One-year safety of ibuprofen/famotidine fixed combination versus ibuprofen alone: pooled analyses of two 24-week randomized, double-blind trials and a follow-on extension

Figures & data

Table 1. Summary of safety studies.

Regimen	Objective	Population	N	Study
Primary Safety Population
Phase 3 combination tablet (ibuprofen 800 mg/famotidine 26.6 mg) vs. ibuprofen 800 mg	Safety and efficacy	Males and females, 40–80 years of age, requiring long-term daily NSAID therapy	906 Total 607 Combination tablet 299 Ibuprofen 800 mg	REDUCE-1
Phase 3 combination tablet (ibuprofen 800 mg/famotidine 26.6 mg) vs. ibuprofen 800 mg	Safety and efficacy	Males and females, 40–80 years of age, requiring long-term daily NSAID therapy	627 Total 415 Combination tablet 212 Ibuprofen 800 mg	REDUCE-2
Safety Extension Population
Phase 3 combination tablet (ibuprofen 800 mg/famotidine 26.6 mg) vs. ibuprofen 800 mg	Safety	Patients who completed studies REDUCE-1 or REDUCE-2 without developing an UGI ulcer	179 Total^a 132 Combination tablet 47 Ibuprofen 800 mg	Extension

^aDue to the entry criteria, the 2:1 randomization was lost for this extension study, resulting in a 3:1 ratio of patients in the combination tablet group versus those in the ibuprofen treatment group.

NSAID = nonsteroidal anti-inflammatory drug; UGI = upper gastrointestinal.

Figure 1. Patient disposition in the pooled primary safety population from REDUCE-1 and REDUCE-2.

Table 2. Overview of select combined safety events in the REDUCE-1 and REDUCE-2 trials.

	REDUCE-1 and REDUCE-2 combined
Safety event	Ibuprofen/ famotidine n = 1022 n (%)	Ibuprofen n = 511 n (%)	p Value
Discontinuations	317 (31.0)	219 (42.9)	<0.0001
Deaths^a	0	1 (0.2)	ND
TEAEs	562 (55.0)	300 (38.7)	0.162
GI disorders	226 (26.0)	145 (28.4)	0.329
Dyspepsia	48 (4.7)	41 (8.0)	0.009
Infections and infestations	211 (20.6)	106 (20.7)	0.960
Cardiac disorders	4 (0.4)	5 (1.0)	ND
Serious GI complications^b	3 (0.3)	0	ND

^aAttributed by the investigator to be acetaminophen-related toxicity.

^bThree gastrointestinal complication cases, none had overt bleeding, transfusion, or hospitalization; endoscopy showed gastric lesion in all cases.

GI = gastrointestinal; ND = not done; TEAE = treatment-emergent adverse event.

Adapted with permission from Schiff and Peura31.

Table 3. Patient demographics and baseline characteristics for the safety extension population.

