ARGENTA 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.
ARGENTA is indicated in adults and adolescents 16 years of age and older for the shortterm
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 ARGENTA during the three days’
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 contraindicated
(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
ARGENTA is administered orally and may be taken with or without food. The onset of the
effect of the medicinal product may be faster when ARGENTA 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 preexisting
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).
ARGENTA tablets contain lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.

Pharmacodynamic interactions
Oral anticoagulants: In subjects stabilised on chronic warfarin therapy, the administration of
Etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin
time International Normalised Ratio (INR). Therefore, patients receiving oral anticoagulants
should be closely monitored for their prothrombin time INR, particularly in the first few days
when therapy with Etoricoxib is initiated or the dose of Etoricoxib is changed (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 coadministration
of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclooxygenase
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,
co-administration of cyclosporin or tacrolimus with any NSAID may increase the
nephrotoxic effect of cyclosporin or tacrolimus. Renal function should be monitored when
Etoricoxib and either of these drugs is used in combination.
Pharmacokinetic interactions
The effect of Etoricoxib on the pharmacokinetics of other drugs
Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma
levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the
combination is being taken and when the NSAID is withdrawn.
Methotrexate: Two studies investigated the effects of Etoricoxib 60, 90 or 120 mg
administered once daily for seven days in patients receiving once-weekly methotrexate doses
of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on
methotrexate plasma concentrations or renal clearance. In one study, Etoricoxib 120 mg had
no effect, but in the other study, Etoricoxib 120 mg increased methotrexate plasma
concentrations by 28% and reduced renal clearance of methotrexate by 13%. Adequate
monitoring for methotrexate-related toxicity is recommended when Etoricoxib and
methotrexate are administered concomitantly.
Oral contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive
containing 35 micrograms ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days
increased the steady state AUC0-24hr of EE by 37%. Etoricoxib 120 mg given with the same
oral contraceptive concomitantly or separated by 12 hours, increased the steady state AUC0-
24hr of EE by 50 to 60%. This increase in EE concentration should be considered when
selecting an oral contraceptive for use with Etoricoxib. An increase in EE exposure can
increase the incidence of adverse events associated with oral contraceptives (e.g., venous
thrombo-embolic events in women at risk).
Hormone Replacement Therapy (HRT): Administration of Etoricoxib 120 mg with hormone
replacement therapy consisting of conjugated estrogens (0.625 mg PREMARINTM) for 28
days, increased the mean steady state AUC0-24hr of unconjugated estrone (41%), equilin
(76%), and 17-β-estradiol (22%). The effect of the recommended chronic doses of Etoricoxib
(30, 60, and 90 mg) has not been studied. The effects of Etoricoxib 120 mg on the exposure
(AUC0-24hr) to these estrogenic components of PREMARIN were less than half of those
observed when PREMARIN was administered alone and the dose was increased from 0.625
to 1.25 mg. The clinical significance of these increases is unknown, and higher doses of
PREMARIN were not studied in combination with Etoricoxib. These increases in estrogenic
concentration should be taken into consideration when selecting post-menopausal hormone
therapy for use with Etoricoxib because the increase in oestrogen exposure might increase the
risk of adverse events associated with HRT.  Prednisone/prednisolone: In drug-interaction studies, Etoricoxib did not have clinically
important effects on the pharmacokinetics of prednisone/prednisolone.
Digoxin: Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not
alter the steady-state plasma AUC0-24hr or renal elimination of digoxin. There was an increase
in digoxin Cmax (approximately 33%). This increase is not generally important for most
patients. However, patients at high risk of digoxin toxicity should be monitored for this when
Etoricoxib and digoxin are administered concomitantly.
Effect of Etoricoxib on drugs metabolised by sulfotransferases
Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and has
been shown to increase the serum concentrations of ethinyl estradiol. While knowledge about
effects of multiple sulfotransferases is presently limited and the clinical consequences for
many drugs are still being examined, it may be prudent to exercise care when administering
Etoricoxib concurrently with other drugs primarily metabolised by human sulfotransferases
(e.g., oral salbutamol and minoxidil).
Effect of Etoricoxib on drugs metabolised by CYP isoenzymes
Based on in vitro studies, Etoricoxib is not expected to inhibit cytochromes P450 (CYP) 1A2,
2C9, 2C19, 2D6, 2E1 or 3A4. In a study in healthy subjects, daily administration of
Etoricoxib 120 mg did not alter hepatic CYP3A4 activity as assessed by the erythromycin
breath test.
Effects of other drugs on the pharmacokinetics of Etoricoxib
The main pathway of etoricoxib metabolism is dependent on CYP enzymes. CYP3A4
appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that
CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway,
but their quantitative roles have not been studied in vivo.
Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for
11 days to healthy volunteers, did not have any clinically important effect on the single-dose
pharmacokinetics of 60 mg etoricoxib (43% increase in AUC).
Voriconazole and Miconazole: Co-administration of either oral voriconazole or topical
miconazole oral gel, strong CYP3A4 inhibitors, with etoricoxib caused a slight increase in
exposure to etoricoxib, but is not considered to be clinically meaningful based on published
data.
Rifampicin: Co-administration of etoricoxib with rifampicin, a potent inducer of CYP
enzymes, produced a 65% decrease in etoricoxib plasma concentrations. This interaction may
result in recurrence of symptoms when etoricoxib is co-administered with rifampicin. While
this information may suggest an increase in dose, doses of etoricoxib greater than those listed
for each indication have not been studied in combination with rifampicin and are therefore
not recommended (see section 4.2). Antacids: Antacids do not affect the pharmacokinetics of etoricoxib to a clinically relevant
extent. 

