AUSTRALIAN PRODUCT INFORMATION

ARCOXIA® (etoricoxib)

1 NAME OF THE MEDICINE

etoricoxib

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Etoricoxib is a white to off-white powder. Etoricoxib is freely soluble in methanol,
tetrahydrofuran, dimethyl sulfoxide, methyl ethyl ketone, dimethyl formamide, and chloroform.
Etoricoxib is soluble in isopropyl acetate, ethanol and toluene, sparingly soluble in 2-propanol,
and practically insoluble in water.

Each tablet of ARCOXIA for oral administration contains either 30, 60, 90 or 120 mg of
etoricoxib.

Excipients with known effect: lactose monohydrate

For the full list of excipients, see Section 6.1 List of Excipients.

3 PHARMACEUTICAL FORM
ARCOXIA (etoricoxib) 30 mg is a blue-green, apple-shaped, biconvex film coated tablet
debossed "101" on one side and "ACX 30" on the other side.

ARCOXIA (etoricoxib) 60 mg is a dark green, apple-shaped, biconvex film coated tablet

engraved "200" on one side and "ARCOXIA 60" on the other side.

ARCOXIA (etoricoxib) 90 mg is a white, apple-shaped, biconvex film coated tablet debossed

"202" on one side and "ARCOXIA 90" on the other side.

ARCOXIA (etoricoxib) 120 mg is a pale green, apple-shaped, biconvex film coated tablet
engraved "204" on one side and "ARCOXIA 120" on the other side.

4 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
ARCOXIA is indicated for:

• Symptomatic treatment of the signs and symptoms of osteoarthritis (OA)

• Treatment of acute gouty arthritis
• Treatment of acute pain, including that related to primary dysmenorrhoea and minor dental
procedures

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of

the individual patient's overall risks.

4.2 DOSE AND METHOD OF ADMINISTRATION

ARCOXIA is administered orally. ARCOXIA may be taken with or without food.
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. Patients on long

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term treatment should be reviewed regularly with regards to efficacy, risk factors and ongoing
need for treatment.
Osteoarthritis
The recommended dose is 30 mg once daily. In some patients with insufficient relief from
symptoms, the dose may be increased to 60 mg once daily. In the absence of therapeutic
benefit after 4 weeks of treatment with etoricoxib 60 mg, other therapeutic options should be
considered.
In the following acute painful conditions:
Acute Gouty Arthritis
The recommended dose is 120 mg once daily.
ARCOXIA should be used only for the acute symptomatic period, limited to a maximum of 8
days treatment.
Primary Dysmenorrhoea
The recommended dose is 120 mg once daily.
ARCOXIA should be used only for the acute symptomatic period, limited to a maximum of 8
days treatment.
Dental Pain
The recommended dose is 90 mg once daily.
ARCOXIA should be used only for the acute symptomatic period, limited to a maximum of 8
days treatment.
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 acute pain, primary dysmenorrhoea, and acute gout should not exceed 120 mg
daily, limited to a maximum of 8 days treatment.
The dose for dental pain should not exceed 90 mg, limited to a maximum of 8 days treatment.
Hepatic insufficiency
In patients with mild hepatic insufficiency (Child-Pugh score 5-6), a dose of 60 mg once daily
should not be exceeded. In patients with moderate hepatic insufficiency (Child-Pugh score 7-
9), the dose should be reduced; a dose of 60 mg every other day should not be exceeded,
administration with 30 mg once daily can also be considered. There are no clinical or
pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score > 9) (see
Section 4.3 Contraindications and Section 4.4 Special Warnings and Precautions for Use).
Renal insufficiency
In patients with advanced renal disease (creatinine clearance <30 mL/min), treatment with
ARCOXIA is not recommended. No dosage adjustment is necessary for patients with lesser
degrees of renal insufficiency (creatinine clearance ≥ 30 mL/min) (see Section 4.4 Special
Warnings and Precautions for Use).
Elderly, gender, race
No dosage adjustment in ARCOXIA is necessary for the elderly or based on gender or race.

4.3 CONTRAINDICATIONS
ARCOXIA is contraindicated in patients with:

• hypersensitivity to any component of this product. A history of asthma, urticaria or other

allergic reactions after taking aspirin or other NSAIDs.

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• congestive heart failure (NYHA II-IV).
• hypertension whose blood pressure is persistently elevated above 140/90mmHg and has
not been adequately controlled.
• established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular
disease (including patients who have recently undergone coronary artery bypass graft
surgery or angioplasty).
• severe hepatic dysfunction (serum albumin < 25 g/l or Child-Pugh score ≥ 10, see
footnote1).
• active peptic ulceration or gastrointestinal (GI) bleeding.
• estimated creatinine clearance < 30 mL/min.

ARCOXIA should not be used as adjunctive therapy with other NSAIDs due to the absence of
any evidence demonstrating synergistic benefits and the potential for additive adverse
reactions.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Cardiovascular effects
Clinical trials suggest that the selective COX-2 inhibitor class of drugs may be associated with
an increased risk of serious thrombotic events (especially MI and stroke), relative to placebo
and some NSAIDs. Long term safety data beyond one year are not currently available for
etoricoxib compared to placebo or NSAIDs other than diclofenac. In the MEDAL Program,
there was no significant difference between etoricoxib and diclofenac in the rate of
cardiovascular thrombotic events over a mean treatment duration of 18 months (see Section
5.1 Pharmacodynamic Properties, Clinical trials, Special studies).

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.

A combined analysis of controlled clinical trials in which patients were treated with etoricoxib
≥ 30 mg daily for 4 weeks or longer was conducted to compare the incidence rate of serious
thrombotic cardiovascular events among patients taking etoricoxib, placebo, naproxen or non-
naproxen NSAIDs. This analysis was not powered to provide a precise estimate of the relative
risk of CV events in patients taking etoricoxib versus the other treatments. The analysis
showed a statistically significant increase in relative risk with etoricoxib vs naproxen 1000 mg
with respect to the Anti-Platelet Trialists' Collaboration (APTC) combined endpoint (ie.
cardiovascular, haemorrhagic and unknown death, non-fatal myocardial ischaemia, and non-
fatal stroke) [RR 2.72 (95% CI 1.18, 6.27)]. This analysis did not demonstrate any statistically
significant increase in the rate of serious thrombotic cardiovascular events in patients taking
etoricoxib over those taking non-naproxen NSAIDs (see Section 5.1 Pharmacodynamic
Properties, Clinical trials, Special studies).

Etoricoxib should be used with caution for patients with known cardiovascular disease, history
of atherosclerotic cardiovascular disease or significant risk factors for cardiovascular events
(including those with diabetes, hypertension, hypercholesterolaemia, a first degree relative
with ischaemic heart disease, cardiac failure or who are smokers).

1 The Child-Pugh score employs five clinical measures of liver disease - bilirubin, serum albumin, INR, ascites
and hepatic encephalopathy. Each measure is scored 1-3, with 3 indicating most severe derangement. The
individual scores are tallied to derive the Child-Pugh score.

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Physicians and patients should remain alert for such CV events, even in absence of previous
CV symptoms. Patients should be informed about signs and/or symptoms of serious CV
toxicity and the steps to take if they occur.

Aspirin substitution
COX-2 selective inhibitors are not a substitute for aspirin for cardiovascular prophylaxis
because of their lack of effect on platelets. Because etoricoxib, a member of this class, does
not inhibit platelet aggregation, antiplatelet therapies should not be discontinued.

Gastrointestinal effects
Physicians should be aware that individual patients may develop upper gastrointestinal (GI)
ulcers/ulcer complications irrespective of treatment. Although the risk of upper GI toxicity is
not eliminated with ARCOXIA, the results of the MEDAL Program demonstrate that in patients
treated with ARCOXIA, the risk of upper GI toxicity with ARCOXIA 60 mg or 90 mg once daily
is significantly less than with diclofenac 150 mg daily (see Section 5.1 Pharmacodynamic
Properties, Clinical trials, Special studies).

In clinical studies with ibuprofen and naproxen, the risk of endoscopically detected upper GI
ulcers was lower in patients treated with ARCOXIA 120 mg once daily than in patients treated
with the non-selective NSAIDs. While the risk of endoscopically detected ulcers was low in
patients treated with ARCOXIA 120 mg it was higher than in patients treated with placebo.
Upper GI ulcers/ulcer complications have occurred in patients treated with ARCOXIA. These
events can occur at any time during use and without warning symptoms. Independent of
treatment, patients with a prior history of GI perforation, ulcers and bleeding (PUB) and
patients greater than 65 years of age are known to be at a higher risk for a PUB.

Patients should be informed about the signs and/or symptoms of serious GI toxicity and the
steps to take if they occur. The utility of periodic laboratory monitoring has not been
demonstrated, nor has it been adequately assessed. Only one in five patients who develop a
serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated
that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in
approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for
one year. These trends continue, thus increasing the likelihood of developing a serious GI
event at some time during the course of therapy. However, even short-term therapy is not
without risk.

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.

Renal effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal
injury. Renal prostaglandins may play a compensatory role in the maintenance of renal
perfusion. Therefore, under conditions of compromised renal perfusion, administration of
ARCOXIA 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.