	Ibuprofen/famotidine (n = 132)	Ibuprofen (n = 47)	Total (N = 179)	p value^a
Age (years)				0.2
Mean (SD)	55.7 (9.6)	53.6 (9.3)	55.7 (9.6)
Median (range)	56.0 (41, 79)	51.0 (41, 75)	54.0 (41, 79)
Age class, n (%)				0.5
<65 years	110 (83.3)	41 (87.2)	151 (84.4)
≥65 years	22 (16.7)	6 (12.8)	28 (15.6)
Gender, n (%)				1.0
Male	42 (31.8)	15 (31.9)	57 (31.8)
Female	90 (68.2)	32 (68.1)	122 (68.2)
Ethnicity, n (%)				0.2
Hispanic or Latino	21 (15.9)	3 (6.4)	24 (13.4)
Not Hispanic or Latino	110 (83.3)	43 (91.5)	153 (85.5)
Not reported	1 (0.8)	1 (2.1)	2 (1.1)
Race, n (%)				0.5
White	119 (90.2)	42 (89.4)	161 (89.9)
Black	9 (6.8)	2 (4.3)	11 (6.1)
Other^b	4 (3.0)	3 (6.4)	7 (3.9)
Weight (kg)				0.6
Mean (SD)	87.80 (23.3)	85.55 (21.2)	87.21 (22.7)
Median	84.6	80.7	83.9
Use of low-dose aspirin and/or other anticoagulant^c, n (%)				1.0
No	112 (84.8)	40 (85.1)	152 (84.9)
Yes	20 (15.2)	7 (14.9)	27 (15.1)
Positive UGI ulcer history^c, n (%)				0.4
No	125 (94.7)	46 (97.9)	171 (95.5)
Yes	7 (5.3)	1 (2.1)	8 (4.5)
Contributing study, n (%)				0.7
REDUCE-1	47 (35.6)	15 (31.9)	62 (34.6)
REDUCE-2	85 (64.4)	32 (68.1)	117 (65.4)
Indication, n (%)				NC
Osteoarthritis	61 (46.2)	31 (66.0)	92 (51.4)
Rheumatoid arthritis	10 (7.6)	0 (0.0)	10 (5.6)
Pain	52 (39.4)	11 (23.4)	63 (35.2)
Other	9 (6.8)	5 (10.6)	14 (7.8)

^ap Values from a two-sample t test for continuous variables and from a Pearson chi-square test for categorical responses.

^b‘Other’ class includes the following races: Native Hawaiian or other Pacific Islander, Asian, American Indian or Alaska Native, and races reported as ‘Other’.

^cAs reported by patient at time of entry into studies REDUCE-1 or REDUCE-2.

NC = not calculated; UGI = upper gastrointestinal.

Figure 2. Patient disposition in the safety extension population.

Table 4. Exposure to study medication in the safety and safety extension populations.

Number of patients by exposure category	Ibuprofen/famotidine	Ibuprofen	Total
Safety population (REDUCE-1 or REDUCE-2)
Drug exposure (days) (mean ± SD)	139.1 ± 51.57 n = 1022	125.8 ± 56.31 n = 511	134.7 ± 53.55 n = 1533
Drug exposure (days) (median)	167.0 n = 1022	164.0 n = 511	167.0 n = 1533
Median ibuprofen dose (mg/day)	2362 n = 987	2368 n = 493	2334.40 n = 1480
Median famotidine dose (mg/day)	77.50 n = 986	23.10 n = 1^a	77.50 n = 987
Safety extension population
Drug exposure (days) (mean ± SD)	348.5 ± 47.96 n = 132	339.80 ± 54.77 n = 47	346.2 ± 49.83 n = 179
Drug exposure (days) (median)	364.0 n = 132	363.0 n = 47	364.0 n = 179
Median ibuprofen dose (mg/day)	2362.10 n = 123	2367.80 n = 45	2364.65 n = 168
Median famotidine dose (mg/day)	78.50 n = 123	11.10 n = 1^a	78.50 n = 124

^aA single patient was mistakenly provided with the ibuprofen/famotidine combination tablet in place of ibuprofen for 32 days during participation in REDUCE-2.

SD = standard deviation.

Table 5. AEs occurring in ≥1% of the extension safety population.

