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

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.

KEYWORDS:

• Acetaminophen
• ibuprofen
• analgesia
• fixed-dose combination
• safety

1 Introduction

Ibuprofen (IBU) and acetaminophen (APAP) are among the most widely used non-prescription OTC analgesic drugs in the United States and globally [1,2]. In the OTC setting, these agents have well-established efficacy for short-term relief of mild-to-moderate acute pain and fever [2–5]. It is known that both drugs are associated with a ceiling effect for analgesic efficacy (400 mg for IBU and 1,000 mg for APAP), where no further analgesic effect occurs at single doses above these thresholds [6–8]. However, no ceiling effect exists regarding safety and tolerability outcomes, and the risk of commonly seen AEs with IBU and APAP, such as upper gastrointestinal toxicity and acute liver failure, respectively, is dose dependent for each agent [7,8]. Indeed, hepatotoxicity concerns with APAP was the impetus for a guidance issued by the US Food and Drug Administration to limit the maximum single dose of APAP to 650 mg and the maximum daily dose to 3,000–3,250 mg in prescription products [9,10]; the maximum recommended OTC dose remains 1,000 mg/dose and 4,000 mg/day [11]. The maximum recommended OTC dose of IBU is up to 1,200 mg/day for up to 10 days [12,13], although prescription-strength doses of 2,400–3,200 mg/day may be taken long-term when used as an anti-inflammatory agent for chronic inflammatory conditions such as rheumatoid arthritis and osteoarthritis [13].

IBU and APAP provide pain relief via different mechanisms. IBU is an NSAID that inhibits the cyclooxygenase (COX)-1 and COX-2 enzymes and the subsequent synthesis of pro-inflammatory prostaglandins [14]. Although the mechanism of action of APAP is not clear, it is thought to involve inhibition of a sub-class of COX enzyme isoforms in the central nervous system [14], inhibition of the L-arginine nitric oxide pathway [15], and/or activation of central serotonergic pain inhibitory pathways [16]. Because the 2 drugs are metabolized by different pathways, no drug-drug interactions are anticipated with concomitant administration. Indeed, pharmacokinetic (PK) trials have demonstrated that there are no alterations of drug concentrations of either IBU or APAP when the 2 analgesics are dosed together [14,17,18]. It is therefore anticipated that IBU and APAP may be successfully combined for effective analgesia and antipyresis. It is anticipated that their combination may allow for effective analgesia despite reduced doses of the individual components compared with what is taken with standard OTC dosing for each agent, and by virtue of these lower drug exposures, may potentially lead to an improved safety and tolerability profile [7,19] versus those of the individual monocomponents.

An oral fixed-dose combination (FDC) formulation composed of IBU 250 mg and APAP 500 mg has been developed. The individual components are used for the relief of minor aches and pains due to headache, toothache, backache, menstrual cramps, the common cold, muscular aches, minor pain of arthritis, and the temporary reduction of fever. In dental pain models, treatment with this FDC produced greater analgesia than the same dose of each individual monocomponent alone [20]. In addition, PK trials have further demonstrated that single or multiple doses of the FDC do not result in increased drug exposure relative to standard OTC monocomponent dosing [21]. Previous investigations of various FDCs of IBU and APAP have demonstrated that the combination is effective in management of acute pain and that it has a safety profile similar to those of corresponding doses of the individual components [3,22–25]. This report characterizes the safety and tolerability of this new FDC of IBU 250 mg/APAP 500 mg as OTC use across 7 separate single-dose or short-course clinical trials and in different sub-populations in comparison to individual IBU and APAP monocomponents and placebo.

