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PharmaNote


VOLUME 20, ISSUE 3 DECEMBER 2004

TOCOh A NW


ETORICOXIB: A NEW
COX-2 INHIBITOR



Heather Hardin, Pharm.D. Candidate


Introduction
Nonsteroidal anti-inflammatory drugs
(NSAIDs) have been widely used to treat pain, in-
flammation and fever. NSAIDs exert their effects
by inhibiting the cyclooxygenase enzyme (COX),
which exists in two isoforms, COX-1 and COX-2.
COX-1 is responsible for the propagation of gastric
cytoprotective products, while COX-2 fosters the
production of compounds that contribute to inflam-
mation, pain and fever. Recent research has focused
on COX-2-specific analgesics that might spare the
gastric mucosa while eliciting anti-inflammatory
and analgesic actions. The FDA has approved three
COX-2-specific NSAIDs: celecoxib (CelebrexTM),
rofecoxib (VioxxTM), and valdecoxib (BextraTM).
Rofecoxib was voluntarily withdrawn from the
Market by Merck on September 30, 2004 due to
concerns regarding its cardiovascular safety. Merck
is in the process of acquiring approval for a new
COX-2 inhibitor, etoricoxib (ArcoxiaTM) with indi-
cations for rheumatoid and osteoarthritis, chronic
low back pain, acute pain, dysmenorrhea, acute
gouty arthritis, and ankylosing spondylitis. Cur-
rently ArcoxiaTM is approved and marketed in 45
countries worldwide, including Latin America,
Europe, and the Asian-Pacific region. The FDA is


currently reviewing the New Drug Application
(NDA) for etoricoxib.1
This paper will present the current evidence
of etoricoxib's efficacy and safety.

Pharmacology and Pharmacokinetics
Prostaglandins (PGs) play a vital role in the
development of inflammation, pain, and fever by
stimulating inflammatory cell chemotaxis, amplify-
ing the formation of pain impulses and causing
vasodilatation. PGs signal the hypothalamus to in-
crease the body's temperature in response to bacte-
rial toxins and other pyrogens. PGs are produced
when COX catalyzes their production from arachi-
donic acid. All NSAIDs decrease PG production by
inhibiting the COX enzyme system. Selective in-
hibitors block primarily COX-2, while non-
selective agents inhibit both COX-1 and COX-2 en-
zymes. COX-1 produces PGs that are cytoprotec-
tive to the gastrointestinal (GI) tract, but also forms
thromboxane A2 in platelets, leading to vasocon-
striction and platelet aggregation. COX-2 is usually
found in smaller concentrations in the body, but can
be induced by cytokines, endotoxins, and tumor
promoters resulting in signs and symptoms of in-
flammation, pain and fever.2 Non-selective






INSIDE THIS ISSUE:
ETORICOXIB: A NEW COX-2 INHIBITOR



,1-4


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Table 1. IC50 values for the inhibition of COX-1 and COX-2 14


Drug
Etoricoxib
Rofecoxib (removed from market 9/04)
Valdecoxib
Celecoxib
Diclofenac
Etodolac
Meloxicam
Indomethacin
Ibuprofen
Piroxicam


ICso COX-1 (AM)
116.00
18.80
26.10
26.10
0.15
9.00
1.40
0.19
4.80
0.76


ICso COX-2 (gM)
1.10
0.53
0.87
0.87
0.05
3.70
0.70
0.44
24.30
9.00


COX-2:COX-1
Ratio (Selectivity)
106.00
35.00
30.00
7.60
3.00
2.40
2.00
0.40
0.20
0.08


*Experiment performed as whole blood assay. ICso= concentration required for 50% inhibition.


