<p>An integrated safety analysis of combined acetaminophen and ibuprofen (Maxigesic^&reg;/ Combogesic^&reg;) in adults</p>

Abstract

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.

Multidisciplinary Guidelines for the Rational Use of Topical Non-Steroidal Anti-Inflammatory Drugs for Musculoskeletal Pain (2022)

“…Meanwhile, of the 65 clinical trials on topical NSAIDs, 57% allowed patients to use acetaminophen as rescue therapy [ 120 ]. Furthermore, a supplementary data analysis summarizing four RCTs found that the concurrent use of oral acetaminophen and oral ibuprofen did not increase the risk of common adverse events [ 121 ].…”

Parenteral Ready-to-Use Fixed-Dose Combinations Including NSAIDs with Paracetamol or Metamizole for Multimodal Analgesia—Approved Products and Challenges

“…When administered orally, paracetamol will suffer first-pass metabolism and be converted into p-aminophenol in the liver and then into N-(4-Hydroxyphenyl) arachidonylamide (AM404) in the brain. The AM404 is a potent agonist of the transient receptor potential vanilloid type 1 (TRPV1), a low-affinity ligand of the cannabinoid receptor type 1 (CB 1 ), an anandamide membrane transporter blocker, and a cyclooxygenase (COX) inhibitor [ 30 ]. When paracetamol is taken intravenously, it is spared from the first-pass process and the biosynthesis of AM404 is less extensive [ 31 ].…”

“…As previously reported, at this moment, the combination of ibuprofen with paracetamol is the unique parenteral analgesic FDC available on the market. Even when taken orally, this combination was shown to be an effective alternative to opioid-based analgesia [ 30 ]. However, there are a limited number of studies assessing the efficacy and safety of parenteral FDCs of ibuprofen/paracetamol [ 3 ].…”

“…The clinical trials presented on the marketing authorization applications were performed by Vale Pharma and AFT Pharmaceuticals to support the safety and efficacy of ibuprofen/paracetamol FDC. A summary of all the clinical trials performed by Vale and AFT was published by Aitken et al [ 30 ]. In total, ten phase I, four phase II/III, and one long-term exposure (phase II) clinical trials were performed [ 30 ].…”

“…A summary of all the clinical trials performed by Vale and AFT was published by Aitken et al [ 30 ]. In total, ten phase I, four phase II/III, and one long-term exposure (phase II) clinical trials were performed [ 30 ]. In this work, the authors reported excellent tolerability and safety profiles after the administration of ibuprofen/paracetamol FDC.…”