21. GI Tolerability Profile
Etoricoxib vs. Naproxen or Ibuprofen Endoscopy Studies:
Gastroduodenal Ulcers
12-Week cumulative
incidence rate (%) a
35
25
RA or OA
30
25.27
25
15
17.02
10
10
0
20
15
20
5
OA
7.42 b
5
1.86 c
1.35 b
Placebo
(n=207)
8.12 d
Etoricoxib
120 mg
(n=207)
Study 1
Naproxen
1000 mg e
(n=164)
0
Placebo
(n=203)
Etoricoxib
120 mg
(n=186)
Ibuprofen
2400 mg f
(n=181)
Study 2
Although the studies were not designed to compare ulcer rates of placebo with etoricoxib,
subsequent analysis revealed significant differences in Study 1 (p=0.002) and Study 2 (p=0.003). 2,3
Cumulative incidence rate of gastroduodenal ulcers 3 mm at week 12. Cumulative incidence rate from life-table analysis may not equal
number
of events/n 100; b p<0.001 for etoricoxib and placebo vs. naproxen; c p<0.001 for placebo vs. ibuprofen; d p=0.007 for etoricoxib vs. ibuprofen;
e
500 mg twice daily; f 800 mg three times daily
a
Adapted from Hunt RH et al Aliment Pharmacol Ther 2003;17:201–210; Hunt RH et al Am J Gastroenterol 2003;98:1725–1733.
22. GI Tolerability Profile
Etoricoxib vs. Nonselective NSAIDs: GI PUBs
Etoricoxib had lower incidence of confirmed PUBs in the clinical
development program*
Cumulative incidence
0.06
Etoricoxib 60 mg (n=3142)
Nonselective NSAIDs combined** (n=1828)
0.04
~55%
Risk
reduction
0.02
0.00
0
90
180
270
360
450
540
Days (active treatment period)
NSAIDs = nonsteroidal anti-inflammatory drugs; PUBs = perforations, ulcers, bleeds
*Combined analysis of 10 clinical trials in OA, RA, and chronic low back pain;
**Naproxen 1000 mg/day, ibuprofen 2400 mg/day, or diclofenac 150 mg/day
Adapted from Hunt RH et al Am J Gastroenterol 2003;98:1725–1733; Curtis S et al. Poster presented at EULAR, 2002.
p<0.001
23. EFFICACY OF ETORICOXIB
OA
RA
AS
GOUT
POST-OPERATION PAIN
CHRONIC PAIN
DYSMENORRHEA
24. Osteoarthritis
Etoricoxib vs. Diclofenac :
WOMAC Pain Subscale*
Mean change from baseline in
pain level (mm)
Etoricoxib provided effective and sustained pain relief similar
to diclofenac
0
Etoricoxib 60 mg once daily (n=253)
Diclofenac 50 mg three times daily
(n=258)
–5
–10
More
pain
–15
–20
–25
–30
Less
pain
–35
–40
S
R
NSAID
washout
period
2
4
Weeks postrandomization
*0- to 100-mm VAS (0 = no pain to 100 = extreme pain)
Adapted from Zacher J et al Curr Med Res Opin 2003;19(8):725–736.
6
25. Rheumatoid Arthritis
Etoricoxib vs. Naproxen :
Swollen-Joint Counta
US (n=805)
Mean change from
baseline (± SE)
5
International (n=878)
5
0
0
–5
–5
–10
b
–10
e–g
c,d
–15
–15
S R
2
4
8
Weeks in study
12
S R
2
4
8
Weeks in study
12 Improved
response
Placebo
e
Naproxen 1000 mgh
(n=315 US, n=349 Int)
a
Etoricoxib 90 mg
(n=321 US, n=351 Int)
(n=169 US, n=178 Int)
Investigator assessment, total 66 each; bp=0.007 for naproxen vs. placebo; cp<0.001 for etoricoxib vs. placebo; dp=0.030 for etoricoxib vs. naproxen;
p=0.005 for etoricoxib vs. placebo; fp=0.024 for naproxen vs. placebo; gp=0.955 for etoricoxib vs. naproxen; h500 mg twice daily
Adapted from Matsumoto AK et al J Rheumatol 2002;29:1623–1630; Collantes E et al BMC Fam Pract 2002;3(1):10.
