for hepatotoxicity exists if dosages exceed 75 mg/kg to 90 mg/kg per 24 h. The most commonly reported scenarios are those of children receiving multiple supratherapeutic doses (15 mg/kg) or appropriate single doses at intervals of <4 h, resulting in total dosages of >90 mg/kg per day for several days (6). A recent Canadian cross-sectional study (7) demonstrated that 41% of febrile children presenting to an urban tertiary children’s hospital had received inadequate (30%) or supratherapeutic (11%) doses. A study from Saudi Arabia reported that the reasons for inaccurate dosing included parental inability to determine, measure or administer the appropriate dose, complicated by package labelling listing doses according to age and not weight, and low parental level of education (8).

Recently in the United Kingdom, the Medicines and Healthcare Products Regulatory Agency published a report regarding acetaminophen dosing in children. It led to changes in the labelling of bottles to ensure that correct, age-based dosing information is presented in an easy-to-read manner (9). The new labelling displays acetaminophen concentrations of 120 mg/5 mL or 250 mg/5 mL in tables with narrow weight intervals.

In Canada, the commercial availability of varying concentrations of acetaminophen creates confusion among parents that could be avoided by mandating all manufacturers to supply a uniform concentration. The current concentrations of many commercial preparations are 160 mg/5 mL or 80 mg/mL. Neither number is easy for parents to multiply if they know the mg/kg dose. A concentration of 15 mg/mL may help to avoid this problem. Because we believe that the optimal dose is 15 mg/kg, parents could be advised to administer 1 mL/kg (recognizing that this does not completely solve the problem because many parents only know their child’s weight in pounds).

Any physician caring for children should remember how critical it is to take the time to explain the appropriate use (ie, formulation, dose and dosing interval) of acetaminophen to caregivers. Child safety and medication efficacy will be further enhanced by the development of simplified weight-based dosing methods and standardized delivery devices (10). To promote proper dosing and child safety, we are advocating clear labelling of weight-based dosing instructions and encourage Health Canada to require manufacturers to make available in Canada a single concentration of acetaminophen liquid formulation for both infants and children.