Etoricoxib 30 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Etoricoxib
Available from:
Bristol Laboratories Limited
ATC code:
M01AH; M01AH05
INN (International Name):
Etoricoxib
Dosage:
30 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Coxibs; etoricoxib
Authorization status:
Not marketed
Authorization number:
PA1240/026/001
Authorization date:
2017-06-16

Read the complete document

Package leaflet: Information for the patient

Etoricoxib 30 mg Film-coated Tablets

Etoricoxib 60 mg Film-coated Tablets

Etoricoxib 90 mg Film-coated Tablets

Etoricoxib 120 mg Film-coated Tablets

Etoricoxib

Read all of this leaflet carefully before you start taking this medicine because

it contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may

harm them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

What this medicine is and what it is used for

What you need to know before you take this medicine

How to take this medicine

Possible side effects

How to store this medicine

Contents of the pack and other information

1. What this medicine is and what it is used for

What is Etoricoxib?

Etoricoxib contains the active substance etoricoxib. Etoricoxib is one of a group of

medicines called selective COX-2 inhibitors. These belong to a family of medicines

called non-steroidal anti-inflammatory drugs (NSAIDs).

What is Etoricoxib used for?

Etoricoxib helps to reduce the pain and swelling (inflammation) in the joints and

muscles of people 16 years of age and older with osteoarthritis, rheumatoid

arthritis, ankylosing spondylitis and gout.

SAME SIZE ARTWORK

520 mm x 150 mm

Etoricoxib is also used for the short term treatment of moderate pain after dental

surgery in people 16 years of age and older.

What is osteoarthritis?

Osteoarthritis is a disease of the joints. It results from the gradual breakdown of

cartilage that cushions the ends of the bones. This causes swelling (inflammation),

pain, tenderness, stiffness and disability.

What is rheumatoid arthritis?

Rheumatoid arthritis is a long term inflammatory disease of the joints. It causes pain,

stiffness, swelling, and increasing loss of movement in the joints it affects. It may also

cause inflammation in other areas of the body.

What is gout?

Gout is a disease of sudden, recurring attacks of very painful inflammation and

redness in the joints. It is caused by deposits of mineral crystals in the joint.

What is ankylosing spondylitis?

Ankylosing spondylitis is an inflammatory disease of the spine and large joints.

2. What you need to know before you take this medicine

Do not take this medicine:

if you are allergic to the active substance or any of the other ingredients of this

medicine (listed in section 6).

if you are allergic to non-steroidal anti-inflammatory drugs (NSAIDs), including

aspirin and COX-2 inhibitors (see Possible Side Effects, section 4)

if you have a current stomach ulcer or bleeding in your stomach or intestines

if you have serious liver disease

if you have serious kidney disease

if you are or could be pregnant or are breast-feeding (see ‘Pregnancy,

breast feeding, and fertility’)

if you are under 16 years of age

if you have inflammatory bowel disease, such as Crohn’s Disease, Ulcerative

Colitis, or Colitis

if you have high blood pressure that has not been controlled by treatment (check

with your doctor or nurse if you are not sure whether your blood pressure is

adequately controlled)

if your doctor has diagnosed heart problems including heart failure (moderate or

severe types), angina (chest pain)

if you have had a heart attack, bypass surgery, peripheral arterial disease (poor

circulation in legs or feet due to narrow or blocked arteries)

if you have had any kind of stroke (including mini-stroke, transient ischaemic

attack or TIA). Etoricoxib may slightly increase your risk of heart attack and stroke

and this is why it should not be used in those who have already had heart

problems or stroke.

If you think any of these are relevant to you, do not take the tablets until you have

consulted your doctor.

Warnings and precautions

Talk to your doctor or pharmacist before taking this medicine if:

You have a history of stomach bleeding or ulcers.

dehydrated,

example

prolonged

bout

vomiting

diarrhoea.

You have swelling due to fluid retention.

