Adults
ETORICOXIB is indicated in adults and adolescents 16 years of age and older for the symptomatic
relief of osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis, and the pain and signs
of inflammation associated with acute gouty arthritis.
ETORICOXIB is indicated in adults and adolescents 16 years of age and older for the short-term
treatment of moderate pain associated with dental surgery.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the
individual patient's overall risks (see sections 4.3, 4.4)

Posology
As the cardiovascular risks of etoricoxib may increase with dose and duration of exposure, the
shortest duration possible and the lowest effective daily dose should be used. The patient's need for
symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients
with osteoarthritis.
Osteoarthritis
The recommended dose is 30 mg once daily. In some patients with insufficient relief from symptoms,
an increased dose of 60 mg once daily may increase efficacy. In the absence of an increase in
therapeutic benefit, other therapeutic options should be considered.
Rheumatoid arthritis
The recommended dose is 60 mg once daily. In some patients with insufficient relief from symptoms,
an increased dose of 90 mg once daily may increase efficacy. Once the patient is clinically stabilised,
down-titration to a 60 mg once daily dose may be appropriate. In the absence of an increase in
therapeutic benefit, other therapeutic options should be considered.
Ankylosing spondylitis
The recommended dose is 60 mg once daily. In some patients with insufficient relief from symptoms,
an increased dose of 90 mg once daily may increase efficacy. Once the patient is clinically stabilised,
down-titration to a 60 mg once daily dose may be appropriate. In the absence of an increase in
therapeutic benefit, other therapeutic options should be considered.
Acute pain conditions
For acute pain conditions, etoricoxib should be used only for the acute symptomatic period.
Acute gouty arthritis
The recommended dose is 120 mg once daily. In clinical trials for acute gouty arthritis, etoricoxib was
given for 8 days.

Postoperative dental surgery pain
The recommended dose is 90 mg once daily, limited to a maximum of 3 days. Some patients may
require other postoperative analgesia in addition to ETORICOXIB during the three day treatment
period.
Doses greater than those recommended for each indication have either not demonstrated additional
efficacy or have not been studied. Therefore:
The dose for OA should not exceed 60 mg daily.
The dose for RA and ankylosing spondylitis should not exceed 90 mg daily.
The dose for acute gout should not exceed 120 mg daily, limited to a maximum of 8 days treatment.
The dose for postoperative acute dental surgery pain should not exceed 90 mg daily, limited to a
maximum of 3 days.
Special populations
Elderly patients
No dosage adjustment is necessary for elderly patients. As with other drugs, caution should be
exercised in elderly patients.
Patients with hepatic impairment
Regardless of indication, in patients with mild hepatic dysfunction (Child-Pugh score 5-6) a dose of
60 mg once daily should not be exceeded. In patients with moderate hepatic dysfunction (Child-Pugh
score 7-9), regardless of indication, the dose of 30 mg once daily should not be exceeded.

Clinical experience is limited particularly in patients with moderate hepatic dysfunction and caution is
advised. There is no clinical experience in patients with severe hepatic dysfunction (Child-Pugh score
≥10); therefore, its use is contra-indicated in these patients.
Patients with renal impairment
No dosage adjustment is necessary for patients with creatinine clearance ≥30 ml/min. The use of
etoricoxib in patients with creatinine clearance <30 ml/min is contra-indicated.

Paediatric population
Etoricoxib is contra-indicated in children and adolescents under 16 years of age.
Method of administration
ETORICOXIB is administered orally and may be taken with or without food. The onset of the effect
of the medicinal product may be faster when ETORICOXIB is administered without food. This
should be considered when rapid symptomatic relief is needed.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Active peptic ulceration or active gastro-intestinal (GI) bleeding. • Patients who, after taking acetylsalicylic acid or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors, experience bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria, or allergic-type reactions. • Pregnancy and lactation. • Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥10). • Estimated renal creatinine clearance <30 ml/min. • Children and adolescents under 16 years of age. • Inflammatory bowel disease. • Congestive heart failure (NYHA II-IV). • Patients with hypertension whose blood pressure is persistently elevated above 140/90 mmHg and has not been adequately controlled. • Established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Gastrointestinal effects
Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them
resulting in fatal outcome, have occurred in patients treated with etoricoxib.
Caution is advised with treatment of patients most at risk of developing a gastrointestinal
complication with NSAIDs; the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly or patients with a prior history of gastrointestinal disease, such as ulceration and GI
bleeding.
There is a further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or
other gastrointestinal complications) when etoricoxib is taken concomitantly with acetylsalicylic acid
(even at low doses). A significant difference in GI safety between selective COX-2 inhibitors +
acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical
trials.