Caution should be used when initiating treatment with ARCOXIA in patients with considerable
dehydration. It is advisable to rehydrate patients prior to starting therapy with ARCOXIA.

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Fluid retention, oedema, hypertension
As with other drugs known to inhibit prostaglandin synthesis, fluid retention, oedema and
hypertension have been observed in patients taking ARCOXIA. All Non-steroidal 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 4.8 Adverse Effects (Undesirable Effects).

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 Contraindications) 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
As with other NSAIDs, elevations of one or more liver function tests may occur in up to 15%
of patients. 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 ARCOXIA 30, 60
and 90 mg daily. In active comparator portions of clinical trials, the incidence of elevated AST
and/or ALT in patients treated with ARCOXIA 60 and 90 mg daily was similar to that of patients
treated with naproxen 1000 mg daily, but notably less than the incidence in the diclofenac 150
mg daily group. These abnormalities may progress, may remain essentially unchanged, or
may resolve in patients with continued treatment of ARCOXIA, with approximately half
resolving while patients remained on therapy. In controlled clinical trials of ARCOXIA 30 mg
daily versus ibuprofen 2400 mg daily or celecoxib 200 mg daily, the incidence of elevations of
ALT or AST was similar.

In post-marketing experience jaundice has been reported rarely. Limited reports of hepatic
failure have been reported, but without clear association to ARCOXIA. Physicians and patients
should remain alert for hepatotoxicity. Patients should be informed about the signs and/or
symptoms of hepatotoxicity. A patient with symptoms and/or signs suggesting liver dysfunction
(e.g. nausea, fatigue, pruritus, jaundice, abdominal tenderness in the right upper quadrant and
“flu-like” symptoms), or in whom an abnormal liver function test has occurred, should be
evaluated for persistently abnormal liver function tests. If signs of hepatic insufficiency occur,
or if persistently abnormal liver function tests (three times the upper limit of normal) are
detected, ARCOXIA should be discontinued.

General
When using etoricoxib in the elderly and in patients with renal, hepatic, or cardiac dysfunction,
medically appropriate supervision should be maintained. If these patients deteriorate during
treatment, appropriate measures should be taken, including discontinuation of therapy.

Serious skin reactions

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 Adverse Effects (Undesirable Effects)). These serious events may occur

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without warning. Patients appear to be at highest risk for these reactions early in the course
of therapy: 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 Adverse Effects (Undesirable
Effects)). 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.

Use in patients with inflammatory bowel disease (IBD)

NSAIDs have been associated with an exacerbation of IBD associated with
spondyloarthropathies. There has only been limited study of etoricoxib in patients with IBD.

Use in patients with fever and infection

ARCOXIA may mask fever, which is a sign of infection. The physician should be aware of this
when using ARCOXIA in patients being treated for infection.

Use in hepatic impairment

See Hepatic effects, above; Section 5.2 Pharmacokinetic Properties, Hepatic insufficiency and
Section 4.2 Dose and Method of Administration, Hepatic insufficiency.

Use in the elderly

Of the 4,562 patients who received ARCOXIA in Phase IIb/III placebo-controlled clinical trials
of at least 6 weeks duration, 1,370 were 65 years of age or older (this included 328 who were
75 years or older). Of the 17,412 patients who received ARCOXIA in the MEDAL Program,
7,234 were 65 years of age or older (this included 2,033 patients who were 75 years or older).
In each of these datasets, a higher incidence of adverse events was seen in older patients
compared to younger patients; the relative differences between the etoricoxib and control
groups were similar in the elderly and the young. Greater sensitivity of some older individuals
cannot be ruled out. As with any NSAID, caution should be exercised in treating the elderly
(65 years and older).

Paediatric use
The pharmacokinetics of etoricoxib in paediatric patients (< 12 years of age) have not been
studied.

The pharmacokinetics in adolescents (aged 12 to 17) weighing 40 to 60 kg given etoricoxib

60 mg once daily and in 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 in patients aged below 18 years have not been established.

Effects on laboratory tests

Please refer to Section 4.4 Special Warnings and Precautions for Use, Hepatic effects, above.

4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTIONS
General: Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1
and has been shown to increase the serum concentrations of ethinyl oestradiol (see Section
4.5 Interactions with Other Medicines and Other Forms of Interactions, Oral contraceptives).

Diuretics, Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin II

Antagonists (AIIAs): Reports suggest that NSAIDs including selective COX-2 inhibitors may

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diminish the antihypertensive effect of diuretics, ACE inhibitors and AIIAs. This interaction
should be given consideration in patients taking ARCOXIA concomitantly with these products.

In some patients with compromised renal function (e.g., elderly patients or patients who are
volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal
anti-inflammatory drugs, including selective COX-2 inhibitors, the co-administration of ACE
inhibitors or AIIAs may result in a further deterioration of renal function, including possible
acute renal failure. These effects are usually reversible. Therefore, the combination should be
administered with caution, especially in the elderly.

Aspirin: ARCOXIA can be used concomitantly with low-dose aspirin at doses for
cardiovascular prophylaxis. At steady state, ARCOXIA 120 mg once daily had no effect on the
anti-platelet activity of low-dose aspirin (81 mg once daily), as assessed by ex vivo platelet
aggregation and serum TXB2 generation in clotting blood. However, concomitant
administration of low-dose aspirin with ARCOXIA increases the rate of GI ulceration or other
complications, compared to use of ARCOXIA alone.

Digoxin: ARCOXIA 120 mg once daily for 10 days did not alter the steady state plasma AUC0-
24hr or renal elimination of digoxin. Therefore, digoxin and ARCOXIA may be co-administered
without dose adjustment.

Frusemide: Clinical studies have shown that NSAIDs can reduce the natriuretic effect of
frusemide and thiazides in some patients. This response has been attributed to inhibition of
renal prostaglandin synthesis.

Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day

increased the AUC of etoricoxib by 43%. The clinical significance of this increase is not known.

Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal
lithium clearance. Thus, when ARCOXIA and lithium are administered concurrently, subjects
should be observed carefully for signs of lithium toxicity.

Methotrexate: Two studies investigated the effects of ARCOXIA 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. ARCOXIA at 60 and 90 mg had no effect on
methotrexate plasma concentrations (as measured by AUC) or renal clearance. In one study,
ARCOXIA 120 mg had no effect on methotrexate plasma concentrations (as measured by
AUC) or renal clearance. In the other study, ARCOXIA 120 mg increased methotrexate plasma
concentrations by 28% (as measured by AUC) and reduced renal clearance of methotrexate
by 13%. In these two studies, at 24 hours post-dose, a similar proportion of patients treated
with methotrexate alone (approximately 93%) and subsequently treated with methotrexate co-
administered with ARCOXIA 120 mg (approximately 82%) had methotrexate plasma
concentrations below the measurable limit (5 ng/mL). Standard monitoring for methotrexate-
related toxicity should be considered when ARCOXIA at doses greater than 90 mg daily and
methotrexate are administered concomitantly.

Oral Contraceptives: ARCOXIA 60 mg given concomitantly with an oral contraceptive

containing 35 mcg ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased
the steady state AUC0-24hr of EE by 37%. ARCOXIA 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 ARCOXIA. An increase in EE exposure can increase the
incidence of adverse events associated with oral contraceptives (e.g. venous thromboembolic
events in women at risk).

Hormone Replacement Therapy: Administration of ARCOXIA 120 mg with hormone

replacement therapy consisting of conjugated oestrogens (0.625 mg PREMARINTM) for 28

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days, increased the mean steady state AUC0-24hr of unconjugated estrone (41%), equilin
(76%), and 17-β-oestradiol (22%). The effect of the recommended chronic doses of ARCOXIA
(30 and 60 mg) has not been studied. The effects of ARCOXIA 120 mg on the exposure (AUC0-
24hr) to these oestrogenic 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 ARCOXIA. These increases in oestrogenic concentration
should be taken into consideration when selecting post-menopausal hormone replacement
therapy for use with ARCOXIA.

Prednisone/prednisolone: Etoricoxib did not have any clinically important effect on the
pharmacokinetics of prednisolone or prednisone.

Rifampicin: Co-administration of ARCOXIA with rifampicin, a potent inducer of hepatic

metabolism, 600 mg daily, produced a 65% decrease in etoricoxib plasma AUC. This
interaction should be taken into consideration when ARCOXIA is co-administered with
rifampicin.

Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after
initiating or changing ARCOXIA therapy in patients receiving warfarin or similar agents, since
these patients are at an increased risk of bleeding complications. In a multiple dose study in
healthy subjects receiving both warfarin and ARCOXIA 120 mg, the steady state prothrombin
time (measured as INR) was increased by approximately 13%.

4.6 FERTILITY, PREGNANCY AND LACTATION

Effects on fertility
Etoricoxib administered to male rats at oral doses up to 100 mg/kg/day (systemic exposure
about 4-fold greater than that in humans at the maximum recommended dose of 120 mg/day,
based on AUC0-24h) had no effects on mating performance, fertility, testicular/epididymal
weights, or histology, or sperm count and motility. Etoricoxib produced post-implantation
losses in female rats at oral doses of 30 mg/kg/day (approximately 3-fold human exposure at
120 mg daily based on the AUC0-24hr). These changes are expected with inhibition of
prostaglandin synthesis and are not the result of permanent alteration of female reproductive
function (see Use in pregnancy).