Pregnancy
No clinical data on exposed pregnancies are available for etoricoxib. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential for human risk in pregnancy is
unknown. Etoricoxib, as with other medicinal products inhibiting prostaglandin synthesis,
may cause uterine inertia and premature closure of the ductus arteriosus during the last
trimester. Etoricoxib is contraindicated in pregnancy (see section 4.3). If a woman becomes
pregnant during treatment, etoricoxib must be discontinued.
Breastfeeding
It is not known whether etoricoxib is excreted in human milk. Etoricoxib is excreted in the milk
of lactating rats. Women who use etoricoxib must not breast feed (see sections 4.3 and 5.3).
Fertility
The use of etoricoxib, as with any drug substance known to inhibit COX-2, is not
recommended in women attempting to conceive.

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

Summary of the safety profile
In clinical trials, etoricoxib was evaluated for safety in 9,295 individuals, including 6,757
patients with OA, RA, chronic low back pain or ankylosing spondylitis (approximately 600
patients with OA or RA were treated for one year or longer).
In clinical studies, the undesirable effects profile was similar in patients with OA or RA
treated with etoricoxib for one year or longer.
In a clinical study for acute gouty arthritis, patients were treated with etoricoxib 120 mg once
daily for eight days. The adverse experience profile in this study was generally similar to that
reported in the combined OA, RA, and chronic low back pain studies.
In a cardiovascular safety outcomes programme of pooled data from three active comparator
controlled trials, 17, 412 patients with OA or RA were treated with etoricoxib (60 mg or 90
mg) for a mean duration of approximately 18 months. The safety data and details from this
programme are presented in section 5.1.  In clinical studies for acute postoperative dental pain following surgery including 614
patients treated with etoricoxib (90 mg or 120 mg), the adverse experience profile in these
studies was generally similar to that reported in the combined OA, RA, and chronic low back
pain studies.
Tabulated list of adverse reactions
The following undesirable effects were reported at an incidence greater than placebo in
clinical trials in patients with OA, RA, chronic low back pain or ankylosing spondylitis
treated with etoricoxib 30 mg, 60 mg or 90 mg up to the recommended dose for up to 12
weeks; in the MEDAL Programme studies for up to 3½ years; in short term acute pain studies
for up to 7 days; or in post-marketing experience (see Table 1): 

*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 ARGENTA 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
To Report Any Side Effects
• Saudi Arabia
The National Pharmacovigilance Centre (NPC):
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Ext 2317-2356-2340
• SFDA Call Center: 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc

• Other GCC States:
• Please contact the relevant competent authority.

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, ARGENTA 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.  

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.

Composition of ARGENTA 60 mg, 90 mg & 120 mg Film Coated Tablets
Core Materials
Microcrystalline Cellulose
(Avicel PH 101) **
Calcium phosphate dibasic anhydrous
Croscarmellose sodium (Primellose)
Ethyl alcohol absolute #
Colloidal silicon dioxide (Aerosil 200 pharma)
Magnesium stearate
COATING
Opadry II 32k210021 Green = for 120 mg
Opadry YS-1-7027 white III = for 90 mg
Opadry II 32k210020 Green = for 60 mg

Not applicable.

3 years (36 Months).

Store below 30 ºC

ARGENTA 90mg is available in packs containing 28 tablets per box

Any unused medicinal product or waste material should be disposed of in accordance with
local requirements, Keep out of the reach & sight of children