You have a history of heart failure, or any other form of heart disease.

You have a history of high blood pressure. Etoricoxib can increase blood pressure

in some people, especially in high doses, and your doctor will want to check your

blood pressure from time to time.

You have any history of liver or kidney disease.

You are being treated for an infection. Etoricoxib can mask or hide a fever, which

is a sign of infection.

You have diabetes, high cholesterol, or are a smoker. These can increase your

risk of heart disease.

You are a woman trying to become pregnant.

You are over 65 years of age.

If you are not sure if any of the above apply to you, talk to your doctor before taking

Etoricoxib to see if this medicine is suitable for you.

Etoricoxib works equally well in older and younger adult patients. If you are over 65

years of age, your doctor will want to appropriately keep a check on you. No dosage

adjustment is necessary for patients over 65 years of age.

Children and adolescents

Do not give this medicine to children and adolescents under 16 years of age.

Taking other medicines

Tell your doctor or pharmacist if you are taking, have recently taken or might take any

other medicines, including medicines obtained without a prescription.

In particular if you are taking any of the following medicines, your doctor may want to

monitor you to check that your medicines are working properly, once you start taking

Etoricoxib:

medicines that thin your blood (anticoagulants), such as warfarin

rifampicin (an antibiotic)

methotrexate (a drug used for suppressing the immune system, and often used in

rheumatoid arthritis)

ciclosporin or tacrolimus (drugs used for suppressing the immune system)

lithium (a medicine used to treat some types of depression)

medicines used to help control high blood pressure and heart failure called ACE

inhibitors and angiotensin receptor blockers, examples include enalapril and ramipril,

and losartan and valsartan

diuretics (water tablets)

digoxin (a medicine for heart failure and irregular heart rhythm)

minoxidil (a drug used to treat high blood pressure)

salbutamol tablets or oral solution (a medicine for asthma)

birth control pills (the combination may increase your risk of side effects)

hormone replacement therapy (the combination may increase your risk of side

effects)

aspirin, the risk of stomach ulcers is greater if you take Etoricoxib with aspirin.

aspirin for prevention of heart attacks or stroke:

Etoricoxib can be taken with low-dose aspirin. If you are currently taking low-dose

aspirin to prevent heart attacks or stroke, you should not stop taking aspirin until

you talk to your doctor.

aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs):

Do not take high dose aspirin or other anti-inflammatory medicines while taking

Etoricoxib.

Taking this medicine with food and drink

The onset of the effect of Etoricoxib may be faster when taken without food.

Pregnancy and breast-feeding

Pregnancy

Etoricoxib tablets must not be taken during pregnancy. If you are pregnant or think you

could be pregnant, or if you are planning to become pregnant, do not take the tablets.

If you become pregnant, stop taking the tablets and consult your doctor. Consult your

doctor if you are unsure or need more advice.

Breast-feeding

It is not known if Etoricoxib is excreted in human milk. If you are breast-feeding, or

planning to breast-feed, consult your doctor before taking Etoricoxib. If you are using

Etoricoxib, you must not breast-feed.

Fertility

Etoricoxibis not recommended in women attempting to become pregnant.

Driving and using machines

Dizziness and sleepiness have been reported in some patients taking Etoricoxib.

Do not drive if you experience dizziness or sleepiness.

Do not use any tools or machines if you experience dizziness or sleepiness.

This medicine contains lactose

If you have been told by your doctor that you have intolerance to some sugars,

contact your doctor before taking this medicine.

3. How to take this medicine

Always take this medicine exactly as your doctor or pharmacist has told you. Check

with your doctor or pharmacist if you are not sure.

Do not take more than the recommended dose for your condition. Your doctor will want

to discuss your treatment from time to time. It is important that you use the lowest dose

that controls your pain and you should not take Etoricoxib for longer than necessary.

This is because the risk of heart attacks and strokes might increase after prolonged

treatment, especially with high doses.