26. Etoricoxib 60 mg in RA
： Physician Global assessment of Disease
Patient Global Assessment of Disease
Patient’s Assessment of Pain (10-cm visual analog scale)
Health Assessment Questionnaire (SF-36)
Acute Phase Reactant (Hypersensitive C-Reactive Protein, HS-CRP/
Erythrocyte Sedimentation Rate, ESR)
1
JC WEI, unpublished data
27. Ankylosing Spondylitis
Etoricoxib vs. Naproxen:
Patient Assessment of Spine Paina (Parts I and II)
Part I
Part II
0
–10
–20
m rf e gna hc nae m SL
o
) ES± e nl esa b
( i
–30
–40
b,c
–50
S
R
2
4
6
8
16
26
34
43
52
Weeks in study
Placebo
(n=93)
Etoricoxib 90 mg
(n=126)
Etoricoxib 120 mg
(n=123)
Naproxen 1000 mgd
(n=125)
0- to 100-mm VAS (0 = none to 100 = severe); bp<0.050, etoricoxib 90 mg vs. naproxen; cp<0.010 etoricoxib, 120 mg vs. naproxen;
500 mg twice daily
Adapted from van der Heijde D et al Arthritis Rheum 2005;52:1205–1215.
a
d
28. Acute Gouty Arthritis
Etoricoxib vs. Indomethacin :
Patient Assessment of Paina
Etoricoxib produced substantial improvement vs. baseline at 4 hours
0.0
Study 1
b,c
baseline (± SE)
LS mean change from
0.0
–0.5
Study 2d,e
–0.5
–1.0
–1.0
–1.5
–1.5
–2.0
–2.0
–2.5
–2.5
–3.0
–3.0
R 4 hr
2
3
4
5
6
7
Day in study
Etoricoxib 120 mg
(n=72 study 1, n=101 study 2)
8
R 4 hr
2
3
4
5
6
7
Day in study
Indomethacin 150 mgf
(n=71 study 1, n=83 study 2)
LS = least squares; SE = standard error; R = randomization; CI = confidence interval
a
0- to 4-point Likert scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme); bLS mean change from baseline four hours after initial
dose = –0.94; 95% CI, –1.11, –0.76; cLS mean difference from indomethacin = 0.09 (–0.14, 0.33) over days 2 to 8; dLS mean change from baseline
four hours after initial dose = –1.04, 95% CI, –1.22, –0.86; eLS mean difference from indomethacin = –0.07 (–0.27, 0.14); f50 mg three times daily
Adapted from Schumacher HR Jr et al BMJ 2002;324:1488–1492; Rubin BR et al Arthritis Rheum 2004;50:598–606.
8
Etoricoxib produced significantly fewer gastroduodenal ulcers than either naproxen or ibuprofen (p<0.001 and p=0.007, respectively) at 12 weeks. At the end of 12 weeks in the RA or OA study, the cumulative incidence rate of gastroduodenal ulcers was 7.42% with etoricoxib 120 mg (p<0.001 vs. naproxen), 25.27% with naproxen 1000 mg, and 1.35% with placebo (p=0.002 vs. etoricoxib, p<0.001 vs. naproxen).3 In the OA study, the cumulative incidence of ulcers was 8.12% with etoricoxib 120 mg (p=0.007 vs. ibuprofen), 17.02% with ibuprofen 2400 mg, and 1.86% with placebo (p=0.003 vs. etoricoxib, p<0.001 vs. ibuprofen).4 In both studies, the incidence of GI ulceration with etoricoxib was low but numerically higher than with placebo.*
*Although the studies were not designed to compare ulcer rates between etoricoxib and placebo, subsequent analysis revealed significant differencesbetween treatment groups in study 1 (p=0.002) and study 2 (p=0.003).3,4
The risk of upper GI perforations, ulcers, and bleeds (PUBs) was significantly lower with etoricoxib than with older conventional NSAIDs* (p<0.001). A blinded expert adjudication of investigator-reported upper GI clinical events compared data from the combined analysis of 10 clinical trials in the clinical development program in patients with OA, RA, and chronic low back pain for the occurrence of PUBs in patients treated with etoricoxib 60, 90, or 120 mg once daily (n=3142) or nonselective NSAIDs (n=1828; naproxen 500 mg twice daily, diclofenac 50 mg three times daily, or ibuprofen 800 mg three times daily). Analysis included PUBs occurring during active treatment or within 14 days of stopping treatment. Confirmed PUBs occurred at a rate of 1.16/100 person-years with etoricoxib and 3.05/100 person-years with nonselective NSAIDs. Etoricoxib 60 mg decreased the risk of PUBs by approximately 55% compared with nonselective NSAIDs* (p<0.001).4,5
*Naproxen 1000 mg/day, ibuprofen 2400 mg/day, or diclofenac 150 mg/day