2 Methods

Adverse event (AE) data were pooled from 7 clinical trials that included an FDC dose of IBU 250 mg/APAP 500 mg. Additionally, 2 other doses of the FDC (IBU 200 mg/APAP 500 mg and IBU 300 mg/APAP 500 mg) were investigated in a proof-of-concept trial. Five of the trials enrolled otherwise healthy adults; two trials included participants that were healthy adolescents. In all, the trials comprised three phase 1 PK trials (2 single-dose trials in adults; 1 single-dose trial in adolescents) [21], 3 dental pain model efficacy trials (a phase 2 single-dose proof-of-concept [26]), a phase 3 single-dose, and a phase 3 multiple-dose trial [20], and 1 single-dose phase 3 trial using an endotoxin-induced fever model. Details of the individual studies included in this pooled safety analysis are provided in Table 1. In all studies, patients were monitored for AEs throughout the study and AEs were reported through 14 days after administration of the last dose of study drug regardless of causality [21,26]. In the dental pain model studies, patients were permitted to take immediate-release tramadol or codeine phosphate at any time during the study as rescue medication, but were encouraged to wait at least 1 hour [26] after study medication administration before doing so. The final protocol, any amendments, and informed consent documentation were reviewed and approved by the Institutional Review Board and/or Independent Ethics Committee(s) at each of the investigational centers participating in the trials. The trials were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. A signed and dated informed consent was obtained from each adult subject or a minor subject’s parent or legal guardian before any screening procedures were performed. Subjects who required a parent or legal guardian to sign the informed consent form were also required to sign an assent. The 3 dental pain trials are registered at ClinicalTrials.gov under identifiers NCT01559259, NCT02912650, and NCT02837952. The induced-fever trial is registered at ClinicalTrials.gov under identifier NCT02761980. The PK trials did not require registration.

Table 1. Summary of trials included in pooled analysis

Trial	ClinicalTrials.gov Identifier	Description	Interventions	Population
PK study 1 [21]	N/A	Single-site, randomized, open-label, single-oral dose, 4-way crossover, relative bioavailability and food effects, in-patient	FDC IBU/APAP 250 mg/500 mg fasted vs FDC IBU/APAP 250 mg/500 mg fed vs IBU 200 mg fasted vs APAP 650 mg fasted	Healthy male and female volunteers aged 18–55 years (n = 35)
PK study 2 [21]	N/A	Single-site, randomized, open-label, single-oral dose, 4-way crossover, bioequivalence, in-patient	FDC IBU/APAP 250 mg/500 mg vs IBU 250 mg + APAP 500 mg vs IBU 250 mg vs APAP 500 mg	Healthy male and female volunteers aged 18–55 years (n = 46)
PK study 3 [21]	N/A	Multicenter, open-label, single-oral dose, in-patient bioavailability	FDC IBU/APAP 250 mg/500 mg (n = 21)	Healthy male and female adolescent volunteers aged 12–17 years
Dental pain study 1 [26]	NCT01559259	Single-center, randomized, double-blind, placebo-controlled, parallel-group, in-patient, proof-of-concept, single-dose	FDC IBU/APAP 200 mg/500 mg (n = 90) vs FDC IBU/APAP 250 mg/500 mg (n = 93) vs FDC IBU/APAP 300 mg/500 mg (n = 89) vs IBU 400 mg (n = 92) vs placebo (n = 30)	Healthy adults and adolescents aged 16–40 years who had undergone extraction of ≥3 third molar teeth
Dental pain study 2 [20]	NCT02912650	Single-center, randomized, double-blind, placebo-controlled, parallel-group, in-patient, full-factorial single-dose	FDC IBU/APAP 250 mg/500 mg vs IBU 250 mg vs APAP 650 mg vs placebo	Healthy male and female subjects aged 18–40 years who had undergone extraction of ≥3 third molar teeth
Dental pain study 3 [20]	NCT02837952	Single center, randomized, double-blind, multiple-dose, placebo-controlled, parallel-group, in-patient, multiple-dose	FDC IBU/APAP 250 mg/500 mg q8h vs placebo q8h	Healthy male and female subjects aged 18–40 years who had undergone extraction of ≥3 third molar teeth
Induced-fever study	NCT02761980	Single-center, single-dose, in-patient, double-blind, randomized, placebo-controlled, full-factorial, parallel-arm, induced-fever antipyresis trial	FDC IBU/APAP 250 mg/500 mg (n = 81) vs IBU 250 mg (n = 83) vs APAP 500 mg (n = 82) vs placebo (n = 27)	Healthy adult male subjects aged 18–55 years

APAP, acetaminophen; FDC, fixed-dose combination; IBU, ibuprofen; PK, pharmacokinetics; q8h, every 8 hours.