There are different strengths available for this medicinal product and depending on

your disease your doctor will prescribe the tablet strength that is appropriate for you.

The recommended dose is:

Osteoarthritis

The recommended dose is 30 mg once a day, increase to a maximum of 60 mg once

a day if needed.

XXXXXX

SAME SIZE ARTWORK

520 mm x 150 mm

Rheumatoid arthritis

The recommended dose is 60 mg once a day, increased to a maximum of 90 mg once

a day if needed.

Ankylosing spondylitis

The recommended dose is 60 mg once a day, increased to a maximum of 90 mg once

a day if needed.

Acute pain conditions

Etoricoxib should be used only for the acute painful period.

Gout

The recommended dose is 120 mg once a day which should only be used for the

acute painful period, limited to a maximum of 8 days treatment.

Postoperative dental surgery pain

The recommended dose is 90 mg once daily, limited to a maximum of 3 days

treatment

People with liver problems

If you have mild liver disease, you should not take more than 60 mg a day.

If you have moderate liver disease, you should not take more than 30 mg a day.

Use in children and adolescents

Etoricoxib tablets should not be taken by children or adolescents under 16 years of

age.

Elderly

No dose adjustment is necessary for elderly patients. As with other medicines,

caution should be exercised in elderly patients.

Method of administration

Etoricoxib is for oral use. Take the tablets once a day. Etoricoxib can be taken with or

without food.

If you take more of this medicine than you should

You should never take more tablets than the doctor recommends. If you do take too

many Etoricoxib tablets, you should seek medical attention immediately.

If you forget to take this medicine

If you forget to take a dose at the usual time, take it as soon as you remember, unless

it is time to take your next dose. Never take more than one dose per day.

Do not take a double dose to make up for a forgotten dose.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets

them.

If you develop any of these signs you should stop taking this medicine and

talk to your doctor immediately (see section 2):

shortness of breath, chest pains, or ankle swelling appear or if they get worse

yellowing of the skin and eyes (jaundice) – these are signs of liver problems

severe or continual stomach pain or your stools become black

an allergic reaction- which can include skin problems such as ulcers or blistering,

or swelling of the face, lips, tongue, or throat which may cause difficulty in

breathing

Very common (may affect more than 1 in 10 people)

stomach pain

Common (may affect up to 1 to 10 people)

dry socket (inflammation and pain after a tooth extraction)

swelling of the legs and/or feet due to fluid retention (oedema)

dizziness, headache

palpitations (fast or irregular heartbeat), irregular heart rhythm (arrhythmia)

increased blood pressure

wheezing or shortness of breath (bronchospasms)

constipation, wind (excessive gas), gastritis (inflammation of the lining of the

stomach), heartburn, diarrhoea, indigestion (dyspepsia)/stomach discomfort,

nausea, being sick (vomiting), inflammation of the oesophagus, mouth ulcers

changes in blood tests related to your liver

bruising

weakness and fatigue, flu-like illness

Uncommon (may affect up to 1 in 100 people)

gastroenteritis

(inflammation

gastrointestinal

tract

that

involves

both

stomach

small

intestine/stomach

flu),

upper

respiratory

infection, urinary tract infection

changes

laboratory

values

(decreased

number

blood

c e l l s ,

decreased number of white blood cells, platelets decreased)

hypersensitivity (an allergic reaction including hives which may be serious enough

to require immediate medical attention)

appetite increases or decreases, weight gain

anxiety, depression, decreases in mental sharpness; seeing, feeling or hearing

things that are not there (hallucinations)

taste alteration, inability to sleep, numbness or tingling, sleepiness

blurred vision, eye irritation and redness

ringing in the ears, vertigo (sensation of spinning while remaining still)

abnormal heart rhythm (atrial fibrillation), fast heart rate, heart failure, feeling of

tightness, pressure or heaviness in the chest (angina pectoris), heart attack

flushing, stroke, mini-stroke (transient ischaemic attack), severe increase in blood