Cardiovascular effects
Clinical trials suggest that the selective COX-2 inhibitor class of drugs may be associated with a risk
of thrombotic events (especially myocardial infarction (MI) and stroke), relative to placebo and some
NSAIDs. As the cardiovascular risks of etoricoxib may increase with dose and duration of exposure,
the shortest duration possible and the lowest effective daily dose should be used. The patient's need
for symptomatic relief and response to therapy should be re-evaluated periodically, especially in
patients with osteoarthritis.
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia,
diabetes mellitus, smoking) should only be treated with etoricoxib after careful consideration.
COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of
cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effect. Therefore
antiplatelet therapies should not be discontinued.
Renal effects
Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore,
under conditions of compromised renal perfusion, administration of etoricoxib may cause a reduction
in prostaglandin formation and, secondarily, in renal blood flow, and thereby impair renal function.
Patients at greatest risk of this response are those with pre-existing significantly impaired renal
function, uncompensated heart failure, or cirrhosis. Monitoring of renal function in such patients
should be considered.

Fluid retention, oedema and hypertension
As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention, oedema
and hypertension have been observed in patients taking etoricoxib. All Nonsteroidal Antiinflammatory
Drugs (NSAIDs), including etoricoxib, can be associated with new onset or recurrent
congestive heart failure. For information regarding a dose related response for etoricoxib. Caution
should be exercised in patients with a history of cardiac failure, left ventricular dysfunction, or
hypertension and in patients with pre-existing oedema from any other reason. If there is clinical
evidence of deterioration in the condition of these patients, appropriate measures including
discontinuation of etoricoxib should be taken.
Etoricoxib may be associated with more frequent and severe hypertension than some other NSAIDs
and selective COX-2 inhibitors, particularly at high doses. Therefore, hypertension should be
controlled before treatment with etoricoxib and special attention should be paid to blood pressure
monitoring during treatment with etoricoxib. Blood pressure should be monitored within two weeks
after initiation of treatment and periodically thereafter. If blood pressure rises significantly, alternative
treatment should be considered.

Hepatic effects
Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)
(approximately three or more times the upper limit of normal) have been reported in approximately
1% of patients in clinical trials treated for up to one year with etoricoxib 30, 60 and 90 mg daily.
Any patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver
function test has occurred, should be monitored. If signs of hepatic insufficiency occur, or if
persistently abnormal liver function tests (three times the upper limit of normal) are detected,
etoricoxib should be discontinued.
General
If during treatment, patients deteriorate in any of the organ system functions described above,
appropriate measures should be taken and discontinuation of etoricoxib therapy should be considered.
Medically appropriate supervision should be maintained when using etoricoxib in the elderly and in
patients with renal, hepatic, or cardiac dysfunction.

Caution should be used when initiating treatment with etoricoxib in patients with dehydration. It is
advisable to rehydrate patients prior to starting therapy with etoricoxib.
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson
syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use
of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance. Patients appear
to be at highest risk for these reactions early in the course of therapy with the onset of the reaction
occurring in the majority of cases within the first month of treatment. Serious hypersensitivity
reactions (such as anaphylaxis and angioedema) have been reported in patients receiving etoricoxib.
Some selective COX-2 inhibitors have been associated with an increased risk of skin reactions in
patients with a history of any drug allergy. Etoricoxib should be discontinued at the first appearance
of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Etoricoxib may mask fever and other signs of inflammation.
Caution should be exercised when co-administering etoricoxib with warfarin or other oral
anticoagulants.
The use of etoricoxib, as with any medicinal product known to inhibit cyclooxygenase / prostaglandin
synthesis, is not recommended in women attempting to conceive.
ETORICOXIB tablets contain lactose. Patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pharmacodynamic interactions
Oral anticoagulants: In subjects stabilised on chronic warfarin therapy, the administration of
etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin time
International Normalised Ratio (INR). Therefore, patients receiving oral anticoagulants should be
closely monitored for their prothrombin time INR, particularly in the first few days when therapy with
etoricoxib is initiated or the dose of etoricoxib is changed.
Diuretics, ACE inhibitors and Angiotensin II Antagonists: NSAIDs may reduce the effect of diuretics
and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated
patients or elderly patients with compromised renal function) the co-administration of an ACE

inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further
deterioration of renal function, including possible acute renal failure, which is usually reversible.
These interactions should be considered in patients taking etoricoxib concomitantly with ACE
inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with
caution, especially in the elderly. Patients should be adequately hydrated and consideration should be
given to monitoring of renal function after initiation of concomitant therapy, and periodically
thereafter.
Acetylsalicylic Acid: In a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had
no effect on the anti-platelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used
concomitantly with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose
acetylsalicylic acid). However, concomitant administration of low-dose acetylsalicylic acid with
etoricoxib may result in an increased rate of GI ulceration or other complications compared to use of
etoricoxib alone. Concomitant administration of etoricoxib with doses of acetylsalicylic acid above
those for cardiovascular prophylaxis or with other NSAIDs is not recommended.
Cyclosporin and tacrolimus: Although this interaction has not been studied with etoricoxib,
coadministration of cyclosporin or tacrolimus with any NSAID may increase the nephrotoxic effect of
cyclosporin or tacrolimus. Renal function should be monitored when etoricoxib and either of these
drugs is used in combination.
Pharmacokinetic interactions
The effect of etoricoxib on the pharmacokinetics of other drugs
Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If
necessary, monitor blood lithium closely and adjust the lithium dosage while the combination is being
taken and when the NSAID is withdrawn.
Methotrexate: Two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once
daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for
rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations
or renal clearance. In one study, etoricoxib 120 mg had no effect, but in the other study, etoricoxib
120 mg increased methotrexate plasma concentrations by 28% and reduced renal clearance of methotrexate by 13%. Adequate monitoring for methotrexate-related toxicity is recommended when
etoricoxib and methotrexate are administered concomitantly.
Oral contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35
micrograms ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady
state AUC0-24hr of EE by 37%. Etoricoxib 120 mg given with the same oral contraceptive
concomitantly or separated by 12 hours, increased the steady state AUC0-24hr of EE by 50 to 60%.
This increase in EE concentration should be considered when selecting an oral contraceptive for use
with etoricoxib. An increase in EE exposure can increase the incidence of adverse events associated
with oral contraceptives (e.g., venous thrombo-embolic events in women at risk).
Hormone Replacement Therapy (HRT): Administration of etoricoxib 120 mg with hormone
replacement therapy consisting of conjugated estrogens (0.625 mg PREMARINTM) for 28 days,
increased the mean steady state AUC0-24hr of unconjugated estrone (41%), equilin (76%), and 17-β-
estradiol (22%). The effect of the recommended chronic doses of etoricoxib (30, 60, and 90 mg) has
not been studied. The effects of etoricoxib 120 mg on the exposure (AUC0-24hr) to these estrogenic
components of PREMARIN were less than half of those observed when PREMARIN was
administered alone and the dose was increased from 0.625 to 1.25 mg. The clinical significance of
these increases is unknown, and higher doses of PREMARIN were not studied in combination with
etoricoxib. These increases in estrogenic concentration should be taken into consideration when
selecting post-menopausal hormone therapy for use with etoricoxib because the increase in oestrogen
exposure might increase the risk of adverse events associated with HRT.
Prednisone/prednisolone: In drug-interaction studies, etoricoxib did not have clinically important
effects on the pharmacokinetics of prednisone/prednisolone.
Digoxin: Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not alter
the steady-state plasma AUC0-24hr or renal elimination of digoxin. There was an increase in digoxin
Cmax (approximately 33%). This increase is not generally important for most patients. However,
patients at high risk of digoxin toxicity should be monitored for this when etoricoxib and digoxin are
administered concomitantly. 

Effect of etoricoxib on drugs metabolised by sulfotransferases
Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and has been
shown to increase the serum concentrations of ethinyl estradiol. While knowledge about effects of
multiple sulfotransferases is presently limited and the clinical consequences for many drugs are still
being examined, it may be prudent to exercise care when administering etoricoxib concurrently with
other drugs primarily metabolised by human sulfotransferases (e.g., oral salbutamol and minoxidil).
Effect of etoricoxib on drugs metabolised by CYP isoenzymes
Based on in vitro studies, etoricoxib is not expected to inhibit cytochromes P450 (CYP) 1A2, 2C9,
2C19, 2D6, 2E1 or 3A4. In a study in healthy subjects, daily administration of etoricoxib 120 mg did
not alter hepatic CYP3A4 activity as assessed by the erythromycin breath test.
Effects of other drugs on the pharmacokinetics of etoricoxib
The main pathway of etoricoxib metabolism is dependent on CYP enzymes. CYP3A4 appears to
contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9,
CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles
have not been studied in vivo.
Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for 11 days
to healthy volunteers, did not have any clinically important effect on the single-dose pharmacokinetics
of 60 mg etoricoxib (43% increase in AUC).
Voriconazole and Miconazole: Co-administration of either oral voriconazole or topical miconazole
oral gel, strong CYP3A4 inhibitors, with etoricoxib caused a slight increase in exposure to etoricoxib,
but is not considered to be clinically meaningful based on published data.
Rifampicin: Co-administration of etoricoxib with rifampicin, a potent inducer of CYP enzymes,
produced a 65% decrease in etoricoxib plasma concentrations. This interaction may result in
recurrence of symptoms when etoricoxib is co-administered with rifampicin. While this information
may suggest an increase in dose, doses of etoricoxib greater than those listed for each indication have
not been studied in combination with rifampicin and are therefore not recommended (see section 4.2).
Antacids: Antacids do not affect the pharmacokinetics of etoricoxib to a clinically relevant extent.

