ARXIA 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.
ARXIA 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.
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 ARXIA 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 contra- indicated 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
ARXIA is administered orally and may be taken with or without food. The onset of the effect of
the medicinal product may be faster when ARXIA 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 (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 140/90 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 (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).

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.).
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-􀈕-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. Effects on ability to drive and use machines
 

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

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 (see Table 1):
Table 1:
System Organ Class Adverse Reactions Frequency
C
Infections and infestations alveolar osteitis Common
gastroenteritis, upper respiratory infection,
urinary tract infection
Uncommon
Blood and lymphatic system
disorders
anaemia (primarily associated with
gastrointestinal bleeding), leukopenia,
thrombocytopenia
Uncommon
Immune system disorders hypersensitivity‡ ß Uncommon
angioedema/anaphylactic /anaphylactoid
reactions including shock‡
Rare
Metabolism and nutrition disorders oedema/fluid retention Common
appetite increase or decrease, weight gain Uncommon
Psychiatric disorders anxiety, depression, mental acuity decreased,
hallucinations‡
Uncommon
confusion‡, restlessness‡ Rare
Nervous system disorders dizziness, headache Common
dysgeusia, insomnia,
paresthaesia/hypaesthesia, somnolence
Uncommon
Eye disorders blurred vision, conjunctivitis Uncommon
Ear and labyrinth disorders tinnitus, vertigo Uncommon
Cardiac disorders palpitations, arrhythmia‡ Common
atrial fibrillation, tachycardia‡, congestive
heart failure, non-specific ECG changes,
angina pectoris‡, myocardial infarction§
Uncommon
Vascular disorders hypertension Common
flushing, cerebrovascular accident§, transient
ischaemic attack, hypertensive crisis‡,
vasculitis‡
Uncommon
Respiratory, thoracic and
mediastinal disorders
bronchospasm‡ Common
cough, dyspnoea, epistaxis Uncommon
Gastrointestinal disorders abdominal pain Very
Constipation, flatulence, gastritis,
heartburn/acid reflux, diarrhea,
dyspepsia/epigastric discomfort, nausea,
vomiting, oesophagitis, oral ulcer
Common
abdominal distention, bowel movement pattern
change, dry mouth, gastroduodenal ulcer,
peptic ulcers including gastrointestinal
perforation and bleeding, irritable bowel
syndrome, pancreatitis‡
Uncommon
Hepatobiliary disorders ALT increased, AST increased Common
hepatitis‡ Rare
hepatic failure‡, jaundice‡ Rare†
Skin and subcutaneous tissue
disorders
ecchymosis Common
facial oedema, pruritus, rash, erythema‡,
urticaria‡
Uncommon
Stevens-Johnson syndrome‡, toxic epidermal
necrolysis‡, fixed drug eruption‡
Rare†
Musculoskeletal and connective
tissue disorders
muscular cramp/spasm, musculoskeletal
pain/stiffness
Uncommon
Renal and urinary disorders proteinuria, serum creatinine increased, renal
failure/renal insufficiency‡(see section 4.4)
Uncommon
General disorders and
administration site conditions
asthenia/fatigue, flu-like disease Common
chest pain Uncommon
Investigations blood urea nitrogen increased, creatine
phosphokinase increased, hyperkalaemia, uric
acid increased
Uncommon
blood sodium decreased Rare
*Frequency Category: Defined for each Adverse Experience Term by the incidence reported in
the clinical trials data base: Very Common (􀂕1/10), Common (􀂕1/100 to <1/10), Uncommon
(􀂕1/1000 to <1/100), Rare (􀂕1/10,000 to
<1/1000), Very Rare (<1/10,000).
‡ This adverse reaction was identified through post-marketing surveillance. Its reported
frequency has been estimated based upon the highest frequency observed across clinical trial
data pooled by indication and approved dose.
The frequency category of “Rare” was defined per the Summary of Product Characteristics
(SmPC) guidance (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95%
confidence interval for 0 events given the number of subjects treated with ARXIA in the
analysis of the Phase III data pooled by dose and indication (n=15,470).
ß Hypersensitivity includes the terms "allergy", "drug allergy", "drug hypersensitivity",
"hypersensitivity", "hypersensitivity NOS", "hypersensitivity reaction" and "nonspecific
allergy".
§Based on analyses of long-term placebo and active controlled clinical trials, selective COX-2
inhibitors have been associated with an increased risk of serious thrombotic arterial events,
including myocardial infarction and stroke. The absolute risk increase for such events is
unlikely to exceed 1% per year based on existing data (uncommon).
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.
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.
To report any side effect(s):
􀃭 The National Pharmacovigilance and Drug Safety Centre (NPC)
􀁸 Fax: +966-11-205-7662
􀁸 Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
􀁸 Toll free phone: 8002490000
􀁸 E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

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, ARXIA 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 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
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 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.
Table 2: Rates of Confirmed Thrombotic CV Events (Pooled MEDAL Programme)
Etoricoxib (N=16,819)
25,836 Patient-Years
Diclofenac (N=16,483)
24,766 Patient-Years
Between
Treatment
Comparison
Rate† (95% CI) Rate† (95% CI) Relative Risk
(95% CI)
Confirmed Thrombotic Cardiovascular Serious Adverse Events
Per-protocol 1.24 (1.11, 1.38) 1.30 (1.17, 1.45) 0.95 (0.81, 1.11)
Intent-to-treat 1.25 (1.14, 1.36) 1.19 (1.08, 1.30) 1.05 (0.93, 1.19)
Confirmed Cardiac Events
Per-protocol 0.71 (0.61, 0.82) 0.78 (0.68, 0.90) 0.90 (0.74, 1.10)
Intent-to-treat 0.69 (0.61, 0.78) 0.70 (0.62, 0.79) 0.99 (0.84, 1.17)
Confirmed Cerebrovascular Events
Per-protocol 0.34 (0.28, 0.42) 0.32 (0.25, 0.40) 1.08 (0.80, 1.46)
Intent-to-treat 0.33 (0.28, 0.39) 0.29 (0.24, 0.35) 1.12 (0.87, 1.44)
Confirmed Peripheral Vascular Events
Per-protocol 0.20 (0.15, 0.27) 0.22 (0.17, 0.29) 0.92 (0.63, 1.35)
Intent-to-treat 0.24 (0.20, 0.30) 0.23 (0.18, 0.28) 1.08 (0.81, 1.44)
†Events per 100 Patient-Years; CI=confidence interval
N=total number of patients included in Per-protocol population
Per-protocol: all events on study therapy or within 14 days of discontinuation (excluded: 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= 17,412 on etoricoxib and 17,289 on diclofenac.
CV mortality, as well as overall mortality, was similar between the etoricoxib and diclofenac
treatment groups. 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 (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 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.

Core:
Pregelatinized maize starch
Microcrystalline cellulose
Croscarmellose sodium
Colloidal silicon dioxide
Hidroxipropilcelullose
Magnesium stearate
Tablet coating:
Opadry Y-1-7000
 

Not applicable.

30 months

Do not store above 30°C.
Store in the original package in order to protect from moisture.

Arxia 90 mg film-coated tablets is contained in packs of 28 tablets in 7 tablets blister packs.
 

No special requirements.