pressure. inflammation of the blood vessels

cough, breathlessness, nose bleed

stomach or bowel bloating, changes in your bowel habits, dry mouth, stomach

ulcer, inflammation of the stomach lining that can become serious and may lead to

bleeding, irritable bowel syndrome, inflammation of the pancreas

swelling of the face, skin rash or itchy skin, redness of the skin

muscle cramp/spasm, muscle pain/stiffness

high levels of potassium in your blood, changes in blood or urine tests

relating to your kidney, serious kidney problems

chest pain

Rare (may affect up to 1 in 1,000 people)

angioedema (an allergic reaction with swelling of the face, lips, tongue and/or

throat which may cause difficulty in breathing or swallowing, which may be

serious enough to require immediate medical attention)/ anaphylactic/anaphylactoid

reactions including shock (a serious allergic reaction that requires immediate

medical attention)

confusion, restlessness

liver problems (hepatitis)

low blood levels of sodium

liver failure, yellowing of the skin and/or eyes (jaundice)

severe skin reactions

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any

possible side effects not listed in this leaflet. You can also report side effects directly in

the UK via: www.mhra.gov.uk/yellowcard. In Ireland via: HPRA Pharmacovigilance,

Earlsfort Terrace, IRL-Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website:

www.hpra.ie, e-mail:medasafety@hpra.ie. By reporting side effects you can help

provide more information on the safety of this medicine.

5. How to store this medicine

Keep this medicine out of the sight and reach of children.

This medicinal product does not require any special storage conditions.

Bottles: Use within 90 days of first opening.

Do not use this medicine after the expiry date which is stated on the carton after

EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste.

your

pharmacist

throw

away

medicines

longer

use. These measures will help protect the environment.

6. Contents of the pack and other information

What this medicine contains

The active substance is 30mg or 60mg or 90mg or 120mg of etoricoxib.

The tablet core contains calcium phosphate dibasic anhydrous, microcrystalline

cellulose, croscarmellose sodium, hydroxy propyl cellulose, magnesium stearate,

silica. The tablet coat contains hypromellose, lactose monohydrate, titanium dioxide

(E171), triacetin, indigo carmine aluminium lake (E132) (only in 30 mg, 60 mg and

120mg) and iron oxide yellow (E172) (only in 30 mg, 60 mg and 120mg).

What this medicine looks like and contents of the pack

30 mg: Bluish green, round, biconvex, film-coated tablets debossed with ‘443’ on

one side and ‘L’ on other side.

60 mg: Green, round, biconvex, film-coated tablets debossed with ‘444’ on one

side and ‘L’ on other side.

90 mg: White to off-white, round, biconvex, film-coated tablets debossed with ‘445’

on one side and ‘L’ on other side.

120 mg: Pale-green, round, biconvex, film-coated tablets debossed with ‘446’ on

one side and ‘L’ on other side.

This medicine is available in blister packs containing 2, 5, 7, 10, 14, 20, 28, 30,

49, 50, 84, 100 tablets or multi-packs containing 98 (2 packs of 49) tablets in

blisters or 30, 90 tablets in bottles. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Name and address:

Bristol Laboratories Ltd,

Unit 3, Canalside, Northbridge Road,

Berkhamsted, Hertfordshire, HP41EG, United Kingdom

Telephone: 0044 (0)1442 200922

F a x :

0044 (0)1442 873717

E-mail:

info@bristol-labs.co.uk

Etoricoxib 30 mg Film-coated Tablets: PL 17907/0574 & PA 1240/026/001

Etoricoxib 60 mg Film-coated Tablets: PL 17907/0575 & PA 1240/026/002

Etoricoxib 90 mg Film-coated Tablets: PL 17907/0576 & PA 1240/026/003

Etoricoxib 120 mg Film-coated Tablets: PL 17907/0577 & PA 1240/026/004

This leaflet was last revised in April 2017

To request a copy of this leaflet in Braille, large print or audio format, please contact the

marketing authorisation holder at the address (or telephone, fax, email) above.