Use in pregnancy
(Category C) Medicines which, owing to their pharmacological effects, have caused
or may be suspected of causing, harmful effects on the human foetus or neonate
without causing malformations. These effects may be reversible. Accompanying texts
should be consulted for further details.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis and, when

given during the latter part of pregnancy, may cause closure of the foetal ductus arteriosis,
foetal renal impairment, inhibition of platelet aggregation, and delay labour and birth. Data
from epidemiological studies suggest an increased risk of miscarriage after the use of a
prostaglandin synthesis inhibitor in early pregnancy.

There are no adequate and well-controlled studies of ARCOXIA in pregnant women.

ARCOXIA should not be used during the first two trimesters of pregnancy unless the potential
benefit justifies the potential risk to the foetus. As with other agents that inhibit prostaglandin
synthesis, treatment with etoricoxib during the third trimester should be avoided because it
may cause closure of the foetal ductus arteriosus.

High placental transfer of etoricoxib has been demonstrated in pregnant rats and rabbits.
Etoricoxib treatment at oral doses ≥ 30 mg/kg/day prior to or during gestation in pregnant rats

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or rabbits caused an increase in embryofetal resorptions and reduced the number of foetuses.
Exposure to etoricoxib at the no-effect dose for increased resorption (10 mg/kg/day in either
species) was lower than that expected in humans after 120 mg, based on AUC. Etoricoxib
was not teratogenic in rats at oral doses of 45 mg/kg/day (approximately 4-fold the expected
human exposure at a dose of 120 mg/day, based on AUC). A low incidence of ventricular
septal defects and other cardiovascular malformations has been observed in rabbits given
etoricoxib at oral doses producing exposure levels comparable to that expected in humans.
Increased post-natal pup mortality with etoricoxib was observed at doses of 15 and 45
mg/kg/day in rats. Maternal drug exposure at the no-effect dose for increased pup mortality (5
mg/kg/day) was lower than human exposure at a dose of 120 mg/day, based on AUC. In
addition, reduced pup weights were observed after oral treatment of pregnant rats with
etoricoxib doses of 45 mg/kg/day during gestation and lactation.

Use in lactation
Etoricoxib is excreted in the milk of lactating rats at concentrations up to two-fold greater than
the maximal maternal plasma concentration. Because many drugs are excreted in human milk
and because of the possible adverse effects of drugs that inhibit prostaglandin synthesis on
nursing infants, a decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

The effect of ARCOXIA on the ability to drive or use machinery has not been studied. However,
based on its pharmacodynamic properties and overall safety profile it is unlikely to have an
effect on these activities.

4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)

In ten Phase IIb/III placebo-controlled clinical trials of at least 6 weeks duration for OA, 1,572
patients were treated with ARCOXIA 30 mg or 60 mg; 563 patients received ARCOXIA for up
to one year.

In the 6 to 12 week placebo-controlled population, discontinuations due to clinical adverse

experiences for ARCOXIA 30 mg, ARCOXIA 60 mg, and placebo were 4.3%, 5.0%, and 6.1%.
The most common reasons for discontinuation due to adverse experiences in OA patients
treated with ARCOXIA, 30 and 60 mg, were dyspepsia and dizziness (0.4% and 0.4% of
patients, respectively). Among patients receiving placebo, 0.3% discontinued due to
dyspepsia and 0.1% due to dizziness (see also Table 1).

In patients treated for up to one year, discontinuations due to clinical adverse experiences for
ARCOXIA 30 mg, ARCOXIA 60 mg, and naproxen were 7.3%, 12.6%, and 18.7% respectively.
The most common reasons for discontinuation due to adverse experiences in patients treated
with ARCOXIA 30 and 60 mg, were dyspepsia and upper abdominal pain (0.9% and 1.1%
respectively); in patients treated with naproxen, discontinuations due to dyspepsia and upper
abdominal pain were 1.6% and 2.3% respectively.

In three Phase IIb/III placebo-controlled studies for rheumatoid arthritis of at least 6 weeks
duration, 810 patients were treated with ARCOXIA 90 mg; 467 patients were treated with
ARCOXIA 90 mg for up to one year.

In the 6 to 12 week RA population, discontinuations due to clinical adverse experiences were

3.5% for ARCOXIA 90 mg and 2.9% for placebo. The most common causes of discontinuation
were dyspnoea, breast malignant neoplasm and headache with each event occurring at 0.2%
in patients treated with ARCOXIA. In the placebo group, 0% of patients discontinued due to
dyspnoea and breast malignant neoplasm; 0.4% due to headache.

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In RA patients treated for up to one year, discontinuations due to clinical adverse experiences
were 7.5% for ARCOXIA 90 mg and 10.5% for naproxen. The most common causes of
discontinuation in patients treated with ARCOXIA were dyspepsia (0.6%) and heartburn
(0.6%). In the naproxen group, 1.1% and 0.9% of patients discontinued due to dyspepsia and
to heartburn, respectively.

In the MEDAL Study, an endpoint driven CV outcomes trial involving 23,504 patients, the
safety of ARCOXIA 60 or 90 mg daily was compared to diclofenac 150 mg daily in patients
with OA or RA (mean duration of treatment was 20 months) (see Additional safety data from
the MEDAL Program studies, below).

In two placebo-controlled clinical trials of 12 weeks duration for chronic low back pain, 425
patients were treated with ARCOXIA 60 mg or 90 mg daily. Discontinuations due to clinical
adverse experiences were reported in ARCOXIA 60 mg (11.3%), ARCOXIA 90 mg (10.8%),
and placebo (7.3 %). The most common causes of discontinuation were asthenia/fatigue, back
strain, and rash with each event occurring at 0.7% in patients treated with ARCOXIA. In the
placebo group, 0% of patients discontinued due to asthenia/fatigue and back strain; 0.5% due
to rash.

In twelve acute analgesia studies, 1,586 patients were treated with ARCOXIA in either a single
dose or multiple dose regimen.

In the single dose population, 1,001 patients were treated with ARCOXIA (dosages of 12.5 to
240 mg). Six patients discontinued due to clinical adverse experiences including 0.9% on
ARCOXIA (less than 120 mg), 0.5% on placebo, 1.6% on ibuprofen, and 0.3% on naproxen.

In the multiple dose acute analgesia study population, 297 patients received ARCOXIA 120
mg as the initial dose followed by 60 mg or 120 mg once daily for up to 7 days.
Discontinuations due to adverse experiences were 8.2%, 5.4%, 4.7%, and 2.7% in the
placebo/placebo group, ARCOXIA 120 mg/60 mg group, ARCOXIA 120 mg/120 mg group,
and the naproxen/placebo group respectively. The most common causes of discontinuation
for those patients treated with ARCOXIA were nausea and confusion. In the post-dental
surgery pain study of 191 patients treated with ARCOXIA 90 mg once daily for up to 3 days,
the adverse experience profile was generally similar to that reported in patients treated with
ARCOXIA 120 mg in all acute analgesia studies.

In two active-comparator clinical trials for acute gouty arthritis, 178 patients were treated with
ARCOXIA 120 mg once daily for eight days. Discontinuations due to adverse experiences
were 3.9 % and 8.1% in patients treated with ARCOXIA and indometacin respectively. The
most common cause of discontinuation was hypertension occurring at 1.1% and 1.2% of
patients treated with ARCOXIA and indometacin, respectively.

Osteoarthritis
The following table lists all adverse experiences, regardless of causality, occurring in at least
2% of patients receiving ARCOXIA in ten placebo-controlled studies of 6- to 12-weeks duration
conducted in patients with OA, at the therapeutically recommended doses (30 mg and 60 mg).
Since these ten trials were of different durations, and patients in the trials may not have been
exposed for the same duration of time, these percentages do not capture cumulative rates of
occurrence.

MK0663-AUS-2017-015150 Page 10 of 27
 Table 1
Clinical Adverse Experiences occurring in 2.0%
of Patients Treated with ARCOXIA in OA Clinical Trials

Placebo Etoricoxib Etoricoxib Celecoxi Ibuprofen Naproxen

30 mg 60 mg b 2400 mg 1000 mg
(N = 1035) (N=1014) (N = 558) 200 mg (N = 756) (N = 494)
(N = 488)
Infections and infestations
Nasopharyngitis 2.3 2.1 3.2 1.4 2.8 3.8
Upper Respiratory 2.2 1.9 5.9 2.3 2.2 4.0
Tract Infection
Urinary Tract 1.3 2.9 2.9 2.5 2.5 2.6
Infection
Nervous system disorders
Dizziness 1.1 1.6 2.2 2.7 1.3 3.4
Headache 3.2 3.3 5.6 3.7 4.2 3.8
Vascular disorders
Hypertension 2.3 3.0 4.5 0.8 5.4 3.0
Gastrointestinal disorders
Abdominal Pain, 1.4 1.4 2.0 0.8 4.6 4.7
Upper
Diarrhoea 3.1 3.6 3.9 2.5 4.4 4.3
Dyspepsia 4.8 2.9 4.1 1.4 7.8 9.9
Nausea 3.1 2.2 3.0 1.8 2.9 6.3
General disorders and administration site conditions
Peripheral Oedema 1.5 2.7 2.9 2.5 3.0 2.6

The following lists additional adverse experiences, regardless of causality, occurring in

patients receiving ARCOXIA with a frequency of between 0.1% and less than 2.0% and at
least 0.1% more frequently than in the placebo treatment group in ten placebo-controlled
studies of 6- to 12-weeks duration conducted in patients with OA at the therapeutically
recommended doses (30 mg and 60 mg).

