Acetaminophen has been well known as an effective analgesic and antipyretic for more than a century. IV acetaminophen (IV APAP) is approved for the short‐term treatment of acute pain and fever in nearly 70 countries outside of the United States and more than 300 million 1‐g doses have been distributed since its first approval in Europe in 2002. IV APAP is under clinical investigation in the United States (Acetavance™, Cadence Pharmaceuticals).
This randomized, double‐blind, double‐dummy study (CPI‐APF‐303) was conducted in 81 healthy adult men with an endotoxin‐induced fever to assess the antipyretic efficacy and safety of a 1‐g dose of IV or PO APAP over 6 hours. After an overnight stay, each subject was assessed to rule out fever or occult infection. Eligible subjects were given IV endotoxin (E, coli 0:113, lot 6, obtained from the National Institutes of Health) 1 ng/kg as a test dose and observed for 1 hour. Subsequently, subjects were administered a 4 ng/kg pyrogenic IV endotoxin dose and monitored until a core temperature > 38.6°C was reached. Subjects achieving a sufficient fever response were randomly assigned to receive either IV APAP 1 g plus a PO placebo (n = 45) or PO APAP 1 g (2 Tylenol® Extra Strength caplets) plus an IV placebo (n = 36). Core temperature was continuously monitored using the VitalSense Monitoring System (Respironics). Subjects who vomited during the first 2 hours after study drug administration were excluded from further participation because it could not be verified that the entire oral dose had been absorbed. The primary efficacy outcome was WSTD2 (defined as the weighted sum of temperature differences from baseline to the temperature at each assessment point through 2 hours). Secondary end points included time to temperature reduction of 1.5°C, 1.0°C, and 0.8°C, WSTD3, WSTD4, WSTD5, and WSTD6, subjects' global evaluations, and the percentage of subjects whose temperature dropped below 38°C and 38.5X. Safety evaluations included adverse event (AE) reporting, physical examinations, and laboratory assessments.
Statistically significant results favoring IV APAP compared with PO APAP were observed for the primary end point of WSTD2 (P = 0.0039), and also for the following protocol‐specified point comparisons after TO: 15 minutes after the end of the IV infusion (30, P = 0.0202), 40 minutes (P = 0.0005), 50 minutes (P =0.0021), 60 minutes (P = 0.0004), 75 minutes (P = 0.0006), and 90 minutes (P = 0.0033). The AE frequency, including hepatic AEs, was comparable between the IV and PO APAP treatment groups. More subjects in the PO APAP group, 15 of 51 (29.4%), were discontinued from the study in the first 2 hours because of vomiting than were subjects in the the IV APAP group (9 of 54; 16.7%). Although this result was not statistically significant, that IV APAP was numerically better at reducing the nausea/vomiting associated with endotoxin administration may be a result of its faster onset of action.
IV acetaminophen had a faster onset of action and was more efficacious than oral Tylenol in rapidly blunting endotoxin‐induced fever within 2 hours of administration.
M. Royal, Cadence Pharmaceuticals, employee/shareholder; L. Fong, Cadence Pharmaceuticals, employee/ shareholder; H. Smith, Cadence Pharmaceuticals, Employee/Shareholder; C. Pan, Cadence Pharmaceuticals, employee/shareholder; W. Smith, New Orleans Center for Clinical Research, Contract Research Organization; J. Breitmeyer, Cadence Pharmaceuticals, Employee/Shareholder.
To cite this abstract:Royal M, Fong L, Smith H, Pan C, Smith W, Breitmeyer J. Randomized Study of the Efficacy and Safety of IV Acetaminophen Compared with Oral Acetaminophen for Treatment of Fever. Abstract published at Hospital Medicine 2009, May 14-17, Chicago, Ill. Abstract 85. https://www.shmabstracts.com/abstract/randomized-study-of-the-efficacy-and-safety-of-iv-acetaminophen-compared-with-oral-acetaminophen-for-treatment-of-fever/. Accessed December 10, 2018.