XXXXXX

V6 20-04-17 D0

Read the complete document

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Etoricoxib 30 mg Film-Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 30 mg of etoricoxib.

Excipient with known effect: Also contains 0.84 mg of lactose monohydrate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Bluish green, round, biconvex, film-coated tablets debossed with ‘443’ on one side and ‘L’ on other side. The tablet

diameter is 6.00 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Etoricoxib is indicated in adults and adolescents 16 years of age and older for the symptomatic relief of osteoarthritis

(OA), rheumatoid arthritis (RA), ankylosing spondylitis, and the pain and signs of inflammation associated with acute

gouty arthritis.

Etoricoxib is indicated in adults and adolescents 16 years of age and older for the short-term treatment of moderate pain

associated with dental surgery.

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's

overall risks (see sections 4.3, 4.4).

4.2 Posology and method of administration

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

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

1

considered.

Acute pain conditions

For acute pain conditions, etoricoxib should be used only for the acute symptomatic period.

Acute gouty arthritis

The recommended dose is 120 mg once daily. In clinical trials for acute gouty arthritis, etoricoxib was given for 8 days.

Postoperative dental surgery pain

The recommended dose is 90 mg once daily, limited to a maximum of 3 days. Some patients may require other

postoperative analgesia in addition to etoricoxib during the three day treatment period.

Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not

been studied. Therefore:

The dose for OA should not exceed 60 mg daily.

The dose for RA and ankylosing spondylitis should not exceed 90 mg daily.

The dose for acute gout should not exceed 120 mg daily, limited to a maximum of 8 days treatment.

The dose for postoperative acute dental surgery pain should not exceed 90 mg daily, limited to a maximum of 3 days.

Special populations

Elderly patients

No dosage adjustment is necessary for elderly patients. As with other drugs, caution should be exercised in elderly

patients (see section 4.4).

Patients with hepatic impairment

Regardless of indication, in patients with mild hepatic dysfunction (Child-Pugh score 5-6) a dose of 60 mg once daily

should not be exceeded. In patients with moderate hepatic dysfunction (Child-Pugh score 7-9), regardless of indication,

the dose of 30 mg once daily should not be exceeded.

Clinical experience is limited particularly in patients with moderate hepatic dysfunction and caution is advised. There is

no clinical experience in patients with severe hepatic dysfunction (Child-Pugh score

10); therefore, its use is contra-

indicated in these patients (see sections 4.3, 4.4 and 5.2).

Patients with renal impairment

No dosage adjustment is necessary for patients with creatinine clearance

30 ml/min (see section 5.2). The use of

etoricoxib in patients with creatinine clearance <30 ml/min is contra-indicated (see sections 4.3 and 4.4).

Paediatric population

Etoricoxib is contra-indicated in children and adolescents under 16 years of age (see section 4.3).

Method of administration

Etoricoxib is administered orally and may be taken with or without food. The onset of the effect of the medicinal

product may be faster when Etoricoxib is administered without food. This should be considered when rapid

symptomatic relief is needed.

4.3 Contraindications

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).

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

2

Estimated renal creatinine clearance <30 ml/min.

Children and adolescents under 16 years of age.

Inflammatory bowel disease.

Congestive heart failure (NYHA II-IV).

Patients with hypertension whose blood pressure is persistently elevated above 140/90mmHg and has not been

adequately controlled.

Established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

4.4 Special warnings and precautions for use

Gastrointestinal effects

Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in fatal

outcome, have occurred in patients treated with etoricoxib.

Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs;

the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly or patients with a prior history of

gastrointestinal disease, such as ulceration and GI bleeding.