Infections and infestations: herpes simplex, infection, pharyngitis, sinusitis, staphylococcal

infection, tonsillitis.

Immune system disorders: seasonal allergy.

Metabolism and nutrition disorders: diabetes mellitus.

Psychiatric disorders: anxiety, anxiety disorder, depression.

Nervous system disorders: carpal tunnel syndrome, paresthesia, somnolence, vasovagal

syncope, tremor.

Eye disorders: blepharitis, conjunctivitis, eye pain, vision blurred.

Ear and labyrinth disorders: tinnitus.

Cardiac disorders: palpitations.

Vascular disorders: diastolic hypertension, flushing, hot flush.

Respiratory, thoracic and mediastinal disorders: cough, dyspnoea exertional, rales, sinus
congestion, wheezing.

MK0663-AUS-2017-015150 Page 11 of 27
Gastrointestinal disorders: abdominal distension, aphthous stomatitis, bowel sounds
abnormal, change of bowel habit, constipation, dry mouth, frequent bowel movements,
gastritis, glossitis, irritable bowel syndrome, mouth ulceration, oral pain, retching, toothache.

Skin and subcutaneous tissue disorders: blister, dermal cyst, dermatitis, eczema,
hyperhidrosis, rash, rash maculopapular, rosacea, skin ulcer.

Musculoskeletal and connective tissue disorders: neck pain, osteoporosis, periarthritis, rotator
cuff syndrome, tendinitis, toe deformity.

Renal and urinary disorders: nephrolithiasis, nocturia, polyuria.

Reproductive system and breast disorders: erectile dysfunction, vaginal haemorrhage.

General disorders and administration site conditions: asthenia, face oedema, fatigue, feeling
hot, oedema.

Investigations: faecal occult blood positive.

Injury, poisoning and procedural complications: contusion, foot fracture, joint sprain, skin
laceration.

The following list includes additional serious adverse experiences that occurred at a frequency
of ≤ 0.1% and in two or more patients in placebo-controlled clinical trials of 6 to 12 weeks
duration, or that occurred in two or more patients taking ARCOXIA in active comparator
controlled trials of up to 190 weeks, regardless of causality. This listing includes events
reported in clinical trials of OA and non-OA indications across a dose range of 30 mg to 120
mg daily. The MEDAL Program data is described separately below.

Infections and infestations: abscess, cellulitis, pneumonia, post operative wound infection,
pyelonephritis, sinusitis, staphylococcosis.

Neoplasms benign and unspecified (including cysts and polyps): bladder malignant neoplasm,
breast malignant neoplasm, malignant melanoma, non-Hodgkin's lymphoma, uterine fibroid.

Nervous system disorders: cerebrovascular accident, grand mal seizure, intracranial

haemorrhage, spinal stenosis, subarachnoid haemorrhage, syncope, transient ischaemic
attack.

Cardiac disorders: angina pectoris, arrhythmia, atrial fibrillation, cardiac arrest, coronary artery
disease, congestive heart failure, ischaemic heart disease, mitral valve regurgitation, unstable
angina.

Vascular disorders: deep venous thrombosis, hypertensive crisis, hypovolemic shock, lacunar
infarction.

Respiratory, thoracic and mediastinal disorders: dyspnoea, pulmonary embolism, respiratory

insufficiency.

Gastrointestinal disorders: gastroesophageal reflux disease, haemorrhagic gastric ulcer,

intestinal diverticulitis, pancreatitis, upper gastrointestinal haemorrhage, vomiting.

Hepatobiliary disorders: cholecystitis, cholelithiasis.

Musculoskeletal and connective tissue disorders: arthralgia, chest pain, hip osteoarthritis,
knee osteoarthritis, knee pain, osteoarthritis, rheumatoid arthritis, rotator cuff trauma.

Renal and urinary disorders: renal colic, urolithiasis.

MK0663-AUS-2017-015150 Page 12 of 27
Pregnancy, puerperium and perinatal conditions: pregnancy.

General disorders and administration site conditions: constricted feeling in chest, fever,
prolapse.

Injury, poisoning and procedural complications: drug overdose, femoral fracture, hip fracture,
humeral fracture, motor vehicle accident, tendon rupture, wrist fracture.

Additional Safety Data from the MEDAL Program Studies

In the MEDAL Study, an endpoint driven CV outcomes trial involving 23,504 patients, the
safety of ARCOXIA 60 or 90 mg daily was compared to diclofenac 150 mg daily in patients
with OA or RA (mean duration of treatment was 20 months). In this large trial, only serious
adverse events and discontinuations due to any adverse events were recorded. The rates of
confirmed thrombotic cardiovascular serious adverse events were similar between ARCOXIA
and diclofenac. The incidence of discontinuations for hypertension-related adverse events
was less than 3% in each treatment group; however, ARCOXIA 60 and 90 mg demonstrated
significantly higher rates of discontinuations for these events than diclofenac. The incidence
of congestive heart failure adverse events (discontinuations and serious events) and the
incidence of discontinuations due to oedema occurred at similar rates on ARCOXIA 60 mg
compared to diclofenac, however, the incidences for these events were higher for ARCOXIA
90 mg compared to diclofenac (see Table 2). The incidence of discontinuations due to atrial
fibrillation was higher for etoricoxib compared to diclofenac (in OA patients: 0.8% versus 0.3
% for etoricoxib 90 mg and diclofenac respectively; 0.3 versus 0.2 for etoricoxib 60 mg versus
diclofenac respectively).

Table 2
Pre-specified Adverse Events of Interest by Disease and Dose

Osteoarthritis 60 mg Osteoarthritis 90 mg Rheumatoid Arthritis

Etoricoxib Diclofenac Etoricoxib Diclofenac Etoricoxib Diclofenac
60 mg 150 mg 90 mg 150 mg 90 mg 150 mg
(N=6769) (N=6700) (N=2171) (N=2162) (N=2841) (N=2855)
Adverse Experience (AE)
Confirmed congestive 0.28 vs 0.21 0.69 vs 0.32 0.63 vs 0.32
heart failure‡ (p-Value 0.487) (p-Value 0.133) (p-Value 0.086)
% of Patients Discontinued due to:
0.83 vs 0.73 1.89 vs 0.79 0.99 vs 0.56
Oedema-related AEs
(p-Value 0.557) (p-Value 0.002) (p-Value 0.071)
2.16 vs 1.63 2.53 vs 1.11 2.43 vs 1.61
Hypertension-related AEs
(p-Value 0.027) (p-Value < 0.001) (p-Value 0.030)
0.33 vs 1.78 0.37 vs 4.07 0.42 vs 1.68
Hepatic-related AEs
(p-Value <0.001) (p-Value <0.001) (p-Value < 0.001)
0.81 vs 0.75 2.30 vs 1.80 1.02 vs 0.98
Renal-related AEs
(p-Value 0.696) (p-Value 0.284) (p-Value 0.895)
N = total number of patients; p-Values are for the difference between etoricoxib and diclofenac
‡ Confirmed cases of CHF which were serious or resulted in discontinuation from the study and resulted

in hospitalisation.

The EDGE and EDGE II studies compared the GI tolerability of etoricoxib 90 mg daily (1.5 to
3 times the doses recommended for OA) and diclofenac 150 mg daily in 7,111 patients with
OA (EDGE Study; mean duration of treatment 9 months) and 4,086 patients with RA (EDGE
II; mean duration of treatment 19 months). In each of these studies, the adverse experience
profile on ARCOXIA was generally similar to that reported in the Phase IIb/III placebo-
controlled clinical studies; however, hypertension and oedema-related adverse events
occurred at a higher rate on etoricoxib than on diclofenac. The rate of confirmed thrombotic
cardiovascular serious adverse events occurring in the two treatment groups was similar.

MK0663-AUS-2017-015150 Page 13 of 27
Acute Pain, including Primary Dysmenorrhoea

Approximately 1,088 patients were treated with ARCOXIA 90 mg or 120 mg in acute analgesia
studies. Patients in primary dysmenorrhoea and dental pain studies may have taken up to
three daily doses of ARCOXIA, and those in the post-orthopaedic surgery pain study were
prescribed seven daily doses of ARCOXIA.

The adverse experience profile in the acute analgesia studies was generally similar to that
reported in the combined OA, RA, and chronic low back pain studies. The following additional
adverse events, which occurred at an incidence of at least 2% of patients treated with
ARCOXIA, were observed in the post-dental pain surgery and primary dysmenorrhoea
studies: dysgeusia, post-dental extraction alveolitis (dry socket).

