Purpose: Multimodal analgesia with acetaminophen and/or nonsteroidal anti-inflammatory drugs is recommended for the treatment of postoperative pain. Although oral fixed-dose combinations (FDCs) are available, parenteral administration may be clinically justified. The goal of this study was to investigate the clinical efficacy and safety of an intravenous FDC of ibuprofen and acetaminophen after bunionectomy. Methods: This study was a prospective, randomized, double-blind, multicenter, placebo-controlled factorial clinical trial conducted at 2 clinical research centers in the United States between November 2016 and June 2017. Eligible patients (male and female subjects, aged 18e65 years, reporting pain intensity levels 40 mm on a 100-mm visual analog scale (VAS) after distal, first metatarsal bunionectomy) were randomized (3:3:3:2) to receive the FDC (ibuprofen 300 mg + acetaminophen 1000 mg), ibuprofen 300 mg, acetaminophen 1000 mg, or placebo (vehicle), administered as 15-minute intravenous infusions every 6 hours for 48 hours. The primary efficacy end point was the time-adjusted sum of pain intensity differences from baseline over 48 hours (SPID 48). In addition to VAS pain intensity scores, pain relief scores, time to perceptible and meaningful pain relief, the use of rescue medication, and participant's global evaluations of the study drug were recorded. Adverse events occurring during the 48-hour treatment period were included in the safety analysis. Findings: A total of 276 participants were enrolled; most were female (82%), the mean age was 42.4 years, and the median baseline VAS was 67 mm, indicating moderate to severe pain. SPID 48 was significantly higher for the FDC (23.4 [2.5] mm) than for ibuprofen (9.5 [2.5] mm), acetaminophen (10.4 [2.5] mm), and placebo (−1.3 [3.1] mm; all, P < 0.001). The superior analgesic effect of the FDC was supported by a range of secondary end points, including reduced opioid usage rates (75% for FDC, 92% for ibuprofen, 93% for acetaminophen, and 96% for placebo; all, P < 0.005). The safety profile of the FDC was comparable to that of intravenous ibuprofen or acetaminophen alone. Three participants withdrew from the study due to adverse events: 2 in the ibuprofen group and 1 in the acetaminophen group. Implications: The study found that repeated administration of an intravenous FDC of ibuprofen and acetaminophen provided statistically significant improvement in SPID 48 over comparable doses of either monotherapy without an increase in adverse events. ClinicalTrials.gov identifier: NCT02689063.

Summary Background Pain following tonsillectomy is often poorly managed in the home setting. Multimodal analgesia with acetaminophen (paracetamol) and nonsteroidal anti‐inflammatory drugs offers superior analgesia over monotherapy but may be difficult for caregivers to manage. A fixed‐dose combination oral suspension product containing paracetamol and ibuprofen has been developed to facilitate pediatric dosing. Aims The aims of this study are to determine the analgesic effectiveness, pharmacokinetics, and safety of the fixed‐dose combination at two doses in the pediatric population. Methods In this prospective, multicenter, randomized, single‐blind, parallel group trial, 251 children aged 2‐12 years undergoing day‐stay (adeno)tonsillectomy were randomized to two dose groups of the fixed‐dose combination. A doubled loading dose was given preoperatively, followed by treatment for up to 11 days (Higher dose: paracetamol 15 mg/kg + ibuprofen 4.5 mg/kg, Lower dose: paracetamol 12 mg/kg + ibuprofen 3.6 mg/kg). Blood samples were collected for pharmacokinetic analysis for up to 6 hours after the loading dose. The analgesic effectiveness was examined on the first day after surgery using both Parents Postoperative Pain Measurement and modified Wong‐Baker Faces pain scales. Rescue medication consumption was recorded throughout the study. Results Differences in maximum plasma concentration (Cmax) and total exposure (AUC0→t) between the treatment groups for both analytes were consistent with a 25% increase in dose; there was no difference in time to peak concentration (Tmax). On the first postoperative day, there was no difference in pain scores or rescue medication use between treatment groups (approximately 30% in both groups). The combination was well tolerated by both groups. The most common adverse events were vomiting and nausea. The incidence of postoperative bleeding was 4.4%. Conclusion The shallow dose‐response relationship and good tolerability of the fixed‐dose combination over an extended study period supports the utility of both doses of the fixed‐dose combination in the home setting.