There is a further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other

gastrointestinal complications) when etoricoxib is taken concomitantly with acetylsalicylic acid (even at low doses). A

significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs +

acetylsalicylic acid has not been demonstrated in long-term clinical trials (see section 5.1).

Cardiovascular effects

Clinical trials suggest that the selective COX-2 inhibitor class of drugs may be associated with a risk of thrombotic

events (especially myocardial infarction (MI) and stroke), relative to placebo and some NSAIDs. As the cardiovascular

risks of etoricoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest

effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-

evaluated periodically, especially in patients with osteoarthritis (see sections 4.2, 4.3, 4.8 and 5.1).

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus,

smoking) should only be treated with etoricoxib after careful consideration (see section 5.1).

COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-

embolic diseases because of their lack of antiplatelet effect. Therefore antiplatelet therapies should not be discontinued

(see sections above, 4.5 and 5.1.).

Renal effects

Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions

of compromised renal perfusion, administration of etoricoxib may cause a reduction in prostaglandin formation and,

secondarily, in renal blood flow, and thereby impair renal function. Patients at greatest risk of this response are those

with pre-existing significantly impaired renal function, uncompensated heart failure, or cirrhosis. Monitoring of renal

function in such patients should be considered.

Fluid retention, oedema and hypertension

As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention, oedema and hypertension

have been observed in patients taking etoricoxib. All Nonsteroidal Anti-inflammatory Drugs (NSAIDs), including

etoricoxib, can be associated with new onset or recurrent congestive heart failure. For information regarding a dose

related response for etoricoxib see section 5.1. Caution should be exercised in patients with a history of cardiac failure,

left ventricular dysfunction, or hypertension and in patients with pre-existing oedema from any other reason. If there is

clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of

etoricoxib should be taken.

Etoricoxib may be associated with more frequent and severe hypertension than some other NSAIDs and selective

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

3

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).

Important information regarding the ingredients of this medicine

This medicine contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total

lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Oral anticoagulants: In subjects stabilised on chronic warfarin therapy, the administration of etoricoxib 120 mg daily

was associated with an approximate 13% increase in prothrombin time International Normalised Ratio (INR).

Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR,

particularly in the first few days when therapy with etoricoxib is initiated or the dose of etoricoxib is changed (see

section 4.4).

Diuretics, ACE inhibitors and Angiotensin II Antagonists: NSAIDs may reduce the effect of diuretics and other

antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients

with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents

that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure,

which is usually reversible. These interactions should be considered in patients taking etoricoxib concomitantly with

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

4

ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution,

especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of

renal function after initiation of concomitant therapy, and periodically thereafter.

Acetylsalicylic Acid: In a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had no effect on the

anti-platelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used concomitantly with

acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant

administration of low-dose acetylsalicylic acid with etoricoxib may result in an increased rate of GI ulceration or other

complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib with doses of

acetylsalicylic acid above those for cardiovascular prophylaxis or with other NSAIDs is not recommended (see sections

5.1 and 4.4.).

Ciclosporin and tacrolimus: Although this interaction has not been studied with etoricoxib, coadministration of

ciclosporin or tacrolimus with any NSAID may increase the nephrotoxic effect of ciclosporin or tacrolimus. Renal

function should be monitored when etoricoxib and either of these drugs is used in combination.

Pharmacokinetic interactions

The effect of etoricoxib on the pharmacokinetics of other drugs

Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor

blood lithium closely and adjust the lithium dosage while the combination is being taken and when the NSAID is

withdrawn.

Methotrexate: Two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once daily for seven

days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60

and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. In one study, etoricoxib 120 mg had

no effect, but in the other study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28% and reduced

renal clearance of methotrexate by 13%. Adequate monitoring for methotrexate-related toxicity is recommended when

etoricoxib and methotrexate are administered concomitantly.

Oral contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 micrograms

ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady state AUC0-24hr of EE by 37%.