In the 161 patients treated with ARCOXIA (average age approximately 65 years) in the post-
orthopaedic surgery pain study, the most commonly reported adverse events were
constipation, insomnia, and nausea.

Acute Gouty Arthritis

In clinical studies for acute gouty arthritis, patients were treated with ARCOXIA 120 mg once
daily for eight days. The adverse experience profile in these studies was generally similar to
that reported in the combined OA, RA and chronic low back pain studies. The most commonly
reported adverse events in patients treated with ARCOXIA 120 mg (N=178) were gout,
dizziness and hypertension at 11.2%, 3.4%, and 7.9% respectively. In patients treated with
indometacin 150 mg daily (N=161), gout, dizziness, and hypertension were observed at 8.7%,
16.1%, and 9.9% respectively.

Rheumatoid Arthritis, Chronic Low Back Pain - Non-approved indications

In clinical studies for rheumatoid arthritis, 810 patients were treated with ARCOXIA 90 mg
daily for 6 to 12 weeks. The most commonly observed adverse events in these patients were
upper respiratory infection, diarrhoea, and headache.

In clinical studies for rheumatoid arthritis, 467 patients were treated with ARCOXIA 90 mg
daily for up to one year. The most commonly observed adverse events in these patients were
upper respiratory infection, urinary tract infection, hypertension and headache.

In clinical studies for chronic low back pain, 425 patients were treated with ARCOXIA 60 mg
or 90 mg for 12 weeks. The most commonly observed adverse events in these patients were
diarrhoea, nausea and headache.

Post-marketing experience

The following adverse reactions have been observed in post-marketing experience:

Psychiatric disorders: insomnia, confusion, hallucinations, depression, restlessness.

Immune system disorders: hypersensitivity reactions, anaphylactic/anaphylactoid reactions

including shock.

Metabolism and nutrition disorders: hyperkalaemia.

Nervous system disorders: dysgeusia, somnolence.

Cardiac disorders: congestive heart failure, palpitations, angina, arrhythmia.

Respiratory, thoracic and mediastinal disorders: bronchospasm, dyspnoea.

MK0663-AUS-2017-015150 Page 14 of 27
Gastrointestinal disorders: abdominal pain, melaena, oral ulcers, peptic ulcers including
perforation and bleeding (mainly in elderly patients).

Skin and subcutaneous tissue disorders: angioedema, rash, pruritus, erythema, Stevens-
Johnson syndrome, toxic epidermal necrolysis, urticaria, fixed drug eruption.

Renal and urinary disorders: renal insufficiency, including renal failure (see Section 4.4 Special
Warnings and Precautions for Use).

Hepatobiliary disorders: hepatitis, jaundice, hepatic failure.

Blood and lymphatic system disorders: thrombocytopenia.

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, hepatotoxicity and pancreatitis.

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration of the medicinal product is important.
It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions at
www.tga.gov.au/reporting-problems.

4.9 OVERDOSE
For information on the management of overdose, contact the Poison Information Centre on
131126 (Australia).

In clinical studies, administration of ARCOXIA at single doses 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 events were not reported in the majority
of cases. The most frequently observed adverse events were consistent with the safety profile
for etoricoxib (e.g. gastrointestinal events, renovascular events).

In the event of overdose, it is reasonable to employ the usual supportive measures, e.g.,
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.

5 PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic Group: M01AH Coxibs

Mechanism of action
Etoricoxib is a member of a new class of agents called Coxibs. Etoricoxib is a potent, orally
active cyclooxygenase-2 (COX-2) specific inhibitor within, and significantly above, the clinical
dose range. Two isoforms of cyclooxygenase have been identified: cyclooxygenase-1 (COX-
1) and cyclooxygenase-2 (COX-2). COX-1 is responsible for prostaglandin-mediated normal
physiologic functions such as gastric cytoprotection and platelet aggregation. Inhibition of
COX-1 by nonselective NSAIDs has been associated with gastric damage and inhibition of
platelet aggregation. COX-2 has been shown to be primarily responsible for the synthesis of
prostanoid mediators of pain, inflammation and fever. Selective inhibition of COX-2 by
etoricoxib (within the clinical dose range) decreases these clinical signs and symptoms with
decreased potential for GI toxicity and effects on platelet aggregation.

MK0663-AUS-2017-015150 Page 15 of 27
Across clinical pharmacology studies, ARCOXIA produced dose-dependent inhibition of COX-
2 without inhibition of COX-1 at doses up to 150 mg daily.

The influence on gastroprotective COX-1 activity was also assessed in a clinical study where
prostaglandin synthesis was measured in gastric biopsy samples from subjects administered
either ARCOXIA 120 mg daily, naproxen 500 mg twice daily, or placebo. ARCOXIA did not
inhibit gastric prostaglandin synthesis as compared to placebo. In contrast, naproxen inhibited
gastric prostaglandin synthesis by approximately 80% compared with placebo. These data
further support the COX-2 selectivity of ARCOXIA.

Platelet Function

Multiple doses of ARCOXIA up to 150 mg administered daily up to nine days had no effect on
bleeding time relative to placebo. Similarly, bleeding time was not altered in a single dose
study with ARCOXIA 250 or 500 mg. There was no inhibition of ex vivo arachidonic acid- or
collagen-induced platelet aggregation at steady state with doses of ARCOXIA up to 150 mg.
These findings are consistent with the COX-2 selectivity of etoricoxib.

The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2
selective inhibitors may be of clinical significance in patients at risk of thromboembolic events.
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.

Clinical trials
Osteoarthritis (OA)

ARCOXIA has demonstrated significant reduction in joint pain compared to placebo.

ARCOXIA was evaluated for the treatment of the signs and symptoms of OA of the knee and
hip in approximately 3,300 patients enrolled in six placebo-controlled Phase III clinical trials
with ARCOXIA 30 mg (12 weeks and 26 weeks) or 60 mg (52 weeks). The pivotal Phase III
studies included: two placebo-controlled studies of etoricoxib 30 mg and ibuprofen 2400 mg,
two placebo-controlled studies of etoricoxib 30 mg and celecoxib 200 mg and two placebo-
controlled studies of etoricoxib 60 mg and naproxen 1000 mg.

Treatment with ARCOXIA resulted in improvement in pain, function (mobility) and

inflammation (stiffness and tenderness), as assessed by the WOMAC (Western Ontario and
McMaster Universities) osteoarthritis questionnaire and patient and investigator assessments.
Once-daily treatment, when administered in the morning with ARCOXIA 30 mg or 60 mg, was
associated with a significant reduction in joint stiffness upon first awakening the next morning.

The effectiveness of ARCOXIA 30 mg was shown to be comparable to ibuprofen 800 mg three

times daily as well as to celecoxib 200 mg daily (see Table 3).

MK0663-AUS-2017-015150 Page 16 of 27
 Table 3
WOMAC Pain and Patient Global Assessment Responses
Time-Weighted Average Response Over the 12-Week Treatment Period
Phase III Etoricoxib 30 mg OA Studies (Protocols 071, 073, 076, and 077)

Baseline
Treatment Group LS Mean Change from Baseline (95% CI)
Mean
Protocol 071
Pain Subscale (WOMAC) (0- to 100-mm VAS)
Placebo (n=101) 69.50 -16.36 (-20.59, -12.13)
Etoricoxib 30 mg (n=212) 68.72 -26.90 (-29.97, -23.83)
Ibuprofen 2400 mg (n=209) 67.78 -25.25 (-28.40, -22.11)
Patient Global Assessment of Disease Status (0- to 100-mm VAS)
Placebo (n=100) 72.60 -16.53 (-20.99, -12.06)
Etoricoxib 30 mg (n=211) 72.24 -27.89 (-31.13, -24.65)
Ibuprofen 2400 mg (n=209) 70.53 -26.53 (-29.83, -23.22)
Protocol 073
Pain Subscale (WOMAC) (0- to 100-mm VAS)
Placebo (n=109) 64.66 -16.47 (-20.55, -12.40)
Etoricoxib 30 mg (n=220) 66.46 -28.14 (-31.23, -25.04)
Ibuprofen 2400 mg (n=211) 64.74 -24.10 (-27.20, -20.99)
Patient Global Assessment of Disease Status (0- to 100-mm VAS)
Placebo (n=107) 66.93 -17.85 (-22.41, -13.29)
Etoricoxib 30 mg (n=220) 70.14 -29.50 (-32.91, -26.10)
Ibuprofen 2400 mg (n=211) 69.88 -25.97 (-29.39, -22.54)
Protocol 076
Pain Subscale (WOMAC) (0- to 100-mm VAS)
Placebo (n=126) 66.63 -12.31 (-16.31, -8.32)
Etoricoxib 30 mg (n=228) 67.36 -27.38 (-30.46, -24.30)
Celecoxib 200 mg (n=236) 67.48 -24.26 (-27.29, -21.23)
Patient Global Assessment of Disease Status (0- to 100-mm VAS)
Placebo (n=126) 69.10 -13.99 (-18.16, -9.83)
Etoricoxib 30 mg (n=228) 72.18 -30.44 (-33.66, -27.21)
Celecoxib 200 mg (n=236) 71.25 -26.39 (-29.55, -23.23)
Protocol 077
Pain Subscale (WOMAC) (0- to 100-mm VAS)
Placebo (n=112) 66.44 -15.21 (-19.49, -10.94)
Etoricoxib 30 mg (n=243) 68.68 -26.77 (-29.68, -23.86)
Celecoxib 200 mg (n=246) 67.27 -26.91 (-29.86, -23.96)
Patient Global Assessment of Disease Status (0- to 100-mm VAS)
Placebo (n=111) 72.30 -12.48 (-16.88, -8.09)
Etoricoxib 30 mg (n=243) 72.98 -28.34 (-31.33, -25.35)
Celecoxib 200 mg (n=246) 70.11 -28.40 (-31.42, -25.37)
LS Mean=Least-squares mean, CI=Confidence interval, VAS=Visual analog scale,
WOMAC=Western Ontario McMaster Universities.