System organ class preferred term	Ibuprofen/famotidine n = 132 n (%)	Ibuprofen n = 47 n (%)	Total N = 179 n (%)	p Value^a
Total patients with ≥1 AE	55 (41.7)	16 (34.0)	71 (39.7)	0.4
Blood and lymphatic system disorders	2 (1.5)	0 (0.0)	2 (1.1)	NC
Anemia	2 (1.5)	0 (0.0)	2 (1.1)
Eye disorders	0 (0.0)	1 (2.1)	1 (0.6)	NC
Cataract	0 (0.0)	1 (2.1)	1 (0.6)
Gastrointestinal disorders	11 (8.3)	2 (4.3)	13 (7.3)	0.4
Abdominal pain upper	2 (1.5)	0 (0.0)	2 (1.1)
Abdominal tenderness	0 (0.0)	1 (2.1)	1 (0.6)
Constipation	2 (1.5)	0 (0.0)	2 (1.1)
Diarrhea	0 (0.0)	1 (2.1)	1 (0.6)
Dyspepsia	3 (2.3)	0 (0.0)	3 (1.7)
Esophageal stenosis	0 (0.0)	1 (2.1)	1 (0.6)
Nausea	2 (1.5)	0 (0.0)	2 (1.1)
Vomiting	0 (0.0)	1 (2.1)	1 (0.6)
General disorders and administration site conditions	1 (0.8)	2 (4.3)	3 (1.7)	NC
Edema peripheral	0 (0.0)	2 (4.3)	2 (1.1)
Gait disturbance	0 (0.0)	1 (2.1)	1 (0.6)
Noncardiac chest pain	1 (0.8)	1 (2.1)	2 (1.1)
Hepatobiliary disorders	1 (0.8)	1 (2.1)	2 (1.1)
Cholelithiasis	0 (0.0)	1 (2.1)	1 (0.6)
Infections and infestations	24 (18.2)	7 (14.9)	31 (17.3)	0.6
Bronchitis	2 (1.5)	1 (2.1)	3 (1.7)
Bronchitis acute	0 (0.0)	1 (2.1)	1 (0.6)
Ear infection	1 (0.8)	1 (2.1)	2 (1.1)
Gastroenteritis viral	4 (3.0)	2 (4.3)	6 (3.4)
Influenza	4 (3.0)	1 (2.1)	5 (2.8)
Laryngitis	0 (0.0)	1 (2.1)	1 (0.6)
Otitis media	2 (1.5)	0 (0.0)	2 (1.1)
Sinusitis	5 (3.8)	0 (0.0)	5 (2.8)
Upper respiratory tract infection	3 (2.3)	1 (2.1)	4 (2.2)
Urinary tract infection	3 (2.3)	0 (0.0)	3 (1.7)
Viral upper respiratory tract infection	3 (2.3)	1 (2.1)	4 (2.2)
Injury, poisoning and procedural complications	5 (3.8)	2 (4.3)	7 (3.9)	NC
Animal bite	2 (1.5)	0 (0.0)	2 (1.1)
Contusion	0 (0.0)	1 (2.1)	1 (0.6)
Fall	0 (0.0)	1 (2.1)	1 (0.6)
Rib fracture	0 (0.0)	1 (2.1)	1 (0.6)
Metabolism and nutrition disorders	3 (2.3)	4 (8.5)	7 (3.9)	0.03
Diabetes mellitus	3 (2.3)	0 (0.0)	3 (1.7)
Diabetes mellitus non-insulin-dependent	0 (0.0)	1 (2.1)	1 (0.6)
Hypercholesterolemia	0 (0.0)	1 (2.1)	1 (0.6)
Hyperglycemia	0 (0.0)	1 (2.1)	1 (0.6)
Hyperlipidemia	0 (0.0)	1 (2.1)	1 (0.6)
Hyperosmolar state	0 (0.0)	1 (2.1)	1 (0.6)
Musculoskeletal and connective tissue disorders	13 (9.8)	1 (2.1)	14 (7.8)	0.09
Arthralgia	3 (2.3)	0 (0.0)	3 (1.7)
Back pain	3 (2.3)	0 (0.0)	3 (1.7)
Knee deformity	0 (0.0)	1 (2.1)	1 (0.6)
Muscle spasms	3 (2.3)	0 (0.0)	3 (1.7)
Tendonitis	2 (1.5)	0 (0.0)	2 (1.1)
Nervous system disorders	6 (4.5)	2 (4.3)	8 (4.5)
Carpal tunnel syndrome	2 (1.5)	0 (0.0)	2 (1.1)
Dizziness	2 (1.5)	1 (2.1)	3 (1.7)
Nerve compression	0 (0.0)	1 (2.1)	1 (0.6)
Psychiatric disorders	1 (0.8)	1 (2.1)	2 (1.1)
Anxiety	0 (0.0)	1 (2.1)	1 (0.6)
Respiratory, thoracic and mediastinal disorders	4 (3.0)	1 (2.1)	5 (2.8)	NC
Throat irritation	1 (0.8)	1 (2.1)	2 (1.1)
Skin and subcutaneous tissue disorders	7 (5.3)	1 (2.1)	8 (4.5)	0.4
Dermatitis	0 (0.0)	1 (2.1)	1 (0.6)
Dermatitis contact	0 (0.0)	1 (2.1)	1 (0.6)
Swelling face	2 (1.5)	0 (0.0)	2 (1.1)
Vascular disorders	5 (3.8)	0 (0.0)	5 (2.8)	NC
Hypertension	4 (3.0)	0 (0.0)	4 (2.2)