Etoricoxib 120 mg given with the same oral contraceptive concomitantly or separated by 12 hours increased the steady

state AUC0-24hr of EE by 50 to 60%. This increase in EE concentration should be considered when selecting an oral

contraceptive for use with etoricoxib. An increase in EE exposure can increase the incidence of adverse events

associated with oral contraceptives (e.g., venous thrombo-embolic events in women at risk).

Hormone Replacement Therapy (HRT): Administration of etoricoxib 120 mg with hormone replacement therapy

consisting of conjugated estrogens (0.625 mg PREMARINTM) for 28 days, increased the mean steady state AUC0-

24hr of unconjugated estrone (41%), equilin (76%), and 17-

-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

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

5

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.

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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

operating machinery.

4.8 Undesirable effects

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

6

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):

Table 1:

System Organ Class

Adverse Reactions

Frequency Category*

Infections and infestations

Alveolar osteitis

Common

Gastroenteritis, upper respiratory

infection, urinary tract infection

Uncommon

Blood and lymphatic system

disorders

Anaemia (primarily associated with

gastrointestinal bleeding) Leukopenia,

thrombocytopenia

Uncommon

Immune system disorders

Hypersensitivity

Uncommon

Angioedema/ anaphylactic/

anaphylactoid reactions including

shock

Rare

Metabolism and nutrition disorders

Oedema/ fluid retention

Common

Appetite increase or decrease, weight

gain

Uncommon

Psychiatric disorders

Anxiety, depression, mental acuity

decreased, hallucinations

Uncommon

confusions

, restlessness

Rare

Nervous system disorders

Dizziness, headache

Common

Dysgeusia, insomnia, paresthaesia/

hypaesthesia, somlnolence

Uncommon

Eye disorders

Blurred vision, conjunctivitis

Uncommon

Ear and labyrinth disorders

Tinnitus, vertigo

Uncommon

Cardiac disorders

Palpitations, arrhythmia

Common

Atrial fibrillation, tachycardia

congestive heart failure, no specific

ECG changes, angina pectoris

myocardial infarction

Uncommon

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

7

Vascular disorders

Hypertension

Common

Flushing, cerebrovascular accident

transient ischaemic attack,

hypertensive crisis

, vasculitis

Uncommon

Respiratory, thoracic and

mediastinal disorders

bronchospasm

Common

Cough, dyspnoea, epistaxis

Uncommon

Gastrointestinal disorders

Abdominal pain

Very common

Constipation, flatulence, gastritis,

heartburn/acid reflux, diarrhoea,

dyspepsia/ epigastric discomfort,

nausea, vomiting, oesophagitis, oral

ulcer

Common

Abdominal distension, bowel

movement pattern change, dry mouth,

gastroduodenal ulcer, peptic ulcers

including gastrointestinal perforation

and bleeding, irritable bowel

syndrome, pancreatitis

Uncommon

Hepatobiliary disorders

ALT increased, AST increased

Common

hepatitis

Rare

Hepatic failure

, jaundice

Rare

Skin and subcutaneous tissue

disorders

ecchymosis

Common

facial oedema, pruritus, rash,

erythema

, urticaria

Uncommon

Stevens-Johnson syndrome

, toxic

epidermal necrolysis

, fixed drug

eruption

Rare

Musculoskeletal and connective

tissue disorders

Muscular cramp/spasm,

musculoskeletal pain/ stiffness

Uncommon

Renal and urinary disorders

Proteinuria, serum creatinine

increased, renal failure/ renal

insufficiency

(see section 4.4)

Uncommon

General disorders and

administration site conditions

Asthenia/ fatigue, flu-like disease

Common

Chest pain

Uncommon

Investigations

Blood urea nitrogen increased,

creatine phosphokinase increased,

hyperkalemia, uric acid increased

Uncommon

Blood sodium decreased

Rare

*Frequency Category: Defined for each Adverse Experience Term by the incidence reported in the clinical trials data

base: Very Common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1000 to <1/100), Rare (>1/10,000 to

<1/1000), Very Rare (<1/10,000).