Etoricoxib 60 mg once daily and diclofenac 50 mg three times daily provided similar, effective, and sustained relief of OA pain over the six-week study. The earliest effect for both drugs, measured on the WOMAC pain subscale, was recorded at the week 2 visit and persisted for the remainder of treatment with the maximum effect occurring at week 6. By the end of the study, VAS scores had decreased from randomization values by 31.3 mm in the etoricoxib 60 mg group and by 30.9 mm in the diclofenac 50 mg three times daily group.8
Etoricoxib was superior to naproxen in one study (p<0.001) and similar to naproxen in another study (p=0.779) in reducing the number of tender joints in RA patients at 12 weeks. In two RA studies, etoricoxib was superior to placebo (p<0.001) in reducing the number of tender joints in RA patients at 12 weeks. In the US trial, 805 patients (n=315 for placebo, n=321 for etoricoxib, and n=169 for naproxen) were analyzed for efficacy, as assessed by investigators. At baseline, patients treated with placebo, etoricoxib 90 mg, and naproxen 1000 mg had an average of 29, 29, and 28 tender joints, which decreased after 12 weeks by 8.05, 14.44, and 10.76, respectively (p<0.001 for etoricoxib vs. placebo; p=0.005 for naproxen vs. placebo; p<0.001 for etoricoxib vs. naproxen). Lack of efficacy led to discontinuations for 54.5% (n=176) of the placebo group, 21.7% (n=70) of the etoricoxib group, and 36.5% (n=62) of the naproxen group.7,10
In the international trial, 878 patients (n=349 for placebo, n=351 for etoricoxib, and n=178 for naproxen) were included in the primary efficacy analyses. Patients in the placebo, etoricoxib 90 mg, and naproxen 1000 mg groups had a mean of 29, 29, and 28 tender joints at baseline that decreased after 12 weeks by 11.09, 14.37, and 13.42, respectively (p<0.001 vs. placebo for both etoricoxib and naproxen; p=0.779 for etoricoxib vs. naproxen). In this trial, 25.2% (n=90) of the patients who took placebo discontinued because of lack of efficacy, compared with 12.5% (n=44) of those treated with etoricoxib and 10.5% (n=19) of patients given naproxen.8,10
Etoricoxib was superior to naproxen in one study (p=0.030) and similar to naproxen in another study (p=0.955) in reducing the number of swollen joints in RA patients at 12 weeks. In two RA studies, etoricoxib was superior to placebo (p0.005) in reducing the number of swollen joints in RA patients at 12 weeks. In the US trial, the respective mean numbers of swollen joints at baseline as assessed by investigators were 21, 23, and 23 in the groups assigned to placebo, etoricoxib 90 mg, and naproxen 1000 mg (500 mg twice daily), and decreased by 6.42, 10.50, and 8.86 joints after 12 weeks (p<0.001 for etoricoxib vs. placebo; p=0.007 for naproxen vs. placebo; p=0.030 for etoricoxib vs. naproxen).7,10
In the international study, patients in the placebo, etoricoxib 90 mg, and naproxen 1000 mg (500 mg twice daily) groups had mean numbers of 19, 19, and 18 swollen joints at baseline and experienced reductions after 12 weeks of 7.53, 8.92, and 8.32 joints, respectively (p=0.005 for etoricoxib vs. placebo; p=0.024 for naproxen vs. placebo; p=0.955 for etoricoxib vs. naproxen).8,10
An assessment of the mean change from baseline in patient assessment of spine pain for both part I (six weeks of treatment) and part II (46 weeks of treatment) indicated that the efficacy of etoricoxib was seen at six weeks and was maintained over a 52-week treatment course. Compared with naproxen 1000 mg (500 mg twice daily), etoricoxib 90 and 120 mg were significantly more effective in relieving spinal pain associated with AS during the first six-weeks (p<0.050 for both) and the entire 52-week course (p<0.050 for etoricoxib 90 mg, p<0.010 for etoricoxib 120 mg). In addition, the combined results of the etoricoxib 90 mg and 120 mg groups indicate etoricoxib is superior to naproxen 1000 mg at six-weeks and 52-weeks (p<0.010 for both time points).1