NSAIDs have been available for many years, but
they must be used with caution in patients at risk
for gastrointestinal (GI) bleeding, such as the eld-
erly, those with a history of GI bleeding, or con-
comitant use of anticoagulants, corticosteroids or
aspirin.
COX-2-specific inhibitors relieve inflam-
mation, pain and fever while decreasing the risk of
gastrointestinal (GI) complications. Though
"selective," they still retain dose-dependent COX-1
inhibition, which is defined by their COX-1/COX-2
ratio. (Table 1)
Etoricoxib is well absorbed with an average
absolute bioavailability of 83% (70-99%), and a
peak plasma concentration of 1.36 mcg/mol
reached within 1 hour of oral administration. The
half-life of etoricoxib is 24.8 hours. Hepatic extrac-
tion appears to be very low (approximately 4%),
contributing to negligible first pass metabolism.
Etoricoxib is extensively metabolized (>98%), pri-
marily by 6'-methyl hydroxylation. Metabolism is
predominantly to a 6'-carboxylic acid and to an O-
P-D-glucuronide conjugate. The carboxylic acid
metabolite is the major renally- and fecally-
excreted metabolite, approximately 80% and 67%,
respectively. The glucuronide appears to be ex-
creted into the bile and further hydrolyzed by gut
bacteria. Hepatic metabolism involves multiple cy-
tochrome P450 (CYP) enzymes, with CYP3A4 ac-
counting for approximately 60%. However, keto-
conazole, a potent CYP3A4 inhibitor, did not result
in a clinically significant effect on the pharmacoki-
netics of etoricoxib.3
The pharmacokinetics of etoricoxib appear
to be linear. The area under the curve rises in pro-


portion to increased doses from 5 to 120 mg.
Agrawal et al.4 studied the pharmacokinetics while
administering etoricoxib with water alone after a
small fast with no serious clinical adverse events,
and no side effects that caused discontinuation.
Further study in the fed state is needed to elucidate
the effect of food on etoricoxib's pharmacokinetics.
In patients with mild hepatic insufficiency
(Child-Pugh score of 5 to 6) a 60 mg once-daily
dose of etoricoxib is suggested. In moderate hepatic
insufficiency (Child-Pugh score of 7 to 9), a 60 mg
every-other-day dosing regimen is recommended.
Absorption does not appear to be affected by he-
patic impairment. Currently no dosing recommen-
dations are available for severe hepatic insuffi-
ciency.5
Preclinical trials have indicated that etori-
coxib significantly inhibited the production of
lipopolysaccharide (LPS)-stimulated-PGE2 (a sur-
rogate for COX-2 activity), but did not significantly
inhibit gastric PGE2 synthesis. Dallob and col-
leagues found that 500 mg of etoricoxib (more than
3 times the therapeutic dose) did not significantly
effect the production of TXB2 (a surrogate for
COX-1 activity) or inhibit the antiplatelet effects of
low-dose aspirin.6 Furthermore, at multiple daily
doses of up to 150 mg, etoricoxib had no effect on
bleeding time.

Clinical Trials

Analgesia
The Dental Impaction Pain Model was used
by Malmstrom et al.7 to compare pain relief be-
tween placebo, etoricoxib 120 mg, naproxen so-


PharmaNote Volume 20, Issue 3, December 2004


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Volume 20, Issue 3, December 2004







dium 550 mg, and acetaminophen/codeine 600/60
mg. Total pain relief score over 8 hours (TOPAR8)
was calculated (higher TOPAR8 scores indicate
greater pain relief). Etoricoxib (20.9 [18.5, 23.3])
and naproxen (21.3 [19.0, 23.7]) were significantly
more effective than acetaminophen/codeine (11.5
[9.1, 13.8]), p = <0.001. All active treatment
groups relieved pain significantly more than pla-
cebo; there was no significant difference between
etoricoxib and naproxen. One hour after the dose,
all medication groups showed improved pain relief
versus placebo. The onset of pain relief was ap-
proximately 30 minutes for all drug treatment
groups. Rescue medications were given if patients
required extra pain relief. Over the 24-hour follow-
up period, 90%, 44%, 52.9%, and 76% of patients
took rescue medication in the placebo, etoricoxib,
naproxen sodium and acetaminophen/codeine
groups, respectively. The time-to-rescue-
medication was significantly longer in patients tak-
ing etoricoxib than in placebo- or acetaminophen/
codeine-treated patients (>24 hours, 1.6 hours, 3.6
hours, respectively, p < 0.001). Time-to-rescue
medication was similar for etoricoxib and
naproxen. Clinical adverse events occurred in 36%,
26%, 37%, and 50% for the placebo, etoricoxib,
naproxen sodium, and acetaminophen/codeine
groups, respectively. The most common complaints
were nausea, post-extraction alveolitis, and head-
ache; headache occurred less frequently in the eto-
ricoxib group compared to other treatment groups.
In this model, etoricoxib appears to have equivalent
efficacy compared to naproxen for relieving acute,
moderate to severe pain.