Safety data were summarized according to the number of subjects with all-causality treatment-emergent AEs (TEAEs), serious AEs, non-serious TEAEs, treatment-related AEs, non-serious treatment-related AEs, AEs leading to trial drug discontinuation, AEs leading to withdrawal from the trial, AEs that caused death, and AEs by severity. An AE was defined as any event that initially occurred or worsened in severity following treatment, i.e. all causality TEAEs. For the PK trials, if an AE occurred during a washout period or follow-up period, it was counted as treatment emergent and assigned to the previous treatment. For the induced-fever trial, endotoxin-related TEAEs (i.e. those that occurred following endotoxin administration but before study medication was given) were not included; only those TEAEs that occurred during the medication period were included. The number and frequency of AEs, whether for any cause or related to treatment, were based on the safety population, which comprised all subjects who took at least 1 dose of trial medication. AEs were classified according to the most current Medical Dictionary for Regulatory Activities (MedDRA) system organ class (version 20.1) and preferred term. Subjects who had multiple occurrences of the same AE were classified according to the worst reported severity; a subject could have had multiple AEs for each system organ class or preferred term but was counted only once.

Results are presented as number and frequency of AEs in the placebo group, in the FDC total group (all doses), and in the IBU and APAP monocomponent groups. Data from all doses of the individual monocomponent arms were combined into a single treatment group (i.e. IBU 200–400 mg, or APAP 500–650 mg). Results for the different FDC dose groups, administered as a single tablet or IBU+APAP combined, are also presented. Subgroup analyses according to age (<18 years and ≥18 years), sex (male and female), and race (white, black, other) were conducted.

3 Results

3.1 Subject disposition

In total, 1,429 (96.8%) of 1,477 subjects completed the trials included in this analysis. Overall, 48 (3.2%) discontinued from any of the trials, including 19 (2.7%) taking the FDC, 8 (1.9%) taking IBU, 11 (3.3%) taking APAP, and 10 (6.4%) taking placebo. Among those, 25 (1.7%) discontinued due to AEs, including 9 (1.3%), 6 (1.4%), 6 (1.8%), and 4 (2.6%) in the FDC, IBU, APAP, and placebo groups, respectively. Subject disposition is summarized in Table 2.

Table 2. Subject disposition

	Study Participants (n, %)
Trial Status	Total (N = 1,477)	FDC Total (n = 715)	IBU (n = 432)	APAP (n = 330)	Placebo (n = 156)
Completed study	1,429 (96.8)	696 (97.3)	424 (98.1)	319 (96.7)	146 (93.6)
Discontinued from study	48 (3.2)	19 (2.7)	8 (1.9)	11 (3.3)	10 (6.4)
Adverse event	25 (1.7)	9 (1.3)	6 (1.4)	6 (1.8)	4 (2.6)
Withdrawal by subject	18 (1.2)	7 (1.0)	1 (0.2)	5 (1.5)	5 (3.2)
Noncompliance with study drug	1 (0.1)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.6)
Other	4 (0.3)	3.(0.4)	1 (0.2)	0 (0.0)	0 (0.0)

APAP, acetaminophen; FDC, fixed-dose combination; IBU, ibuprofen.

3.2 Participants and baseline characteristics

Of the 1,477 subjects enrolled in the 7 clinical trials, 715 subjects were administered IBU/APAP in combination, either as monocomponents or as the FDC. Baseline characteristics within each of the treatment cohorts were well balanced between groups (Table 3). Approximately 44% of subjects were female; the majority (86.5%) were white and of non-Hispanic or non-Latino ethnicity (88.4%). The overall mean age of subjects was 23 years. Two of the 7 trials enrolled adolescents; therefore, 13.2% of subjects analyzed were <18 years of age. Neither of the 2 adolescent trials included an APAP arm, so no subjects <18 years received this treatment.