Pregnancy
No clinical data on exposed pregnancies are available for etoricoxib. Studies in animals have shown
reproductive toxicity (see section 5.3). The potential for human risk in pregnancy is unknown.
Etoricoxib, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine
inertia and premature closure of the ductus arteriosus during the last trimester. Etoricoxib is
contraindicated in pregnancy (see section 4.3). If a woman becomes pregnant during treatment,
etoricoxib must be discontinued.

Breastfeeding
It is not known whether etoricoxib is excreted in human milk. Etoricoxib is excreted in the milk of
lactating rats. Women who use etoricoxib must not breast feed (see sections 4.3 and 5.3).
Fertility
The use of etoricoxib, as with any drug substance known to inhibit COX-2, is not recommended in
women attempting to conceive.

Patients who experience dizziness, vertigo or somnolence while taking etoricoxib should refrain from
driving or operating machinery.

Summary of the safety profile
In clinical trials, etoricoxib was evaluated for safety in 9,295 individuals, including 6,757 patients
with OA, RA, chronic low back pain or ankylosing spondylitis (approximately 600 patients with OA
or RA were treated for one year or longer).
In clinical studies, the undesirable effects profile was similar in patients with OA or RA treated with
etoricoxib for one year or longer.

In a clinical study for acute gouty arthritis, patients were treated with etoricoxib 120 mg once daily for
eight 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.
In a cardiovascular safety outcomes programme of pooled data from three active comparator
controlled trials, 17, 412 patients with OA or RA were treated with etoricoxib (60 mg or 90 mg) for a
mean duration of approximately 18 months. The safety data and details from this programme are
presented in section 5.1.
In clinical studies for acute postoperative dental pain following surgery including 614 patients treated
with etoricoxib (90 mg or 120 mg), the adverse experience profile in these studies was generally
similar to that reported in the combined OA, RA, and chronic low back pain studies.
Tabulated list of adverse reactions
The following undesirable effects were reported at an incidence greater than placebo in clinical trials
in patients with OA, RA, chronic low back pain or ankylosing spondylitis treated with etoricoxib 30
mg, 60 mg or 90 mg up to the recommended dose for up to 12 weeks; in the MEDAL Programme
studies for up to 3½ years; in short term acute pain studies for up to 7 days; or in post-marketing
experience 

In clinical studies, administration of single doses of etoricoxib up to 500 mg and multiple doses up to
150 mg/day for 21 days did not result in significant toxicity. There have been reports of acute
overdosage with etoricoxib, although adverse experiences were not reported in the majority of cases.
The most frequently observed adverse experiences were consistent with the safety profile for
etoricoxib (e.g. gastrointestinal events, cardiorenal events).
In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove
unabsorbed material from the GI tract, employ clinical monitoring, and institute supportive therapy, if
required.
Etoricoxib is not dialysable by haemodialysis; it is not known whether etoricoxib is dialysable by
peritoneal dialysis.