Acute Gout
Rubin et al.8 conducted a randomized, con-
trolled, double blind, active comparator versus pla-
cebo-controlled study to investigate the effective-
ness of etoricoxib in acute gout. A once-daily 120
mg dose of etoricoxib was compared to a indo-
methacin 50 mg three-times daily, and placebo.
Based on a 5-point pain score with increasing val-
ues representing increased pain, the decrease in
joint pain over days 2-5 of treatment was compara-
ble in the etoricoxib and indomethacin groups, -
1.79 (95% CI -1.95, -1.63) and -1.71 (95% CI -
1.88, -1.54), respectively. Differences between the
two medications were not significant (p = 0.46).


These results remained comparable after 8 days of
treatment. No significant difference was noted be-
tween the two medications (p = 0.52), nor was the
global assessment significantly different (p = 0.43).
Patients appeared to get equal relief of pain from
etoricoxib or indomethacin. Drug-related adverse
effects were significantly lower in the etoricoxib
group (16.5%) compared to the indomethacin group
(37.2%), p = 0.002. Twice as many patients taking
indomethacin (20.9%) experienced GI adverse ef-
fects compared with etoricoxib (9.7%), yet none of
these were serious enough to discontinue therapy.
Etoricoxib 120 mg once-daily is as effective as in-
domethacin 50 mg three times daily, and appears to
have fewer adverse effects.

Osteoarthritis and Rheumatoid Arthritis
Zacher et al.9 conducted a 6-week double-
blind, active comparator-controlled parallel-group
study comparing the efficacy, safety and tolerabil-
ity of 60 mg of etoricoxib once daily with di-
clofenac 50 mg three times daily in patients with
osteoarthritis. Etoricoxib and diclofenac were com-
parable in reducing pain as per a patient reported
pain scale. Pain relief was similar between the eto-
ricoxib (-31.3 [-33.6, -29.0]) and diclofenac (-30.9
[-33.2, -28.6]) groups over the 6-week period. No
significant difference was noted between the
groups. The number of patients who reported an ex-
cellent response to therapy at 4 hours post-dose on
the first day of treatment via 5-point Likert scale (0
= excellent, 4 = no response) was significantly
higher in etoricoxib-treated patients: 31.5% (24.96,
38.73) for etoricoxib versus 19.1% (13.88, 25.25)
for diclofenac. The 12.4% difference between the
two drugs was statistically significant (CI 3.84,
21.07; p = 0.007), illustrating etoricoxib's rapid on-
set of action compared to diclofenac. The incidence
of NSAID-related GI adverse events, lower extrem-
ity edema, and hypertension was similar. Less than
1% of patients in either group had to discontinue
treatment due to these effects. Increases in AST and
ALT enzymes were significantly higher in the di-
clofenac group: 11% and 24% (AST and ALT, re-
spectively), while patients treated with etoricoxib
showed no increases in liver enzymes. Drug-related
abnormal laboratory values assessed by routine
blood chemistries, hematology and urine analyses,
were significantly less with etoricoxib (2.7%) com-


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Volume 20, Issue 3, December 2004








Table 2. Adverse events occurring in >1% of patients treated with etoricoxib.


Digestive
Diarrhea"1
Nausea11'12
Gast/Duod Ulcers > 3mm13
Respiratory
Respiratory Tract Infections"
Central Nervous System
Dizziness7
Somnolence7
Miscellaneous
Headaches"


pared to diclofenac (7.3%), p = 0.025. Based on
these results, once daily 60 mg etoricoxib is as ef-
fective as diclofenac 50 mg three times daily for
osteoarthritis with fewer patients exhibiting in-
creased AST, ALT, and abnormal lab values.
When Collantes et al.10 studied etoricoxib in
rheumatoid arthritis, the findings resembled those
in patients with osteoarthritis. Etoricoxib adminis-
tered at a dose of 90 mg once daily was found to
be comparable to naproxen 500 mg twice-daily
during a 12-week follow-up period. Both groups
experienced significant improvements compared
with placebo in all efficacy endpoints (p < 0.05).
Both naproxen and etoricoxib were well tolerated.