The dose-ranging study, Protocol 007, included 617 OA patients randomised to placebo or
etoricoxib doses of 5, 10, 30, 60 and 90 mg. Protocol 007 demonstrated that all etoricoxib
doses (5, 10, 30, 60, 90 mg) were significantly better than placebo for the 3 primary endpoints:
the WOMAC Pain Subscale, the Investigator Global Assessment of Disease Status, and the
Patient Global Assessment of Response to Therapy, as shown in the accompanying figure
(see Figure 1). The 60 mg dose met three out of three predefined efficacy criteria, whereas
the 30 mg dose met two out of three predefined efficacy criteria; and etoricoxib 60 mg
demonstrated significantly greater efficacy than etoricoxib 30 mg. Etoricoxib 90 mg did not
demonstrate greater efficacy than the etoricoxib 60 mg dose.

MK0663-AUS-2017-015150 Page 17 of 27
 Figure 1
OA Dose-Ranging Study (Protocol 007)
Analysis of Primary Endpoints (6 week treatment period)
(0-100 mm VAS) (0-4 point Likert)
10 0.5
LS Mean Difference with 95% CIs

0 0.0
Treatment in Part I

-10 -0.5 Etoricoxib 5 mg

Etoricoxib 10 mg
Etoricoxib 30 mg
-20 -1.0 Etoricoxib 60 mg
Etoricoxib 90 mg

-30 -1.5

-40 -2.0
WOMAC Pain Patient Global Inv. Global
Subscale (VAS) Response to Assessment of
Therapy (Likert) Disease
Status (Likert)

Primary Endpoints

The effectiveness of ARCOXIA 60 mg was shown to be comparable to naproxen 500 mg twice

daily for treatment of the signs and symptoms of OA (see Table 4). Onset of efficacy was
evaluated only in the 60 mg studies and was demonstrated within the first 24 hours of initiating
treatment. In patients with OA of the hand, reductions in pain and stiffness, and improvement
in physical function, as measured by the AUSCAN questionnaire were superior to placebo and
similar to that in patients treated with naproxen.

Table 4
WOMAC Pain and Patient Global Assessment Responses
Time-Weighted Average Response Over the 12-Week Treatment Period
Phase III Etoricoxib 60 mg OA Studies (Protocols 018, 019)

Baseline
Treatment Group LS Mean Change From Baseline (95% CI)
Mean
Protocol 018
Pain Subscale (WOMAC) (0- to 100-mm VAS)
Placebo (n=55) 71.14 -15.74 (-21.54, -9.94)
Etoricoxib 60 mg (n=220) 68.87 -30.41 (-33.51, -27.31)
Naproxen 1000 mg (n=217) 69.01 -32.27 (-35.42, -29.11)
Patient Global Assessment of Disease Status (0- to 100-mm VAS)
Placebo (n=55) 71.75 -10.50 (-16.51, -4.50)
Etoricoxib 60 mg (n=220) 67.61 -27.10 (-30.31, -23.90)
Naproxen 1000 mg (n=217) 68.69 -29.10 (-32.36, -25.83)
Protocol 019
Pain Subscale (WOMAC) (0- to 100-mm VAS)
Placebo (n=56) 68.70 -15.33 (-20.70, -9.96)
Etoricoxib 60 mg (n=223) 64.92 -25.76 (-28.58, -22.94)
Naproxen 1000 mg (n=219) 65.66 -25.32 (-28.13, -22.50)
Patient Global Assessment of Disease Status (0- to 100-mm VAS)
Placebo (n=56) 73.55 -16.59 (-22.26, -10.92)
Etoricoxib 60 mg (n=222) 66.86 -25.93 (-28.90, -22.95)
Naproxen 1000 mg (n=218) 67.83 -24.18 (-27.15, -21.21)
LS Mean=Least-squares mean, CI=Confidence interval, VAS=Visual analog scale,
WOMAC=Western Ontario McMaster Universities.

MK0663-AUS-2017-015150 Page 18 of 27
The clinical benefit of both ARCOXIA 30 mg and 60 mg was maintained for the duration of the
studies.

Acute Gouty Arthritis

ARCOXIA 120 mg once daily, over an eight-day treatment period, demonstrated reductions in
joint pain and inflammation (tenderness, swelling, and erythema) comparable to indometacin
50 mg three times daily in the treatment of patients experiencing moderate to extreme pain
(approximately 150 patients) during an attack of acute gouty arthritis. Reduction in pain was
observed as early as four hours after initiation of treatment (the first determination).

Acute Pain including Post-Operative Dental Pain and Primary Dysmenorrhoea

In single-dose clinical studies which treated approximately 1,200 patients, ARCOXIA relieved
moderate-to-severe pain in acute analgesic models of post-operative dental pain and primary
dysmenorrhoea. The analgesic effect of a 120 mg dose of ARCOXIA was similar to a
maximum analgesic dose of naproxen sodium (550 mg) or ibuprofen (400 mg) and greater
than paracetamol (600 mg) with codeine (60 mg). The onset of analgesia with ARCOXIA
occurred as early as 24 minutes after dosing and persisted for as long as 24 hours.

In a multiple-dose post-dental surgery study (Protocol 092), ARCOXIA 90 mg administered

once daily for up to three days provided a significantly greater analgesic effect compared to
placebo. ARCOXIA 90 mg provided a shorter time to onset and longer duration of pain relief,
greater peak pain relief, in addition to a lower use of rescue analgesic medication following
the initial first day dose compared to placebo. ARCOXIA 90 mg was non-inferior to ibuprofen
600 mg four times daily, and superior to paracetamol/codeine 600 mg/60 mg four times daily
in total pain relief.

Special Studies

Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program

The MEDAL Program was a prospectively designed Cardiovascular (CV) Safety Outcomes
program of pooled data from three individual, randomised, double-blind active comparator
(diclofenac)-controlled trials (MEDAL study, EDGE II and EDGE). The MEDAL Program also
evaluated upper and lower GI safety. The Program consisted of 34,701 OA and RA patients
treated with etoricoxib 60 mg daily (OA) or etoricoxib 90 mg daily (OA and RA, 1.5 to 3 times
the doses recommended for OA) versus diclofenac 150 mg daily for a mean period of
approximately 18 months; approximately 12,800 had more than 24 months of exposure with
some patients receiving up to 42 months of treatment.

Patients enrolled in the MEDAL Program had a wide range of baseline cardiovascular and
gastrointestinal risk factors. Approximately 47% of patients had a history of hypertension,
approximately 12% had a history of symptomatic atherosclerotic cardiovascular disease
(ASCVD) and approximately 38% of patients had an increased cardiovascular risk at baseline
(defined as having either a previous history of symptomatic ASCVD or ≥ 2 Cardiovascular Risk
Factors from among the following 5: [history of hypertension, history of diabetes mellitus,
history of dyslipidaemia, family history of cardiovascular disease, cigarette use]). Patients with
a recent history of myocardial infarction, coronary artery bypass grafting or percutaneous
coronary intervention within 6 months preceding enrolment were excluded. Use of
gastroprotective agents and low-dose aspirin were permitted in the studies with approximately
50% of the patients on gastroprotective agents and approximately 35% of the patients on low-
dose aspirin. In the studies, efficacy of etoricoxib 60 mg and 90 mg was shown to be
comparable to diclofenac.

MK0663-AUS-2017-015150 Page 19 of 27
The cardiovascular and gastrointestinal safety data are summarised below (Table 5). Other
important safety data, including renovascular data, is described in Section 4.8 Adverse Effects
(Undesirable Effects).

Cardiovascular data: The MEDAL Program showed that the rates of confirmed thrombotic
cardiovascular serious adverse events (consisting of cardiac, cerebrovascular and peripheral
vascular events) were comparable between etoricoxib and diclofenac (see Table 5). For the
primary endpoint of confirmed thrombotic CV events, the relative risk between etoricoxib and
diclofenac was 0.95 (95% CI: 0.81, 1.11) in the pre-specified primary analysis. The event rates
for individual types of thrombotic events (e.g. myocardial infarction and stroke) were also
similar between etoricoxib and diclofenac. The rates were similar between etoricoxib and
diclofenac over the entire duration of the study, including in the subset of patients who were
on treatment for greater than 24 months. There were no discernible differences in thrombotic
event rates between etoricoxib and diclofenac across all subgroups analysed, including
patient categories across a range of baseline cardiovascular risk. CV mortality, as well as
overall mortality, was similar between the etoricoxib and diclofenac treatment groups.