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids, coxibs,
ATC code: M01 AH05
Mechanism of Action
Etoricoxib is an oral, selective cyclo-oxygenase-2 (COX-2) inhibitor within the clinical dose range.
Across clinical pharmacology studies, ETORICOXIB produced dose-dependent inhibition of COX-2
without inhibition of COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit gastric
prostaglandin synthesis and had no effect on platelet function.
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2,
have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by proinflammatory
stimuli and has been postulated to be primarily responsible for the synthesis of
prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation,
implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous
system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to
ulcer healing has not been established.
Clinical efficacy and safety
Efficacy
In patients with osteoarthritis (OA), etoricoxib 60 mg once daily provided significant improvements
in pain and patient assessments of disease status. These beneficial effects were observed as early as
the second day of therapy and maintained for up to 52 weeks. Studies with etoricoxib 30 mg once
daily demonstrated efficacy superior to placebo over a 12 week treatment period (using similar
assessments as the above studies). In a dose ranging study, etoricoxib 60 mg demonstrated
significantly greater improvement than 30 mg for all 3 primary endpoints over 6 weeks of treatment.
The 30 mg dose has not been studied in osteoarthritis of hands.
In patients with rheumatoid arthritis (RA), etoricoxib 60 mg and 90 mg once daily both provided
significant improvements in pain, inflammation, and mobility. In studies evaluating the 60 mg and 90
mg dose, these beneficial effects were maintained over the 12-week treatment periods. In a study
evaluating the 60 mg dose compared to the 90 mg dose, etoricoxib 60 mg once daily and 90 mg once
daily were both more effective than placebo. The 90 mg dose was superior to the 60 mg dose for
Patient Global Assessment of Pain (0-100mm visual analogue scale), with an average improvement of
-2.71 mm (95% CI: -4.98 mm, -0.45 mm).
In patients experiencing attacks of acute gouty arthritis, etoricoxib 120 mg once daily over an eightday
treatment period, relieved moderate to extreme joint pain and inflammation comparable to
indomethacin 50 mg three times daily. Pain relief was observed as early as four hours after initiation
of treatment.
In patients with ankylosing spondylitis, etoricoxib 90 mg once daily provided significant
improvements in spine pain, inflammation, stiffness and function. The clinical benefit of etoricoxib
was observed as early as the second day of therapy after initiation of treatment and was maintained
throughout the 52-week treatment period. In a second study evaluating the 60 mg dose compared to
the 90 mg dose, etoricoxib 60 mg daily and 90 mg daily demonstrated similar efficacy compared to
naproxen 1,000 mg daily. Among inadequate responders to 60 mg daily for 6 weeks, dose escalation
to 90 mg daily improved spinal pain intensity score (0-100 mm visual analogue scale) compared to 

continuing on 60 mg daily, with an average improvement of -2.70 mm (95% CI: -4.88 mm, -0.52
mm).
In a clinical study evaluating postoperative dental pain, etoricoxib 90 mg was administered once daily
for up to three days. In the subgroup of patients with moderate pain at baseline, etoricoxib 90 mg
demonstrated a similar analgesic effect to that of ibuprofen 600 mg (16.11 vs. 16.39; P=0.722), and
greater than that of paracetamol/codeine 600 mg/60 mg (11.00; P<0.001) and placebo (6.84; P<0.001)
as measured by total pain relief over the first 6 hours (TOPAR6). The proportion of patients reporting
rescue medication usage within the first 24 hours of dosing was 40.8% for etoricoxib 90 mg, 25.5%
for ibuprofen 600 mg Q6h, and 46.7% for paracetamol/codeine 600 mg/60 mg Q6h compared to
76.2% for placebo. In this study, the median onset of action (perceptible pain relief) of 90 mg
etoricoxib was 28 minutes after dosing.
Safety
Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Programme
The MEDAL Programme was a prospectively designed Cardiovascular (CV) Safety Outcomes
Programme of pooled data from three randomized, double-blind active comparator controlled trials,
the MEDAL study, EDGE II and EDGE.
The MEDAL Study, was an endpoint driven CV Outcomes study in 17,804 OA and 5,700 RA
patients treated with etoricoxib 60 (OA) or 90 mg (OA and RA) or diclofenac 150 mg daily for a
mean period of 20.3 months (maximum of 42.3 months, median 21.3 months). In this trial, only
serious adverse events and discontinuations due to any adverse events were recorded.
The EDGE and EDGE II studies compared the gastrointestinal tolerability of etoricoxib versus
diclofenac. The EDGE study included 7,111 OA patients treated with a dose of etoricoxib 90 mg
daily (1.5 times the dose recommended for OA) or diclofenac 150 mg daily for a mean period of 9.1
months (maximum 16.6 months, median 11.4 months). The EDGE II study included 4,086 RA
patients treated with etoricoxib 90 mg daily or diclofenac 150 mg daily for a mean period of 19.2
months (maximum 33.1 months, median 24 months).
In the pooled MEDAL Programme, 34,701 patients with OA or RA were treated for a mean duration
of 17.9 months (maximum 42.3 months, median 16.3 months) with approximately 12,800 patients
receiving treatment for more than 24 months. Patients enrolled in the Programme had a wide range of