Chronic Low Back Pain
Birbara et al.11 performed a randomized,
placebo-controlled, parallel-group, 12-week, dou-
ble-blind, phase III study to evaluate the efficacy,
safety, and tolerability of etoricoxib in treating
chronic lower back pain. Once daily doses of 60
and 90 mg were studied. Both doses showed sig-
nificant improvement in low back pain intensity af-
ter 4 weeks of treatment compared with placebo
(60 mg vs. placebo: -12.94 [95% CI -19.03, -6.86]
and 90 mg vs placebo: -10.29[-16.26, -4.31]). Simi-
lar results were seen over the entire 12-week study.
No significant differences were noted between the
two doses of etoricoxib. Rescue doses of aceta-
minophen were offered to every subject. Similar
numbers of patients utilized rescue treatment. No


significant differences in clinical adverse events
was found between the placebo, 60 mg etoricoxib,
and the 90 mg etoricoxib treatment groups: 46.8%,
58.3%, and 52.3%, respectively. The most fre-
quently reported events were headache, nausea, di-
arrhea, and upper respiratory tract infections. The
90 mg dose of etoricoxib was associated with a
higher incidence of drug-related adverse events
compared to placebo (27.1% vs. 11.9%, p = 0.006),
while the 60 mg dose was similar to placebo
(20.7% vs. 11.9%, p = 0.133). No significant differ-
ence in drug-related adverse events (as determined
by the investigator) resulting in discontinuation of
therapy was noted between placebo (4.6%), 60 mg
(7.8%), and 90 mg (9.3%), although such events
were numerically higher the active treatment
groups. Etoricoxib is effective for treating chronic
lower back pain. Thus, the 90 mg dose was no more
effective than 60 mg, but it was associated with
more drug-related adverse events in this population.

Dysmenorrhea
Etoricoxib 120 mg administered once daily
was compared to 550 mg of naproxen sodium or
placebo for acute onset dysmenorrhea. Pain relief
scores over 8 hours were higher for both etoricoxib
(20.0) and naproxen (21.5) versus placebo (12.6), p
< 0.001, but no significant difference was noted be-
tween the two active treatments (p = 0.326). Time-
to-onset of action and duration of analgesia were
significantly better than placebo and similar for


mm
PharmaNote Volume 20, Issue 3, December 2004


60 mg


Etoricoxib


120 mg


90 mP


8.4%
7.5%


Placebo


3.9%
5.8%


5.8%


3.0%
8.1%


2.8%


1.8%
2.8%
1.9%


6.4%


6.0%
0.0%


5.5%


11.7%


2.0%
4.0%


5.6%


" "


PharmaNote


Volume 20, Issue 3, December 2004







etoricoxib and naproxen. No serious adverse events
occurred. The incidence of clinical adverse experi-
ences were 15%, 12%, and 25% for placebo, etori-
coxib, and naproxen, respectively. Headache and
nausea were the most frequently reported events.
The authors concluded that etoricoxib was as effec-
tive as naproxen sodium for treating dysmenorrhea,
while exhibiting similar safety to placebo and
greater safety compared to naproxen in this popula-
tion.12

Dosing and Administration
Etoricoxib is effective for each of the fol-
lowing indications at the respective doses: os-
teoarthritis, 60 mg;9 rheumatoid arthritis, 90 mg;10
chronic low back pain, 60-90 mg;1 acute pain, 120
mg;7 gout, 120 mg;8 and primary dysmenorrhea,
120 mg.2 Given the extended half-life, once daily
administration is sufficient. In mild hepatic dys-
function, doses of 60 mg daily are suggested, and
in moderate hepatic impairment a dose of 60 mg
every other day is recommended.7
Further studies need to be conducted to in-
vestigate dosing in renal impairment and the eld-
erly. The effect of co-administration of food
should also be addressed in future studies.