All active treatments were significantly more effective than placebo (p<0.001) at six weeks. Because patients were randomly assigned again to active treatment after part I, the results for the placebo group do not continue past this time point.1
There was no significant difference between the etoricoxib 90 mg and 120 mg groups during either the six- or 52-week treatment period.1
The most common reason for discontinuation of treatment throughout the 52-week study period was lack of efficacy.1
During the first six weeks of treatment, a significantly smaller percentage of patients given etoricoxib 90 mg, etoricoxib 120 mg, or naproxen than of those given placebo discontinued treatment due to lack of efficacy (p<0.001). In addition, compared with patients in the naproxen group, a significantly smaller percentage of patients given etoricoxib discontinued treatment (etoricoxib 90 and 120 mg, p=0.008; etoricoxib 90 mg, p=0.014). Etoricoxib 120 mg had a numerically smaller percentage of patients discontinue treatment vs. naproxen 1000 mg (p=0.068). Among the 387 patients who received study medication during part I, 44 (47%) of those given placebo discontinued treatment due to lack of efficacy, compared with 8 (8%) of those given etoricoxib 90 mg, 9 (10%) of those given etoricoxib 120 mg, and 20 (20%) of those given naproxen over six weeks.1
A similar pattern of discontinuation was seen during the final 46 weeks of treatment, with the highest percentage of discontinuations occurring in the naproxen group. Among the 374 patients who entered part II, 22 (18%) of those given naproxen discontinued due to lack of efficacy, versus 10 (8%) of those given etoricoxib 90 mg and 12 (10%) of those given etoricoxib 120 mg over 46 weeks.1
Etoricoxib provided considerable pain relief similar to that of indomethacin in patients with acute gouty arthritis (days 1 to 8). Patients with acute gouty arthritis rated their pain at baseline screening, four hours after the initial dose on day 1, and four hours after the morning dose on days 2 to 8. Baseline pain intensity was similar in the etoricoxib 120 mg and indomethacin 150 mg groups, and both drugs afforded similar relief during the seven days of treatment. Both drugs had a rapid onset of action: four hours after the first dose, the patient assessment of pain indicated substantial improvement from baseline (least squares [LS] mean change and 95% CIs: –0.94 [–1.11, –0.76] and –0.91 [–1.09, –0.73] for etoricoxib and indomethacin, respectively, in Study 1 and –1.04 [–1.22, –0.86] and –0.84 [–1.02, –0.66] in Study 2). The response was consistent in patients with polyarticular or monoarticular gout. The LS mean difference between etoricoxib and indomethacin over days 2 to 8 was 0.09 (95% CI, –0.41, 0.33) in Study 1 and –0.07 (95% CI, –0.27, 0.14) in Study 2.7,8,24
In clinical trials, etoricoxib was evaluated for safety in approximately 4800 individuals, including approximately 3400 patients with OA, RA, or chronic low back pain (approximately 600 patients with OA or RA were treated for one year or longer). The adverse experience profile was similar in patients with OA or RA treated with etoricoxib for one year or longer. In a clinical study of acute gouty arthritis, patients were treated with etoricoxib 120 mg once daily for eight days. In clinical studies of acute analgesia, patients were treated with etoricoxib 120 mg once daily for one to seven days. The adverse-experience profile in this study was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.
The table lists all adverse events, regardless of causality, occurring in at least 2% of patients receiving etoricoxib at the recommended doses (60 and 90 mg) or naproxen 1000 mg daily in six placebo-controlled studies of 12 weeks’ duration.