IntroductionAcetaminophen (APAP) and ibuprofen (IBP) are two analgesic compounds with a long history of use. Both are considered safe at recommended over-the-counter daily doses. Chronic use, high doses, or concomitant medication can produce safety risks for both drugs. APAP is associated with increased risk of hepatic injury, while IBP can produce gastric bleeding and thromboembolic events. Using a combination of APAP and IBP provides superior analgesia without transgressing daily dose limits of each individual drug.MethodsThe present study aimed to determine if treatment with a fixed-dose combination (FDC) containing APAP and IBP results in any unexpected adverse events (AEs) and/or changes in the safety profiles of its two ingredients compared to monotherapy. The analysis will examine clinical safety data obtained from either single dose trials, multiple dose trials, a long-term exposure trial, and post-marketing surveillance data of APAP/IBP FDC tablets (Maxigesic®/Combogesic®, AFT Pharmaceuticals Ltd). The largest dataset was obtained by pooling the four randomized-controlled, multiple-dose clinical studies with either APAP 325 mg + IBP 97.5 mg (FDC 325/97.5, three tablets per dose) or APAP 500 mg + IBP 150 mg (FDC 500/150, two tablets per dose). At maximum doses, the two FDCs are bioequivalent, permitting the pooling of data for the analysis of safety.ResultsA safety population of 922 patients who received full doses of either FDC, APAP alone, IBP alone, or placebo was compiled from the four studies. A total of 521 AEs were experienced with the incidence of FDC AEs similar to or below either monotherapy group or placebo. The FDC did not alter the incidence and percentage of the most common AEs, including gastrointestinal events and postoperative bleeding.ConclusionOverall, the FDC is well tolerated and has a strong safety profile at single and multiple doses with improved efficacy over monotherapy.

The use of fixed-dose combination pain relief has the potential to enhance analgesic efficacy. The pharmacokinetic properties of oral medication can be altered by many factors, including food, concomitant medications, and drug formulation. During the present study the pharmacokinetic parameters of an acetaminophen and ibuprofen combination was tested in four formulations. Testing was performed in two clinical trials examining either fasting or fed dosing conditions in healthy male participants. Both trials were single center, open-label, randomized, single dose studies with a four-way crossover design to compare an oral suspension product, a sachet product, and two different tablet formulations (FDC500/150 and FDC325/97.5). Each dose contained acetaminophen 975-1000 mg and ibuprofen 292.5-300 mg. A total of 26 participants completed the fasting study, while 28 completed the fed study. The absorption limits of different formulations of acetaminophen and ibuprofen were within the 80-125% bioequivalence range in both fasting and fed conditions as measured by the area under the plasma concentrationtime curve from time zero to the time of the last measurable plasma concentration (AUC (0-t)) and the area under the curve from time zero to infinity (AUC (0-∞)). The maximum measured plasma concentration (C max) for the two tablet formulations were bioequivalent in fed conditions for both acetaminophen and ibuprofen, while in fasting conditions ibuprofen was also bioequivalent. Food reduced the C max and increased the time at which maximum measured plasma concentration occurred (t max) of both acetaminophen and ibuprofen. This effect was largest in the sachet and oral suspension formulations, likely due to the drug being dissolved prior to administration, conferring more rapid absorption from the gastrointestinal tract. All treatments were well tolerated, with no treatment-emergent adverse events occurring. Overall, differing formulations and fasting conditions can alter the pharmacokinetic parameters C max , AUC (0-t) , AUC (0-∞) and t max of acetaminophen and ibuprofen combinations although the overall absorption remains bioequivalent.