Toxicity and Safety
Hunt et al.13 performed a 12 week, multi-
center, multinational, randomized, double-blind,
parallel-group, active comparator- and placebo-
controlled study to investigate the incidence of gas-
tric and/or duodenal ulcers with the use of 120 mg
once-daily etoricoxib, 2400 mg of ibuprofen (800
mg three times daily), and placebo. Aspirin use
was permitted (<100 mg daily). Ibuprofen pro-
duced significantly more gastric and/or duodenal
ulcers >3 mm (17.02%) than etoricoxib (8.12%) or
placebo (1.86%). Ibuprofen, etoricoxib, and pla-
cebo resulted in ulcers >5 mm at a rate of 12.32%,
6.18%, and 0.45%, respectively. The difference be-
tween etoricoxib and ibuprofen was significant
(6.14%; 95% CI 0.63, 11.65; p = 0.035). In con-
trast, overall adverse effects occurred at a similar
rate with ibuprofen, etoricoxib, and placebo:
58.0%, 56.6%, and 53.6% respectively. When
drug-related adverse events were analyzed, ibupro-
fen resulted in significantly higher rates (34.5%)
than placebo (24.9%, p = 0.025), but the incidence


Table 3. Comparative NSAID retail prices for a 30-day supply*
Naproxen Sodium 500 mg, BID, #60 $27.81
Ibuprofen 800 mg, TID, #90 $22.03
Celecoxib 200 mg, QD, #30 $89.87
Cost represents the average retail price from 3 local community pharmacies.

for etoricoxib (32.1%) was not different from pla-
cebo. Discontinuation rates were similar between
all three groups.
Digestive system-specific drug-related ad-
verse events were higher in the ibuprofen group
(26.5%) than in the placebo group (17.6%), al-
though no significant difference between placebo
and etoricoxib (24%, 95% CI for difference = -1.1,
13.8) was shown. Out of the 221 subjects on etori-
coxib, two serious clinical adverse events of the di-
gestive system were reported. One patient experi-
enced gastroesophageal reflux disease and one pa-
tient had a hemorrhagic gastric ulcer. A meta-
analysis demonstrated the relative risk for GI-
related complications with etoricoxib versus other
NSAIDs was 0.44 (95% CI 0.27, 0.72; p < 0.001).
These results suggest that etoricoxib might result in
fewer gastric and duodenal ulcers compared non-
selective COX inhibitors.
A summary of adverse effects reported in
clinical trials is presented in Table 2.

Cost
Since etoricoxib has not been approved by
the FDA, no cost information is currently available;
however, similar to other selective agents, the cost
of etoricoxib will be substantially more than con-
ventional NSAIDs which are available over-the-
counter. See Table 3 for comparative pricing of
other NSAIDs.

Summary
Etoricoxib is a long-acting, highly selective
COX-2 inhibitor, which is effective in acute gout,
osteoarthritis, rheumatoid arthritis, chronic low
back pain and dysmenorrhea. Its quick onset of ac-
tion (less than 1 hour) helps to provide rapid pain
relief. Adverse effects are similar to that observed
with other COX-2 inhibitors. Given the recent
events with rofecoxib and emerging evidence of a
class effect, it seems prudent to select patients most
likely to benefit from COX-2 selective drugs (i.e.,


PharmaNote Volume 20, Issue 3, December 2004


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Volume 20, Issue 3, December 2004








those at high risk for GI bleeding) and a low risk of
cardiovascular events. The role of etoricoxib as a
COX-2 selective inhibitor remains to be seen and
will most likely hinge on its cardiovascular safety.

References
1. Merck & Co., Inc. Arcoxiam: Significantly reduced
the risk of upper gastrointestinal side effects com-
pared to three other NSAIDS, data presented at
EULAR Congress Show. Merck website news re-
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press releases research and develop-
ment/2004 0611.html (accessed 2004 Sep 5).
2. Brenner, GM. Drugs for pain, inflammation, and
arthritic disorders. In: Pharmacology. Pennsyl-
vania: WB Saunders Co: 2000:317-328.
3. Rodrigues AD, Halpin RA, Geer LA, et al. Absorp-
tion, metabolism, and excretion of etoricoxib, a po-
tent and selective cyclooxygenase-2 inhibitor, in
healthy male volunteers. Drug Metabolism and
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4. Agrawal NG, Porras AG, Matthews CZ, et al. Dose
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10. Collantes E, Curtis SP, Lee KW, et al. A multina-


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primary dysmenorrhea: results of a randomized,
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13. Hunt RH, Harper S, Watson DJ, et al. The gastroin-
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U U U


~
PharmaNote Volume 20, Issue 3, December 2004


The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida



John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D.


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