Table 3. Baseline characteristics

	FDC Total (n = 715)	IBU (n = 432)	APAP (n = 330)	Placebo (n = 156)
Sex, n (%)
Female	335 (46.9)	183 (42.4)	132 (40.0)	71 (45.5)
Male	380 (53.1)	249 (57.6)	198 (60.0)	85 (54.5)
Age, years, mean (SD)	23 (9)	25 (10)	27 (11)	22 (6)
Age, n (%)
<18 years	149 (20.8)	31 (7.2)	0	15 (9.6)
≥18 years	566 (79.2)	401 (92.8)	330 (100.0)	141 (90.4)
Race, n (%)
White	598 (83.6)	328 (75.9)	241 (73.0)	136 (87.2)
Black	55 (7.7)	57 (13.2)	49 (14.8)	8 (5.1)
Other	62 (8.7)	47 (10.9)	40 (12.1)	12 (7.7)
Ethnicity, n %
Hispanic or Latino	93 (13.0)	64 (14.8)	56 (17.0)	23 (14.7)
Not Hispanic or Latino	622 (87.0)	368 (85.2)	274 (83.0)	133 (85.3)

APAP, acetaminophen; FDC, fixed-dose combination; IBU, ibuprofen.

3.3 Overall safety

There were no deaths or serious AEs in any of the trials. All-causality TEAEs occurred in 291 (19.7%) of subjects in the 7 trials, with most being mild to moderate in severity. Twenty-six participants (1.8%) experienced severe TEAEs: 16 (2.2%) with the FDC group, 6 (1.4%) with IBU, 0% with APAP, and 4 (2.6%) with placebo. Severe nausea occurred in 11 (1.5%) with FDC treatment, 4 (0.9%) with IBU, 0% with APAP, and 4 (2.6%) subjects with placebo. Severe vomiting occurred in 14 (0.9%) overall, including 8 (1.1%), 4 (0.9%), 0%, and 2 (1.3%), respectively, in the FDC, IBU, APAP and placebo groups. Nausea, vomiting, and dizziness were the most common TEAEs overall, occurring at similar frequencies among all active treatment groups but at lower rates than those observed with placebo. All TEAEs reported in ≥1% of any treatment group are presented in Table 4.

Table 4. Summary of AEs and TEAEs by preferred term occurring in ≥1% of subjects in any treatment group

AE, n (%)	FDC Total (n = 715)	IBU (n = 432)	APAP (n = 330)	Placebo (n = 156)
All-cause TEAE	127 (17.8)	72 (16.7)	47 (14.2)	49 (31.4)
Serious AE	0	0	0	0
Treatment-related AE	13 (1.8)	2 (0.5)	3 (0.9)	9 (5.8)
AE leading to discontinuation of trial medication	3 (0.4)	1 (0.2)	0	0
AE with severity: severe	16 (2.2)	6 (1.4)	0	4 (2.6)
TRAE with severity: severe	0	0	0	0
TEAEs Occurring in ≥1% in Any Treatment Group, n (%)
Nausea	80 (11.2)	47 (10.9)	33 (10.0)	39 (25.0)
Vomiting	36 (5.0)	29 (6.7)	20 (6.1)	24 (15.4)
Dizziness	30 (4.2)	13 (3.0)	13 (3.9)	11 (7.1)
Headache	6 (0.8)	3 (0.7)	4 (1.2)	4 (2.6)
Feeling hot	9 (1.3)	4 (0.9)	0	2 (1.3)
Tremor	7 (1.0)	2 (0.5)	0	2 (1.3)
Alveolar osteitis	8 (1.1)	2 (0.5)	0	0
Flushing	0	2 (0.5)	1 (0.3)	2 (1.3)
Dyspepsia	0	0	1 (0.3)	2 (1.3)

AE, adverse event; APAP, acetaminophen; FDC, fixed-dose combination; IBU, ibuprofen; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.