cardiovascular and gastrointestinal risk factors at baseline. Patients with a recent history of
myocardial infarction, coronary artery bypass grafting or percutaneous coronary intervention within 6
months preceding enrollment were excluded. Use of gastroprotective agents and low dose aspirin
were permitted in the studies.
Overall Safety:
There was no significant difference between etoricoxib and diclofenac in the rate of cardiovascular
thrombotic events. Cardiorenal adverse events were observed more frequently with etoricoxib than
with diclofenac, and this effect was dose-dependent (see specific results below). Gastrointestinal and
hepatic adverse events were observed significantly more frequently with diclofenac than etoricoxib.
The incidence of adverse experiences in EDGE and EDGE II and of adverse experiences considered
serious or resulting in discontinuation in the MEDAL study was higher with etoricoxib than
diclofenac.
Cardiovascular safety results:
The rate of confirmed thrombotic cardiovascular serious adverse events (consisting of cardiac,
cerebrovascular, and peripheral vascular events) was comparable between etoricoxib and diclofenac,
and data are summarized in the table below. There were no statistically significant differences in
thrombotic event rates between etoricoxib and diclofenac across all subgroups analyzed including
patient categories across a range of baseline cardiovascular risk. When considered separately, the
relative risks for confirmed thrombotic cardiovascular serious adverse events with etoricoxib 60 mg
or 90 mg compared with diclofenac 150 mg were similar.

Cardiorenal Events:
Approximately 50% of patients enrolled in the MEDAL study had a history of hypertension at
baseline. In the study, the incidence of discontinuations due to hypertension-related adverse events
was statistically significantly higher for etoricoxib than for diclofenac. The incidence of congestive
heart failure adverse events (discontinuations and serious events) occurred at similar rates on
etoricoxib 60 mg compared to diclofenac 150 mg but was higher for etoricoxib 90 mg compared to
diclofenac 150 mg (statistically significant for 90 mg etoricoxib vs. 150 mg diclofenac in MEDAL
OA cohort). The incidence of confirmed congestive heart failure adverse events (events that were
serious and resulted in hospitalisation or a visit to an emergency department) was non-significantly

higher with etoricoxib than diclofenac 150 mg, and this effect was dose-dependent. The incidence of
discontinuations due to oedema-related adverse events was higher for etoricoxib than diclofenac 150
mg, and this effect was dose-dependent (statistically significant for etoricoxib 90 mg, but not for
etoricoxib 60 mg).
The cardiorenal results for EDGE and EDGE II were consistent with those described for the MEDAL
Study.
In the individual MEDAL Programme studies, for etoricoxib (60 mg or 90 mg), the absolute
incidence of discontinuation in any treatment group was up to 2.6% for hypertension, up to 1.9% for
oedema, and up to 1.1% for congestive heart failure, with higher rates of discontinuation observed
with etoricoxib 90 mg than etoricoxib 60 mg.
MEDAL Programme Gastrointestinal Tolerability Results:
A significantly lower rate of discontinuations of treatment for any clinical (e.g., dyspepsia, abdominal
pain, ulcer) GI adverse event was observed with etoricoxib compared with diclofenac within each of
the three component studies of the MEDAL Programme. The rates of discontinuations due to adverse
clinical GI events per hundred patient-years over the entire period of study were as follows: 3.23 for
etoricoxib and 4.96 for diclofenac in the MEDAL Study; 9.12 with etoricoxib and 12.28 with
diclofenac in the EDGE study; and 3.71 with etoricoxib and 4.81 with diclofenac in the EDGE II
study.
MEDAL Programme Gastrointestinal Safety Results:
Overall upper GI events were defined as perforations, ulcers and bleeds. The subset of overall upper
GI events considered complicated included perforations, obstructions, and complicated bleeding; the
subset of upper GI events considered uncomplicated included uncomplicated bleeds and
uncomplicated ulcers. A significantly lower rate of overall upper GI events was observed with
etoricoxib compared to diclofenac. There was no significant difference between etoricoxib and
diclofenac in the rate of complicated events. For the subset of upper GI haemorrhage events
(complicated and uncomplicated combined), there was no significant difference between etoricoxib
and diclofenac. The upper GI benefit for etoricoxib compared with diclofenac was not statistically
significant in patients taking concomitant low-dose aspirin (approximately 33% of patients).