^ap Value calculated from a Cochran–Mantel–Haenszel test for adverse events occurring in ≥1% of patients and presented if <0.05 between treatment groups.

AE = adverse event; NC = not calculated because of the small sample size.

Table 6. Serious AEs in the safety extension population.

System organ class preferred term^a	Ibuprofen/famotidine n = 132 n (%)	Ibuprofen n = 47 n (%)	Total N = 179 n (%)
Total number of patients with ≥1 serious adverse event	4 (3.0)	2 (4.3)	6 (3.4)
Total with a serious adverse event leading to discontinuation	1 (0.8)	0 (0.0)	1 (0.6)
Gastrointestinal disorders	1 (0.8)	1 (2.1)	2 (1.1)
Diabetic gastroparesis	1 (0.8)	0 (0.0)	1 (0.6)
Esophageal stenosis	0 (0.0)	1 (2.1)	1 (0.6)
General disorders and administration site conditions	1 (0.8)	0 (0.0)	1 (0.6)
Non-cardiac chest pain	1 (0.8)	0 (0.0)	1 (0.6)
Hepatobiliary disorders	1 (0.8)	0 (0.0)	1 (0.6)
Cholecystitis	1 (0.8)	0 (0.0)	1 (0.6)
Infections and infestations	1 (0.8)	1 (2.1)	2 (1.1)
Cellulitis	1 (0.8)	0 (0.0)	1 (0.6)
Gastroenteritis viral	0 (0.0)	1 (2.1)	1 (0.6)
Metabolism and nutrition disorders	1 (0.8)	1 (2.1)	2 (1.1)
Diabetes mellitus	1 (0.8)	0 (0.0)	1 (0.6)
Hyperglycemia	0 (0.0)	1 (2.1)	1 (0.6)
Hyperosmolar state	0 (0.0)	1 (2.1)	1 (0.6)
Vascular disorders	1 (0.8)	0 (0.0)	1 (0.6)
Hypertension	1 (0.8)	0 (0.0)	1 (0.6)

^aA patient with multiple events per system organ class or per preferred term category was counted only once per row.

AE = adverse event.

Table 7. AEs leading to discontinuation in the safety extension population.

System organ class preferred term	Ibuprofen/famotidine n = 132 n (%)	Ibuprofen n = 47 n (%)	Total N = 179 n (%)
Total patients with an adverse event leading to discontinuation^a,b	2 (1.5)	1 (2.1)	3 (1.7)
Gastrointestinal disorders	1 (0.8)	0 (0.0)	1 (0.6)
Abdominal pain	1 (0.8)	0 (0.0)	1 (0.6)
Diabetic gastroparesis	1 (0.8)	0 (0.0)	1 (0.6)
Investigations	1 (0.8)	0 (0.0)	1 (0.6)
Blood creatinine increased	1 (0.8)	0 (0.0)	1 (0.6)
Respiratory, thoracic and mediastinal disorders	0 (0.0)	1 (2.1)	1 (0.6)
Throat irritation	0 (0.0)	1 (2.1)	1 (0.6)

^aA patient with multiple events per system organ class or per preferred term category was counted only once per row.

