ETOXA 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.
ETOXA 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 (see sections
4.3, 4.4, 4.8 and 5.1).
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.
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 ETOXA
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 (see section 4.4).
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 contraindicated in these patients (see sections 4.3, 4.4 and 5.2).
Patients with renal impairment
No dosage adjustment is necessary for patients with creatinine clearance ≥30
ml/min (see section 5.2). The use of etoricoxib in patients with creatinine clearance
<30 ml/min is contra-indicated (see sections 4.3 and 4.4).
Paediatric population
Etoricoxib is contra-indicated in children and adolescents under 16 years of age
(see section 4.3).
Method of administration
ETOXA is administered orally and may be taken with or without food. The onset
of the effect of the medicinal product may be faster when ETOXA 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 or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors, experience bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria, or allergic-type reactions. • Pregnancy and lactation (see sections 4.6 and 5.3). • 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 140/90mmHg 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 (see section 5.1).
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 (see sections 4.2, 4.3, 4.8 and 5.1).
Patients with significant risk factors for cardiovascular events (e.g. hypertension,
hyperlipidaemia, diabetes mellitus, smoking) should only be treated with
etoricoxib after careful consideration (see section 5.1).
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 (see
sections above, 4.5 and 5.1.).
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 Anti-inflammatory Drugs (NSAIDs), including
etoricoxib, can be associated with new onset or recurrent congestive heart failure.
For information regarding a dose related response for etoricoxib see section 5.1.
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 (see
section 4.3) 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 (see section 4.8). 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 (see section 4.8). 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 (see section 4.5).
The use of etoricoxib, as with any medicinal product known to inhibit
cyclooxygenase / prostaglandin synthesis, is not recommended in women
attempting to conceive (see sections 4.6, 5.1, and 5.3).
ETOXA tablets contain lactose. Patients with rare hereditary problems ofgalactose
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 (see section 4.4).
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 (see sections 5.1 and 4.4.).
Ciclosporin and tacrolimus: Although this interaction has not been studied with
etoricoxib, coadministration of ciclosporin or tacrolimus with any NSAID may
increase the nephrotoxic effect of ciclosporin 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 coadministered 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 category: X
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 7152 individuals, including
4614 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 (see Table 1)

The following serious undesirable effects have been reported in association with
the use of NSAIDs and cannot be ruled out for etoricoxib: nephrotoxicity including
interstitial nephritis and nephrotic syndrome.
Description of selected adverse reactions: NA
Pediatric population:
Etoricoxib is contra-indicated in children and adolescents under 16 years of age
(see section 4.3)
Special populations
Elderly patients
No dosage adjustment is necessary for elderly patients. As with other drugs,
caution should be exercised in elderly patients (see section 4.4).
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 contraindicated in these patients (see sections 4.3, 4.4 and 5.2).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product
is important. It allows continued monitoring of the benefit/risk balance of the
medicinal product

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, nonsteroids, coxibs, ATC code: MO1 AH05
Mechanism of Action
-Please contact the relevant competent authority.
- National Pharmacovigilance Center (NPC)
O Fax: +966-11-205-7662
O Call NPC at +966-112038222, Exts: 2317-2356-2353-2354-2334-2340
O Toll free phone: 8002490000
O E-mail: npc.drug@sfda.gov.sa
O Website: www.sfda.gov.sa/npc
Etoricoxib is an oral, selective cyclo-oxygenase-2 (COX-2) inhibitor within the
clinical dose range.
Across clinical pharmacology studies, ETOXA 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 pro-inflammatory 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 90 mg once daily provided
significant improvements in pain, inflammation, and mobility. These beneficial
effects were maintained over the 12-week treatment periods.
In patients experiencing attacks of acute gouty arthritis, etoricoxib 120 mg once
daily over an eight-day 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 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 7111 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 4086 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 dosedependent (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 MEDALstudy
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 150mg
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 edema-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:
patients who took < 75% of their study medication or took non-study NSAIDs >10% of the
time).
Intent-to-treat: all confirmed events up to the end of the trial (included patients potentially
exposed to non-study interventions following discontinuation of study medication). Total
number of patients randomised, n= 17412 on etoricoxib and 17289 on diclofenac.
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 (p-value 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 3100
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 rangeof
concentrations of 0.05 to 5 µg/ml. The volume of distribution at steady state (Vdss)
was approximately 120 l 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 (90mg). 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
 

Calcium hydrogen phosphate anhydrous, Microcrystalline cellulose (Avicel PH
112), Croscarmellose sod, Colloidal silicon dioxide (Aerosil200), Magnesium
Stearate, Opadry II green or Opadry II White
 

N/A
 

2 Years

Store below 30°C
 

ETOXA 60 mg is provided in Alu/Alu blister
Packs contains 30 film coated tablet
ETOXA 90 mg is provided in Alu/Alu blister
6. Pharmaceutical particulars
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
Packs contains 30 film coated tablet
ETOXA 120 mg is provided in Alu/Alu blister
Packs contains 7 film coated tablet
 

No special requirements