Table 5
Overall Rates of Confirmed Thrombotic CV Events (Pooled MEDAL Program)

Etoricoxib Diclofenac
(N=16,819) (N=16,483) Between Treatment
25,836 24,766 Comparison
Patient-Years Patient-Years
Rate† Rate† Relative Risk (95% CI)
(95% CI) (95% CI)
Total number of patients 1.24 (1.11, 1.38) 1.30 (1.17, 1.45) 0.95 (0.81, 1.11)
with Endpoint
Cardiac Events 0.71 (0.61, 0.82) 0.78 (0.68, 0.90) 0.90 (0.74, 1.10)
zCerebrovascular Events 0.34 (0.28, 0.42) 0.32 (0.25, 0.40) 1.08 (0.80, 1.46)
Peripheral Vascular 0.20 (0.15, 0.27) 0.22 (0.17, 0.29) 0.92 (0.63, 1.35)
Events
†Events per 100 Patient-Years.

N=total number of patients; CI=confidence interval

Gastrointestinal data: 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. The rates per
hundred patient-years of confirmed 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). No significant difference was
observed in rates of complicated upper GI clinical events between etoricoxib and diclofenac
(0.30 vs 0.32 per hundred patient-years). As the risk for upper GI events increases with age,
the rate for these events in elderly patients was evaluated. The largest risk reduction was
observed in patients ≥ 75 years of age; the rate per hundred patient-years for a confirmed
upper GI event was lower for etoricoxib compared to diclofenac (1.35 [95% CI 0.94, 1.87] vs
2.78 [95% CI 2.14, 3.56]). The rates for confirmed upper GI events in patients taking
concomitant low-dose aspirin and/or gastroprotective agents were also evaluated and are
presented in Table 6. The rates of confirmed lower GI clinical events were 0.32 (95% CI 0.25,
0.39) vs 0.38 (95% CI 0.31, 0.46) per hundred patient-years for etoricoxib vs diclofenac,
yielding a relative risk of 0.84 (95% CI 0.63, 1.13).

MK0663-AUS-2017-015150 Page 20 of 27
 Table 6
Confirmed Upper GI Events (Pooled MEDAL Program)

Etoricoxib Diclofenac
Rate† (95% CI) Rate† (95% CI)
Overall Rate 0.67 (0.57, 0.77) 0.97 (0.85, 1.10)
[Relative Risk 0.69 (0.57,0.83)]
Concomitant Low Dose Aspirin Use
No 0.38 (0.29, 0.48) 0.73 (0.60, 0.87)
Yes 1.14 (0.94, 1.37) 1.37 (1.15, 1.63)
Concomitant Gastroprotective Agents Use‡
No 0.63 (0.49, 0.79) 0.83 (0.67, 1.02)
Yes 0.70 (0.57, 0.84) 1.07 (0.91, 1.25)
†Rate = Events per 100 patient-years = (n/PYR)x100.
CI=Confidence Interval.
‡Proton pump inhibitors and misoprostol accounted for approximately 96% of

patients taking gastroprotective agents

GI tolerability, defined as patients discontinuing the study for any clinical (e.g., dyspepsia,
abdominal pain, ulcer) or laboratory (e.g., increased ALT, AST) GI adverse experience
including hepatic events, was also evaluated in each individual study within the MEDAL
Program. The EDGE and EDGE II studies assessed GI tolerability as the primary endpoint.
They compared etoricoxib 90 mg daily and diclofenac 150 mg daily in patients with OA (EDGE)
and RA (EDGE II). The MEDAL Study compared GI tolerability between etoricoxib 60 mg (OA)
or 90 mg (OA and RA) to diclofenac 150 mg daily as a secondary objective. In all three studies,
etoricoxib demonstrated superior GI tolerability compared to diclofenac (p-values < 0.001; see
Figure 2). The GI tolerability benefit for etoricoxib was significant both for the clinical and for
the laboratory components that make up this composite endpoint.

Figure 2
GI Tolerability

25
Discontinuations Due to GI Adverse Experiences

19.86
20
(events/100 patient years)

17.13

15

9.71
9.13
10 8.61 8.69 8.45

5.22
3.96 4.41
5

0
60 mg OA 90 mg OA 90 mg RA 90 mg RA 90 mg OA

MEDAL Study EDGE II EDGE

Etoricoxib Diclofenac 150 mg

Hepatic-related adverse events resulting in discontinuation were evaluated in each individual

study within the MEDAL Program. The incidences of discontinuations were significantly lower

MK0663-AUS-2017-015150 Page 21 of 27
in the etoricoxib 60 and 90 mg treatment groups compared with the diclofenac 150 mg
treatment groups for both OA and RA patients in all three studies.

Additional Thrombotic Cardiovascular Safety Data

In a combined analysis of all Phase IIB to Phase V clinical studies of 4 weeks duration or
longer (excluding the MEDAL Program Studies), there was no discernible difference in the
rate of confirmed serious thrombotic cardiovascular events between patients receiving
etoricoxib ≥30 mg 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, with
a statistically significant increase in relative risk with etoricoxib with respect to the Anti-Platelet
Trialists' Collaboration (APTC) combined endpoint. In the studies which directly compared
etoricoxib to placebo (6 to 12 weeks duration), there was no discernable difference in the event
rates between patients receiving etoricoxib or placebo; however there were few events and
the studies were limited in duration (see Section 4.4 Special Warnings and Precautions for
Use, Cardiovascular effects).

Table 7
Etoricoxib Development Program
Summary of Confirmed Thrombotic Events and Confirmed APTC Combined Endpoint

Comparisons N n/PYR† Rate‡ (95% CI) Relative Risk (95% CI)

Confirmed Thrombotic Events
Etoricoxib 3,940 9/810 1.11 (0.51, 2.11) 1.07 (0.36, 3.22)
Placebo 2,337 5/450 1.11 (0.36, 2.59) --
Etoricoxib 2,147 14/1,815 0.77 (0.42, 1.29) 0.73 (0.27, 1.98)
Non-Naproxen NSAIDs 1,470 6/649 0.92 (0.34, 2.01) --
Etoricoxib 1,960 34/2,480 1.37 (0.95, 1.92) 1.70 (0.91, 3.18)
Naproxen 1000 mg 1,497 14/1,727 0.81 (0.44, 1.36) --
Confirmed APTC Combined Endpoint
Etoricoxib 3,940 7/810 0.86 (0.35, 1.78) 1.95 (0.37, 19.19)
Placebo 2,337 2/450 0.44 (0.05, 1.60) --
Etoricoxib 2,147 11/1,817 0.61 (0.30, 1.08) 0.80 (0.25, 2.59)
Non-Naproxen NSAIDs 1,470 4/649 0.62 (0.17, 1.58) --
Etoricoxib 1,960 27/2,481 1.09 (0.72, 1.58) 2.72 (1.18, 6.27)
Naproxen 1000 mg 1,497 7/17,28 0.41 (0.16, 0.83) --
† Patient-years at risk.
‡ Per 100 PYR.

APTC = Antiplatelet Trialists’ Collaboration ; CI = Confidence interval; PYR = Patient-years at risk.

APTC combined endpoint includes (cardiovascular, haemorrhagic and unknown death, non-fatal
myocardial ischaemia, and non-fatal stroke).

Additional Gastrointestinal Safety Data

The following special studies were conducted to evaluate whether ARCOXIA, a COX-2
selective inhibitor, is associated with less GI toxicity than nonselective NSAIDs.

Upper Endoscopy in Patients with Rheumatoid Arthritis or Osteoarthritis

The cumulative incidence of gastroduodenal ulcers was significantly lower in patients treated
with ARCOXIA 120 mg once daily than in patients treated with either of two nonselective
NSAIDs (naproxen 500 mg twice daily or ibuprofen 800 mg three times daily) in two 12-week
double-blind endoscopy studies. Seven hundred patients with either OA or RA were treated
in Study 1, while 655 patients with OA were treated in Study 2. Patients treated with ARCOXIA
had a higher cumulative incidence of ulcers as compared to patients treated with placebo (see
Figure 3 for the results of these studies).

MK0663-AUS-2017-015150 Page 22 of 27
Both endoscopy studies included the following patients at a higher risk for GI ulcers: patients
with active Helicobacter pylori infection; baseline gastroduodenal erosions; prior history of
perforation, ulcer or bleed (PUB); and/or concomitant use of corticosteroids. Four hundred
patients (28%) were 65 years of age and older. The advantage of ARCOXIA versus naproxen
or ibuprofen was maintained in these higher risk subgroups.

