Antipyretic efficacy and tolerability of a single intravenous dose of the acetaminophen prodrug propacetamol in children: a randomized, double-blind, placebo-controlled trial.

BACKGROUND

Propacetamol is an acetaminophen prodrug that was available in Europe as an IV formu lation for the treatment of pain and fever for some time. One gram of propacetamol is hydrolyzed in blood to release 0.5 g of acetaminophen and pharmacologically inactive N,N-diethylglycine.

OBJECTIVE

This study compared the antipyretic efficacy and tolerability of IV propacetamol and placebo after a single administration in children with acute fever of infectious origin. The study was performed in anticipation of an application for US registration.

METHODS

This was a double-blind, placebo-controlled trial in which patients with a body temperature (tympanic probe) of 38.5 degrees C to 41 degrees C were randomized to receive propacetamol 30 mg/kg IV or a placebo of identical appearance, both administered as 15-minute infusions. Temperature was measured at baseline, 0.5 hour after drug administration, and hourly thereafter for 6 hours or until use of rescue medication. The primary efficacy variable was the change in body temperature at each evaluation time compared with baseline. Secondary efficacy variables included the number of children requiring rescue medication and the time to remedication; the number of children with a body temperature <38 degrees C during the evaluation period and the time to reach this temperature; maximal body temperature reduction; and the weighted sum of changes in body temperature over the evaluation period. Tolerability was assessed based on changes in vital signs, monitored for 6 hours after administration of study drug, and adverse events recorded during the 24 hours after administration.

RESULTS

Twenty children received propacetamol and 21 received placebo. Twenty patients were white, 17 black, and 4 Hispanic; their age ranged from 3 to 12 years. The actual mean (SD) dose of propacetamol received was 25.5 (0.6) mg/kg (equivalent to acetaminophen 12.8 [0.3] mg/kg). The reduction in body temperature was significantly greater in the propacetamol group compared with the placebo group at each time point over the 6-hour follow-up period (P < 0.001). Rescue medication was administered to 10.0% of patients in the propacetamol group, compared with 52.4% of those in the placebo group (P = 0.004). The weighted mean (SD) sum of the change in body temperature indicated greater antipyretic efficacy for propacetamol compared with placebo (-7.9 [3.8] degrees C x h vs 0.1 [3.6] degrees C x h, respectively; P < 0.001). There was no difference in the number of patients with treatment-emergent adverse events in the propacetamol and placebo groups (8 [40.0%] and 8 [38.1%]). The incidence of IV-site reactions was 10.0% in the propacetamol group and 9.5% in the placebo group.

CONCLUSIONS

In these 41 children with acute fever of infectious origin, a propacetamol dose of 25.5 (0.6) mg/kg IV had significantly greater antipyretic efficacy than placebo and was equally well tolerated. Comparisons of this preparation with other IV antipyretic medications are needed.