AEs considered by the investigator to be treatment-related occurred in 26 subjects (1.8%) overall, including 13 (1.8%) with the FDC, 2 (0.5%) with IBU, 3 (0.9%) with APAP, and 9 (5.8%) with placebo (Table 4). No treatment-related AEs occurred at a rate of ≥1% with any active treatments. Nausea (n = 7; 4.5%) and vomiting (n = 5; 3.2%) were the only treatment-related AEs that occurred in ≥1% of subjects treated with placebo. In the dental pain studies, a greater proportion of patients randomized to placebo than to active treatment took opioid rescue medication.

Twenty-five subjects (1.7%) discontinued from the 7 trials due to an AE. All 21 participants who discontinued from the induced-fever trial did so due to the endotoxin (for fever induction) administration. Only 4 subjects discontinued from any of the included trials due to treatment-related AEs; all of these discontinuations were due to vomiting: 3 in the FDC group (0.4%) and 1 in the IBU group (0.2%).

Across the different trials, most of the vital sign measures taken at baseline and at the end of trial fell within normal ranges; any mean changes observed between baseline and respective trial endpoints were not considered clinically significant.

3.4 Safety in different FDC dose groups

All trials utilized an FDC IBU/APAP 250 mg/500 mg treatment arm. Additionally, 1 trial (i.e. the proof-of-concept trial) employed 2 other FDC regimens: FDC IBU/APAP 200 mg/500 mg and FDC IBU/APAP 300 mg/500 mg. In total, 75% of the FDC exposures occurred with the FDC IBU/APAP 250 mg/500 mg dose formulation. Subjects in the FDC IBU/APAP 250 mg/500 mg dose group reported the lowest incidence of TEAEs (13.4%) compared with the other 2 FDC dose groups (FDC IBU/APAP 200 mg/500 mg, 36.7%; FDC IBU/APAP 300 mg/500 mg, 24.7%). The incidence of severe AEs was also lower with the FDC IBU/APAP 250 mg/500 mg dose (1.3%) than with FDC IBU/APAP 200 mg/500 mg (3.3%) and FDC IBU/APAP 300 mg/500 mg (6.7%). Thirteen (1.8%) subjects receiving the FDC experienced a total of 16 treatment-related AEs, all occurring in the FDC IBU/APAP 250 mg/500 mg group. All occurred at an incidence of <1.0% and included nausea (n = 5; 0.7%), dizziness (n = 3; 0.4%), vomiting and headache (n = 2 for each; 0.3%, respectively), and constipation, somnolence, macular rash, and vessel puncture site bruise (n = 1 each; 0.1%, respectively).

3.5 Safety in subgroups

The incidence of TEAEs in subjects taking the FDC by sex, age, and race subgroups is shown in Table 5. Across all treatment groups, female subjects experienced TEAEs more frequently than men (30.6% vs 11.1%, respectively); lack of symptom control was considered to contribute to the relatively higher incidence of TEAEs in the placebo arm. The same pattern was found in the FDC dose group, where 26.9% of women versus 9.7% of men reported a TEAE (Table 5).

Table 5. Summary of AEs for subgroups receiving FDC

AE, n (%)	FDC Total (n = 715)	Sex		Age		Race
		Female (n = 335)	Male (n = 380)	<18 Years (n = 149)	≥18 Years (n = 566)	White (n = 598)	Black (n = 55)	Other (n = 62)
All-cause TEAE	127 (17.8)	90 (26.9)	37 (9.7)	41 (27.5)	86 (15.2)	114 (19.1)	5 (9.1)	8 (12.9)
Treatment-related AE	13 (1.8)	12 (3.6)	1 (0.3)	1 (0.7)	12 (2.1)	8 (1.3)	3 (5.5)	2 (3.2)
AE leading to discontinuation of trial medication	3 (0.4)	1 (0.3)	2 (0.5)	1 (0.7)	2 (0.4)	3 (0.5)	0	0
AE with severity: severe	16 (2.2)	12 (3.6)	4 (1.1)	8 (5.4)	8 (1.4)	14 (2.3)	0	2 (3.2)

AE, adverse event; FDC, fixed-dose combination; TEAE, treatment-emergent adverse event.