Gastrointestinal Safety Combined Analysis

In a combined analysis of all Phase IIb to V clinical studies of 4 weeks duration or longer
(excluding the MEDAL Program Studies), the rate of PUB events (gastroduodenal
perforations, symptomatic gastrointestinal ulcers or upper GI bleeds) for combined doses of
etoricoxib ranging from 30 mg to 120 mg daily (N = 4,107 patients with a mean duration of
treatment of approximately 220 days) was compared to non-selective NSAIDs (naproxen 1000
mg daily, diclofenac 150 mg daily and ibuprofen 2400 mg daily; total N = 2,967 patients with
a mean duration of treatment of approximately 182 days). The event rates of confirmed PUBs
for the etoricoxib group were approximately half of those in the nonselective NSAIDs group
during the first year of treatment (1.13 events per hundred-patient years for etoricoxib
compared to 2.64 events per hundred patient-years for NSAIDs; relative risk 0.47 [95%CI:
0.28, 0.76]). The results were consistent over the entire follow-up period. In the combined
analysis, the magnitude of the risk reduction for the complicated events (primarily a result of
upper GI haemorrhages) was generally consistent over the entire treatment period with results
for overall upper GI clinical events (relative risk 0.57 [95%CI: 0.31, 1.07]), although the number
of events is more limited.

Gastrointestinal Clinical Tolerability Combined Analysis

A pre-specified, combined analysis of eight clinical trials of approximately 4,000 patients with
OA, RA or chronic low back pain assessed the incidence rate for the following endpoints: 1)
discontinuation for upper GI symptoms; 2) discontinuation for any GI adverse events; 3) new
use of gastroprotective medications (including H2 receptor antagonists, misoprostol, and
proton pump inhibitors) and 4) new use of any GI medications. There was an approximate
50% risk reduction for these endpoints in patients treated with ARCOXIA (60, 90 or 120 mg

MK0663-AUS-2017-015150 Page 23 of 27
daily) as compared to patients treated with nonselective NSAIDs (naproxen 500 mg twice daily
or diclofenac 50 mg three times daily). There were no statistically significant differences
between ARCOXIA and placebo.

Assessment of Faecal Occult Blood Loss in Healthy Subjects

To assess mucosal integrity throughout the gastrointestinal tract, faecal blood loss with
ARCOXIA 120 mg daily, ibuprofen 2400 mg daily, and placebo was compared in a study
utilising 51Cr-tagged red blood cells in 62 healthy males. After four weeks of treatment with
ARCOXIA 120 mg, there was no significant increase in the amount of faecal blood loss
compared with placebo-treated subjects. In contrast, ibuprofen 2400 mg daily produced a
significant increase in faecal blood loss as compared to subjects treated with placebo and
subjects treated with ARCOXIA.

Renal Function Study in Elderly Subjects

A randomised, double-blind, placebo-controlled, parallel-group study evaluated the effects of

15 days of treatment of etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg
twice daily) 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).

5.2 PHARMACOKINETIC PROPERTIES

Absorption
Orally administered etoricoxib is well absorbed. The mean oral bioavailability is approximately
100%. Following 120 mg once-daily dosing to steady state, the peak plasma concentration
(geometric mean Cmax = 3.6 mcg/mL) was observed at approximately 1 hour (Tmax) after
administration to fasted adults. The geometric mean AUC0-24hr was 37.8 mcg•hr/mL. The
pharmacokinetics of etoricoxib are linear across the clinical dose range.

A standard meal had no clinically meaningful effect on the extent or rate of absorption of a
dose of etoricoxib 120 mg. In clinical trials, etoricoxib was administered without regard to food.

The pharmacokinetics of etoricoxib in 12 healthy subjects were similar (comparable AUC, Cmax
within approximately 20%) when administered alone, with a magnesium/aluminium hydroxide
antacid or a calcium carbonate antacid (approximately 50 mEq acid-neutralising capacity).

Distribution
Etoricoxib is approximately 92% bound to human plasma protein over the range of
concentrations of 0.05 to 5 mcg/mL. The volume of distribution at steady state (Vdss) is
approximately 120 L in humans.

Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.

Metabolism
Etoricoxib is extensively metabolised with <1% of a dose recovered in urine as the parent
drug. Five metabolites have been identified in humans. Metabolism in vitro involves conversion
primarily to the 6'-hydroxymethyl derivative, mainly (ca. 60%) by CYP3A4, with less
contribution by CYPs 1A2, 2C9, 2C19 and 2D6 (ca. 40% collectively). The 6'-hydroxymethyl
derivative is further metabolised by oxidation to the principal metabolite, the 6'-carboxylic acid
derivative of etoricoxib. These principal metabolites either demonstrate no measurable activity

MK0663-AUS-2017-015150 Page 24 of 27
or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1 (see
also Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion
Following administration of a single 25 mg radiolabelled 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 an accumulation half-life of approximately 22 hours. The plasma clearance is estimated to
be approximately 50 mL/min.

Gender
The pharmacokinetics of etoricoxib are similar between men and women (see Section 4.2
Dose and Method of Administration).

Elderly
Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young.
No dosage adjustment is necessary for elderly patients (for elderly patients with hepatic
impairment see Section 4.2 Dose and Method of Administration, Hepatic insufficiency).

Race
There is no clinically important effect of race on the pharmacokinetics of etoricoxib (see
Section 4.2 Dose and Method of Administration).

Hepatic insufficiency
Patients with mild hepatic insufficiency (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 insufficiency (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
insufficiency (Child-Pugh score > 9) (see Section 4.2 Dose and Method of Administration,
Hepatic insufficiency).

Renal insufficiency
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).

Paediatric patients
The pharmacokinetics of etoricoxib in paediatric patients (<12 years of age) 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
in 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.

MK0663-AUS-2017-015150 Page 25 of 27
5.3 PRECLINICAL SAFETY DATA
Genotoxicity
Etoricoxib was not genotoxic in assays for gene mutations (in vitro bacterial and human
lymphoblast [TK locus] cell assays), chromosomal damage (CHO cells in vitro, rat bone
marrow in vivo) and other genotoxic effects (alkaline elution assay of DNA damage in vitro
and in vivo, DNA adduct formation in vitro).

Carcinogenicity
When etoricoxib at doses ≥ 30 mg/kg/day (> 6 times the daily human dose [90 mg]) was
administered orally for up to 2 years in rats, liver adenomas were observed in the males and
females and thyroid follicular cell adenomas were observed in the males, as well. At the lower
dose tested in this species (10 mg/kg/day), hepatic cell and thyroid follicular cell hypertrophy
were observed in both sexes, and were associated with systemic exposure (AUC0-24h) lower
than that expected in humans at the maximum recommended dose of 120 mg.

Etoricoxib was not carcinogenic in mice given oral doses up to 400 mg/kg/day for males and
up to 600 mg/kg/day for females for two years. Systemic exposure (AUC0-24h) at these dose
levels was similar to that in humans at the maximum recommended dose of 120 mg.

6 PHARMACEUTICAL PARTICULARS
6.1 LIST OF EXCIPIENTS
Each tablet of ARCOXIA for oral administration contains the following excipients: calcium
hydrogen phosphate, carnauba wax, croscarmellose sodium, hypromellose, lactose
monohydrate, magnesium stearate, microcrystalline cellulose, titanium dioxide, triacetin. The
30, 60 and 120 mg tablets also contain iron oxide yellow CI77492 and indigo carmine CI73015.

6.2 INCOMPATIBILITIES
Incompatibilities were either not assessed or not identified as part of the registration of this
medicine.

6.3 SHELF LIFE

The expiry date can be found on the packaging. In Australia, information on the shelf life can
be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 SPECIAL PRECAUTIONS FOR STORAGE

ARCOXIA Tablets should be stored below 30°C. Store in the original package.

6.5 NATURE AND CONTENTS OF CONTAINER

ARCOXIA (etoricoxib) 30 mg is available in PA/Aluminium-PVC/Aluminium blister packs of 5
tablets#, 10 tablets (starter pack) # and 30 tablets.

ARCOXIA (etoricoxib) 60 mg is available in PA/Aluminium-PVC/Aluminium blister packs of 5

tablets#, 10 tablets#, and 30 tablets.

ARCOXIA (etoricoxib) 90 mg is available in PA/Aluminium-PVC/Aluminium blister packs of 2

tablets# (starter pack), 5 tablets#, and 10 tablets#.

ARCOXIA (etoricoxib) 120 mg is available in PA/Aluminium-PVC/Aluminium blister packs of 2

tablets (starter pack) #, 5 tablets#, and 10 tablets.
#
Presentation not currently marketed in Australia.

MK0663-AUS-2017-015150 Page 26 of 27
6.6 SPECIAL PRECAUTIONS FOR DISPOSAL
In Australia, any unused medicine or waste material should be disposed of by taking to your
local pharmacy.

6.7 PHYSICOCHEMICAL PROPERTIES

ARCOXIA tablets contain etoricoxib, which is described chemically as 5-chloro-6'-methyl-3-
[4-(methylsulfonyl)phenyl]-2,3'-bipyridine. The empirical formula is C18H15ClN2O2S. The
molecular weight is 358.84.

Chemical structure
The structural formula is:

CAS number
The CAS Registry Number is 202409-33-4

7 MEDICINE SCHEDULE (POISONS STANDARD)

Prescription only medicine (S4)

8 SPONSOR
Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road
Macquarie Park NSW 2113
www.msd-australia.com.au

9 DATE OF FIRST APPROVAL

11 October 2002

10 DATE OF REVISION
08 May 2020

SUMMARY TABLE OF CHANGES

Section
Summary of new information
Changed
4.8, 5.1, 6.1 Updated medicine ingredient name

MK0663-AUS-2017-015150 Page 27 of 27