^bA patient in the combination therapy treatment group was also discontinued because of an adverse event, edema peripheral. In error, the event was not recorded as an adverse event and is not in the database.

AE = adverse event.

Table 8. Incidence of AEs of special interest in the safety extension population.

	Ibuprofen/famotidine n = 132	Ibuprofen n = 47	Total N = 179
AE of special interest^a	n (%)	n (%)	n (%)	p value^e
Total number of patients with ≥1 cardiovascular event^b	14 (10.6)	1 (2.1)	15 (8.4)	0.0632
Hypertension	11 (8.3)	1 (2.1)	12 (6.7)	0.1275
Blood pressure increased	2 (1.5)	0 (0.0)	2 (1.1)	0.4044
Accelerated hypertension	1 (0.8)	0 (0.0)	1 (0.6)	0.5395
Palpitations	1 (0.8)	0 (0.0)	1 (0.6)	0.5395
Total number of patients with ≥1 dyspepsia-related AE^c
Including nausea	22 (16.7)	6 (12.8)	28 (15.6)	0.5496
Excluding nausea	20 (15.2)	5 (10.6)	25 (14.0)	0.4648
Dyspepsia	8 (6.1)	1 (2.1)	9 (5.0)	0.3074
Nausea	5 (3.8)	2 (4.3)	7 (3.9)	0.8747
Abdominal pain upper	3 (2.3)	1 (2.1)	4 (2.2)	0.9716
Abdominal tenderness	2 (1.5)	1 (2.1)	3 (1.7)	0.8146
Stomach discomfort	3 (2.3)	0 (0.0)	3 (1.7)	0.2837
Abdominal discomfort	1 (0.8)	1 (2.1)	2 (1.1)	0.3902
Abdominal pain	1 (0.8)	1 (2.1)	2 (1.1)	0.4705
Gastritis	1 (0.8)	1 (2.1)	2 (1.1)	0.4331
Epigastric discomfort	1 (0.8)	0 (0.0)	1 (0.6)	0.5721
Total number of patients with ≥1 serious gastrointestinal complication^d	0 (0.0)	0 (0.0)	0 (0.0)

^aA patient with multiple events per AE of special interest is counted only once per patient.

^bAll preferred terms of the system organ class cardiac disorders and preferred terms hypertension, accelerated hypertension, prehypertension, increased blood pressure and heart rate irregular.

^cDyspepsia-related AEs include preferred terms: abdominal pain, abdominal discomfort, abdominal pain upper, abdominal tenderness, dyspepsia, epigastric discomfort, gastritis, stomach discomfort, with inclusion and exclusion of preferred term nausea.

^dSerious gastrointestinal complications were recorded separately from adverse events in the study database.

^ep Value from a Cochran–Mantel–Haenszel test, controlling for study.

AE = adverse event.

Table 9. Cumulative incidence of treatment-emergent adverse events of special interest by exposure time.