Subjects aged <18 years were only eligible for participation in 2 of the 7 trials and comprised only 13.2% of the total population, making comparisons of rates across treatment groups difficult. Overall, the incidence of TEAEs observed in adolescents taking the FDC was higher than that of adults taking the FDC (27.5% vs 15.2%, Table 5).

Regardless of race, all the active treatment groups had a lower incidence of TEAEs compared with placebo. The overall incidence of TEAEs was 20.9% in white participants, 9.1% in black participants, and 14.9% in other races. In subjects taking the FDC, the incidence of AEs was 19.1% in whites, 9.1% in blacks, and 12.9% in ‘other’ race groups. Across all subgroups, the incidence of TEAEs and treatment-related AEs in the FDC group was similar to that in the overall population; no sex-, age-, or race-specific safety signals were identified.

4 Discussion

Across the 7 clinical trials included in this pooled analysis, the FDC of IBU/APAP demonstrated efficacy similar to that achieved with higher doses of its monocomponents while potentially providing a more rapid onset of action [20,26]. As a result, the FDC may offer efficacy advantages over the monocomponents administered individually. In this pooled analysis, the overall safety profile of the FDC of IBU/APAP was similar to those of the individual component drugs used at OTC strengths. There were no deaths or severe treatment-related AEs. No new safety issues or signals were identified, and the safety profile of the FDCs examined here was consistent with those seen in previous trials of IBU/APAP fixed-dose combinations [22–24].

The FDC IBU/APAP 250 mg/500 mg dose, which was chosen for commercial development, was generally well tolerated in this analysis; the most commonly reported all-causality TEAEs occurring with this dose were nausea, vomiting, and dizziness. It should be noted that 3 of the 7 trials in this pooled analysis, comprising 73.5% of the overall population, were in the third molar extraction model of dental pain. While some TEAEs may be causally related to use of the trial drug, these specific AEs are commonly encountered in those undergoing extraction of wisdom teeth and may be related to the pain and trauma of surgery and/or the use of opioid rescue medication [26]. Indeed, the incidence of nausea and vomiting was higher in the placebo group, which had greater use of opioid rescue medication than the active treatment groups. In the induced-fever trial, administration of the endotoxin elicited an acute illness, symptoms of which included nausea. In this analysis the incidence of these and most other TEAEs was consistently greater in the placebo arm (mainly due to lack of symptom control by placebo) than in the FDC arms, and the incidence of treatment-related AEs was quite low.

Women had more than twice as many TEAEs than men in both the treatment and placebo groups. The reason for this disparity by gender is not known, and we are not aware of other literature reporting similar findings with either acetaminophen or ibuprofen. However, the incidence of TEAEs was lower in the FDC group than in the placebo group regardless of gender, and rates were similar to those observed with the IBU or APAP monocomponents. Although there were differences observed in the incidence of all-causality TEAEs among races, the number of participants in the nonwhite subgroups was quite small and not evenly distributed across trials; therefore, it is difficult to make any inferences regarding AE rates between races. All active treatment groups had a lower incidence of all-causality TEAEs compared with placebo, and the incidence of all-causality TEAEs in those treated with the FDC was similar to that in the overall population.

The population studied included 195 subjects <18 years of age across 2 studies (dental pain proof of concept and adolescent PK). Unlike in the other studies, investigations in the adolescent population did not include assessments of an APAP monotherapy arm for comparison. In adolescents, the FDC and IBU treatment groups had similar rates of AEs; these AE rates were lower than that found with placebo. All-causality AE frequencies were similar among active treatment groups in adolescents. Overall, 57/195 (29.2%) of adolescents had AEs, including 41/149 (27.5%) in the FDC group and 7/31 (22.6%) in the IBU group; in contrast, all-causality AEs were noted in 9/15 (60.0%) of those taking placebo. Treatment-related AEs were mild or moderate in severity. The FDC was safe and generally well tolerated in subjects aged <18 years, with no apparent difference in the frequency of TEAEs compared with adults, indicating that this formulation can be safely used in younger individuals.

