Safety and tolerability of fixed-dose combinations of ibuprofen and acetaminophen: pooled analysis of phase 1–3 clinical trials

Abstract

ABSTRACT OBJECTIVES An ibuprofen (IBU)/acetaminophen (APAP) fixed-dose combination (FDC) for over-the-counter (OTC) use was developed with the goal of providing the same effective analgesic activity as full doses of the individual monocomponents, while reducing individual monocomponent drug exposures. Here, the safety and tolerability of the FDC is characterized using pooled safety data from phase 1–3 clinical trials in the FDC development program. METHODS We conducted a pooled safety analysis of data from 7 clinical trials: three phase 1 pharmacokinetic trials, a phase 2 proof-of-concept trial, and three phase 3 trials (a single- and a multiple-dose trial in a dental pain model and a single-dose trial in an induced-fever model). Safety and tolerability of the FDC were assessed by adverse events (AEs) for the total group and subgroups (age, sex, race). RESULTS A total of 1,477 participants were enrolled in the 7 trials; 715 were treated with FDC IBU/APAP, 432 with IBU monotherapy, 330 with APAP monotherapy, and 156 with placebo. Most subjects were white (86.5%), and 44% were female. Two trials enrolling 195 adolescents accounted for 13.2% of the overall study population. All-causality treatment-emergent AEs (TEAEs) occurred in 19.7% of the 1477 participants. Nausea (13.5%), vomiting (7.4%), dizziness (4.5%), headache (1.2%), and feeling hot (1.0%) were the only TEAEs reported in ≥1% of subjects. Treatment-related AEs occurred in 1.8% of the subjects in the overall population. The incidence of AEs, including treatment-related AEs, was consistently lower in all active treatment groups than in the placebo group; this also applied to subgroups according to sex, race, and age, including adolescents aged 12–17 years. The higher rate of AEs with placebo was likely due to lack of pain/fever control. CONCLUSION Single-dose or short-course FDC IBU/APAP OTC use was well tolerated, with an AE profile similar to its IBU and APAP monocomponents. ClinicalTrials.gov Registration NCT01559259; NCT02912650; NCT02837952; NCT02761980. The pharmacokinetic studies (n = 3) did not require registration.