	Ibuprofen/famotidine (n = 132)					Ibuprofen (n = 47)
	Number at risk	Number of events	Cumulative estimate event-free	Probability of event (SE)	Hazard rate	Number at risk	Number of events	Cumulative estimate event-free	Probability of event (SE)	Hazard rate
	Cardiovascular event					Cardiovascular event
Days 1–27 (Week 1–4)	132	1	1.000	0.008 (0.0075)	0.0019	47	0	1.000	0.000 (0.0000)	0.0000
Days 28–55 (Week 4–8)	131	4	0.992	0.031 (0.0150)	0.0078	47	0	1.000	0.000 (0.0000)	0.0000
Days 56–111 (Week 8–16)	127	4	0.962	0.031 (0.0155)	0.0040	47	1	1.000	0.021 (0.0210)	0.0027
Days 112–167 (Week 16–24)	123	2	0.932	0.016 (0.0114)	0.0020	46	0	0.979	0.000 (0.0000)	0.0000
Days 168–265 (Week 24–38)	121	0	0.917	0.000 (0.0000)	0.0000	46	0	0.979	0.000 (0.0000)	0.0000
Days 266–349 (Week 38–50)	112	3	0.917	0.028 (0.0160)	0.0024	42	0	0.979	0.000 (0.0000)	0.0000
Days 350–391 (Week 50–56)	99	0	0.891	0.000 (0.0000)	0.0000	38	0	0.979	0.000 (0.0000)	0.0000
	Dyspepsia-related events (including nausea)					Dyspepsia-related events (including nausea)
Days 1–27 (Week 1–4)	132	4	1.000	0.030 (0.0149)	0.0077	47	2	1.000	0.043 (0.0294)	0.0109
Days 28–55 (Week 4–8)	128	2	0.970	0.016 (0.0110)	0.0039	45	1	0.957	0.022 (0.0220)	0.0056
Days 56–111 (Week 8–16)	126	6	0.955	0.048 (0.0190)	0.0061	44	1	0.936	0.023 (0.0225)	0.0029
Days 112–167 (Week 16–24)	120	3	0.909	0.025 (0.0143)	0.0032	43	2	0.915	0.047 (0.0321)	0.0060
Days 168–223 (Week 24–32)	117	5	0.886	0.044 (0.0193)	0.0032	41	0	0.872	0.000 (0.0000)	0.0000
Days 266–349 (Week 38–50)	104	2	0.847	0.020 (0.0139)	0.0017	36	0	0.872	0.000 (0.0000)	0.0000
Days 350–391 (Week 50–56)	95	0	0.830	0.000 (0.0000)	0.0000	33	0	0.872	0.000 (0.0000)	0.0000
	Dyspepsia-related events (excluding nausea)					Dyspepsia-related events (excluding nausea)
Days 1–27 (Week 1–4)	132	3	1.000	0.023 (0.0130)	0.0057	47	2	1.000	0.043 (0.0294)	0.0109
Days 28–55 (Week 4–8)	129	2	0.977	0.016 (0.0109)	0.0039	45	1	0.957	0.022 (0.0220)	0.0056
Days 56–111 (Week 8–16)	127	5	0.962	0.039 (0.0173)	0.0050	44	1	0.936	0.023 (0.0225)	0.0029
Days 112–167 (Week 16–24)	122	3	0.924	0.025 (0.0140)	0.0031	43	1	0.915	0.023 (0.0230)	0.0029
Days 168–223 (Week 24–32)	119	5	0.902	0.043 (0.0190)	0.0032	42	0	0.894	0.000 (0.0000)	0.0000
Days 266–349 (Week 38–50)	106	2	0.862	0.020 (0.0137)	0.0016	37	0	0.894	0.000 (0.0000)	0.0000
Days 350–391 (Week 50–56)	97	0	0.845	0.000 (0.0000)	0.0000	34	0	0.894	0.000 (0.0000)	0.0000

All adverse events were coded using the Medical Dictionary for Regulatory Activities, Version 9.1 (MedDRA, McLean, VA, USA).

Estimates are life table estimates from Proc Lifetest (SAS Institute Inc., Cary, NC, USA). Cumulative estimate event-free is the life table estimated proportion of patients that are event free at the beginning of the interval. Probability of event is the life table estimate for the probability of a patient experiencing an event during that interval. The hazard rate is estimated at the midpoint of the interval.

SE = standard error.

Schiff M, Peura D. HZT-501 (Duexis; ibuprofen 800 mg/famotidine 26.6 mg) GI protection in the treatment of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Exp Rev Gastroenterol Hepatol 2012;6:25-35

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