There was some variability in AE event rates across the different treatment subgroups and among the different FDC dose groups (tested in the dental pain proof-of-concept study only). This was likely due to the different design methodologies and study populations of the trials included in this analysis, combined with the fact that not every trial included every FDC dose and monocomponent group. However, it is evident that the FDC is safe and well tolerated, with AE rates consistently lower than those seen with placebo across all trials.

Although this pooled analysis included more than 700 subjects who took an FDC, it is possible that rare but medically significant AEs such as hepatotoxicity or gastrointestinal bleeding would not be reported in a population of this size [27,28]. The lack of long-term studies in patients taking repeated doses of the FDC is a limitation of this analysis. Most of the trials included involved only single doses of trial drug; the one multiple-dose trial included in this analysis comprised subjects who took a maximum of 6 doses. As a result of the limited drug exposure, the chances of observing rare or dose-related AEs were further diminished. However, previous trials using other FDC IBU/APAP formulations of similar doses to those used here have not revealed any safety concerns. For example, a previous single-dose study using FDC IBU/APAP 200 mg/500 mg was associated with lower rates of treatment-related AEs (18.2%) compared with IBU 400 mg (27.5%), APAP 1,000 mg (35.3%), and placebo (41.9%) [22]. And in another study, significantly lower rates of treatment-related AEs were noted between the first and second treatments with the FDC (6.3%) compared with IBU 200 mg (16.0%; P< .05) and APAP 500 mg (22.4%; P< .001) [23], supporting the results reported here. Additionally, a higher-dose FDC comprising 400 mg ibuprofen and 1,000 mg APAP found an AE frequency of 5.4% with this combination, providing further support of overall tolerability [23]. Although the safety and tolerability of FDC IBU/APAP 250 mg/500 mg over an extended duration of administration was not tested, an earlier study by Doherty and colleagues found that the FDC IBU/APAP 200 mg/500 mg was associated with similar rates of treatment-related AEs (50.5%) to IBU 400 mg (41.5%) and paracetamol 1,000 mg (45.5%) [24] when administered for up to 13 weeks.

5 Conclusions

This pooled analysis of data from more than 700 subjects indicates that a single dose or short course of an FDC of IBU 250 mg/APAP 500 mg as OTC use is safe and generally well tolerated, with an AE profile similar to its monocomponents alone and to placebo. No unexpected TEAEs were observed. There were no apparent safety concerns in different sex, race, and age subgroups, including adolescents. Taken together with previous efficacy data, these safety findings suggest that this FDC may provide another OTC non-opioid treatment option for acute pain.

Author contributions

Trial designs: David Kellstein, Mario Cruz-Rivera, Suzanne Meeves

Collection and assembly of data: Rina Leyva

Data analysis: Rina Leyva

Data interpretation: All authors

Manuscript preparation: All authors

Manuscript review and revisions: All authors

Final approval of manuscript: All authors

Declaration of interest

No potential conflict of interest was reported by the author(s).

Disclosure of interest

Jiangfeng Su is an employee of Pfizer Inc.

Rina Leyva is an employee of GSK Consumer Healthcare.

David Kellstein was an employee of Pfizer Inc. at the time this research was conducted and may own stock/stock options in Pfizer Inc.

Mario Cruz-Rivera was an employee of Pfizer Inc. at the time this research was conducted and may own stock/stock options in Pfizer Inc.

Suzanne Meeves was an employee of Pfizer Inc. at the time this research was conducted and may own stock/stock options in Pfizer Inc.

Declaration of funding

GSK Consumer Healthcare has provided funding for this article.

Declaration of financial/other relationships

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data sharing statement

Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer. On 1 August 2019, Pfizer Consumer Healthcare became part of GSK Consumer Healthcare.

Glossary

AE, adverse event; APAP, acetaminophen; COX, cyclooxygenase; FDC, fixed-dose combination; IBU, ibuprofen; MedDRA, Medical Dictionary for Regulatory Activities; OTC, over-the-counter; PK, pharmacokinetics; q8h, every 8 hours; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.

Acknowledgments

The authors would like to acknowledge John H Simmons (Peloton Advantage, LLC, an Open Health Company) for his medical writing support.

The authors would also like to acknowledge Patricia Williams for guidance on the safety strategy and analysis.