The rates per hundred patient-years of confirmed complicated and uncomplicated upper GI clinical
events (perforations, ulcers and bleeds (PUBs)) were 0.67 (95% CI 0.57, 0.77) with etoricoxib and
0.97 (95% CI 0.85, 1.10) with diclofenac, yielding a relative risk of 0.69 (95% CI 0.57, 0.83).
The rate for confirmed upper GI events in elderly patients was evaluated and the largest reduction was
observed in patients ≥ 75 years of age (1.35 [95% CI 0.94, 1.87] vs. 2.78 [95% CI 2.14, 3.56] events
per hundred patient-years for etoricoxib and diclofenac, respectively.
The rates of confirmed lower GI clinical events (small or large bowel perforation, obstruction, or
haemorrhage, (POBs)) were not significantly different between etoricoxib and diclofenac.
MEDAL Programme Hepatic Safety Results:
Etoricoxib was associated with a statistically significantly lower rate of discontinuations due to
hepatic-related adverse experiences than diclofenac. In the pooled MEDAL Programme, 0.3% of
patients on etoricoxib and 2.7% of patients on diclofenac discontinued due to hepatic-related adverse
experiences. The rate per hundred patient-years was 0.22 on etoricoxib and 1.84 for diclofenac (pvalue
was <0.001 for etoricoxib vs. diclofenac). However, most hepatic adverse experiences in the
MEDAL Programme were non-serious.
Additional Thrombotic Cardiovascular Safety Data
In clinical studies excluding the MEDAL Programme Studies, approximately 3,100 patients were
treated with etoricoxib ≥60 mg daily for 12 weeks or longer. There was no discernible difference in
the rate of confirmed serious thrombotic cardiovascular events between patients receiving etoricoxib
≥60 mg, placebo, or non-naproxen NSAIDs. However, the rate of these events was higher in patients
receiving etoricoxib compared with those receiving naproxen 500 mg twice daily. The difference in
antiplatelet activity between some COX-1 inhibiting NSAIDs and selective COX-2 inhibitors may be
of clinical significance in patients at risk of thrombo-embolic events. Selective COX-2 inhibitors
reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting
platelet thromboxane. The clinical relevance of these observations has not been established.

Additional Gastrointestinal Safety Data
In two 12-week double-blind endoscopy studies, the cumulative incidence of gastroduodenal
ulceration was significantly lower in patients treated with etoricoxib 120 mg once daily than in

patients treated with either naproxen 500 mg twice daily or ibuprofen 800 mg three times daily.
Etoricoxib had a higher incidence of ulceration as compared to placebo.
Renal Function Study in the Elderly
A randomized, double-blind, placebo-controlled, parallel-group study evaluated the effects of 15 days
of treatment of etoricoxib (90 mg), celecoxib (200 mg bid), naproxen (500 mg bid) and placebo on
urinary sodium excretion, blood pressure, and other renal function parameters in subjects 60 to 85
years of age on a 200-mEq/day sodium diet. Etoricoxib, celecoxib, and naproxen had similar effects
on urinary sodium excretion over the 2 weeks of treatment. All active comparators showed an
increase relative to placebo with respect to systolic blood pressures; however, etoricoxib was
associated with a statistically significant increase at Day 14 when compared to celecoxib and
naproxen (mean change from baseline for systolic blood pressure: etoricoxib 7.7 mmHg, celecoxib
2.4 mmHg, naproxen 3.6 mmHg).

Absorption
Orally administered etoricoxib is well absorbed. The absolute bioavailability is approximately 100%.
Following 120 mg once-daily dosing to steady state, the peak plasma concentration (geometric mean
Cmax = 3.6 μg/ml) was observed at approximately 1 hour (Tmax) after administration to fasted adults.
The geometric mean area under the curve (AUC0-24hr) was 37.8 μg•hr/ml. The pharmacokinetics of
etoricoxib are linear across the clinical dose range.
Dosing with food (a high-fat meal) had no effect on the extent of absorption of etoricoxib after
administration of a 120-mg dose. The rate of absorption was affected, resulting in a 36% decrease in
Cmax and an increase in Tmax by 2 hours. These data are not considered clinically significant. In
clinical trials, etoricoxib was administered without regard to food intake.
Distribution
Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of
0.05 to 5 μg/ml. The volume of distribution at steady state (Vdss) was approximately 1,20l in humans.
Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.

Biotransformation
Etoricoxib is extensively metabolised with <1% of a dose recovered in urine as the parent drug. The
major route of metabolism to form the 6'-hydroxymethyl derivative is catalyzed by CYP enzymes.
CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that
CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their
quantitative roles in vivo have not been studied.
Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid
derivative of etoricoxib formed by further oxidation of the 6'-hydroxymethyl derivative. These
principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2
inhibitors. None of these metabolites inhibit COX-1.

