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

Figures & data

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.

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.

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.

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.

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.

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