Elimination
Following administration of a single 25-mg radiolabeled intravenous dose of etoricoxib to healthy
subjects, 70% of radioactivity was recovered in urine and 20% in faeces, mostly as metabolites. Less
than 2% was recovered as unchanged drug.
Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal excretion.
Steady state concentrations of etoricoxib are reached within seven days of once daily administration
of 120 mg, with an accumulation ratio of approximately 2, corresponding to a half-life of
approximately 22 hours. The plasma clearance after a 25-mg intravenous dose is estimated to be
approximately 50 ml/min.
Characteristics in patients
Elderly patients: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the
young.
Gender: The pharmacokinetics of etoricoxib are similar between men and women.
Hepatic impairment: Patients with mild hepatic dysfunction (Child-Pugh score 5-6) administered
etoricoxib 60 mg once daily had an approximately 16% higher mean AUC as compared to healthy
subjects given the same regimen. Patients with moderate hepatic dysfunction (Child-Pugh score 7-9)
administered etoricoxib 60 mg every other day had similar mean AUC to the healthy subjects given
etoricoxib 60 mg once daily; etoricoxib 30 mg once daily has not been studied in this population.
There are no clinical or pharmacokinetic data in patients with severe hepatic dysfunction (Child-Pugh
score ≥10). (See sections 4.2 and 4.3.)

Renal impairment: The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with
moderate to severe renal insufficiency and patients with end-stage renal disease on haemodialysis
were not significantly different from those in healthy subjects. Haemodialysis contributed negligibly
to elimination (dialysis clearance approximately 50 ml/min). (See sections 4.3 and 4.4.)
Paediatric patients: The pharmacokinetics of etoricoxib in paediatric patients (<12 years old) have
not been studied.
In a pharmacokinetic study (n=16) conducted in adolescents (aged 12 to 17) the pharmacokinetics in
adolescents weighing 40 to 60 kg given etoricoxib 60 mg once daily and adolescents >60 kg given
etoricoxib 90 mg once daily were similar to the pharmacokinetics in adults given etoricoxib 90 mg
once daily. Safety and effectiveness of etoricoxib in paediatric patients have not been established (see
section 4.2).

In preclinical studies, etoricoxib has been demonstrated not to be genotoxic. Etoricoxib was not
carcinogenic in mice. Rats developed hepatocellular and thyroid follicular cell adenomas at >2-times
the daily human dose [90 mg] based on systemic exposure when dosed daily for approximately two
years. Hepatocellular and thyroid follicular cell adenomas observed in rats are considered to be a
consequence of rat-specific mechanism related to hepatic CYP enzyme induction. Etoricoxib has not
been shown to cause hepatic CYP3A enzyme induction in humans.
In the rat, gastrointestinal toxicity of etoricoxib increased with dose and exposure time. In the 14-
week toxicity study etoricoxib caused gastrointestinal ulcers at exposures greater than those seen in
man at the therapeutic dose. In the 53- and 106-week toxicity study, gastrointestinal ulcers were also
seen at exposures comparable to those seen in man at the therapeutic dose. In dogs, renal and
gastrointestinal abnormalities were seen at high exposures.
Etoricoxib was not teratogenic in reproductive toxicity studies conducted in rats at 15 mg/kg/day (this
represents approximately 1.5 times the daily human dose [90 mg] based on systemic exposure). In
rabbits, a treatment related increase in cardiovascular malformations was observed at exposure levels
below the clinical exposure at the daily human dose (90 mg). However no treatment-related external
or skeletal foetal malformations were observed. In rats and rabbits, there was a dose dependent

increase in post implantation loss at exposures greater than or equal to 1.5 times the human exposure
(see sections 4.3 and 4.6).
Etoricoxib is excreted in the milk of lactating rats at concentrations approximately two-fold those in
plasma. There was a decrease in pup body weight following exposure of pups to milk from dams
administered etoricoxib during lactation.

Anhydrous Dibasic Calcium Phosphate (Cal - A)
Microcrystalline Cellulose PH101
Povidone K-29/32
Croscarmellose Sodium
Magnesium Stearate
Opadry II White 32K280000
Purified water (evaporated during coating)

Not applicable.

24 months

Do not store above 30°C.

Alu-Alu blister pack
Pack sizes: 3 X 10’s Blister Pack

Any unused product should be disposed of in accordance with local requirements.