This adverse reaction was identified through post-marketing surveillance. Its reported frequency has been estimated

based upon the highest frequency observed across clinical trial data pooled by indication and approved dose.

The frequency category of “Rare” was defined per the Summary of Product Characteristics(SmPC) guidance (rev.

2, Sept 2009) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number

of subjects treated with etoricoxib in the analysis of the Phase III data pooled by dose and indication (n=15,470).

Hypersensitivity includes the terms "allergy", "drug allergy", "drug hypersensitivity", "hypersensitivity",

"hypersensitivity NOS", "hypersensitivity reaction" and "nonspecific allergy".

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

8

The following serious undesirable effects have been reported in association with the use of NSAIDs and cannot be

ruled out for etoricoxib: nephrotoxicity including interstitial nephritis and nephrotic syndrome

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal

product

is important.

allows continued

monitoring of

the benefit/risk balance of

the medicinal

product.

Healthcare professionals are asked to report

suspected adverse reactions via the HPRA website: www.hpra.ie or email to: medsafety@hpra.ie.

4.9 Overdose

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 over dosage 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, cardio renal 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, non-steroids, coxibs, ATC code:

M01AH05

Mechanism of action

Etoricoxib is an oral, selective cyclo-oxygenase-2 (COX-2) inhibitor within the clinical dose range.

Across clinical pharmacology studies, etoricoxib produced dose-dependent inhibition of COX-2 without inhibition of

COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit gastric prostaglandin synthesis and had no effect on

platelet function. Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2,

have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by 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.

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).

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

9

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 7111 OA patients treated with a dose of etoricoxib 90 mg daily (1.5 times the dose recommended for

OA) or diclofenac 150 mg daily for a mean period of 9.1 months (maximum 16.6 months, median 11.4 months). The

EDGE II study included 4086 RA patients treated with etoricoxib 90 mg daily or diclofenac 150 mg daily for a mean

period of 19.2 months (maximum 33.1 months, median 24 months).

In the pooled MEDAL Programme, 34,701 patients with OA or RA were treated for a mean duration of 17.9 months

(maximum 42.3 months, median 16.3 months) with approximately 12,800 patients receiving treatment for more than 24

months. Patients enrolled in the Programme had a wide range of cardiovascular and gastrointestinal risk factors at

baseline. Patients with a recent history of myocardial infarction, coronary artery bypass grafting or percutaneous

coronary intervention within 6 months preceding enrolment were excluded. Use of gastro protective 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.

Cardio renal 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

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

1

0

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 analysed 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.

Cardio renal Events

Approximately 50% of patients enrolled in the MEDAL study had a history of hypertension at baseline. In the study,

the incidence of discontinuations due to hypertension-related adverse events was statistically significantly higher for

etoricoxib than for diclofenac. The incidence of congestive heart failure adverse events (discontinuations and serious

events) occurred at similar rates on etoricoxib 60 mg compared to diclofenac 150 mg but was higher for etoricoxib 90

mg compared to diclofenac 150 mg (statistically significant for 90 mg etoricoxib vs. 150 mg diclofenac in MEDAL OA

cohort). The incidence of confirmed congestive heart failure adverse events (events that were serious and resulted in

hospitalisation or a visit to an emergency department) was non-significantly higher with etoricoxib than diclofenac 150

mg, and this effect was dose-dependent. The incidence of discontinuations due to edema-related adverse events was

higher for etoricoxib than diclofenac 150 mg, and this effect was dose-dependent (statistically significant for etoricoxib

90 mg, but not for etoricoxib 60 mg).

Table 2: Rates of confirmed Thrombotic CV events (Pooled MEDAL

programme)

Etoricoxib

(N=16819)

25836 Patient-

years

Diclofenac

(N=16483)

24766 Patient

Years

Between

Treatment

comparison

Rate

+

(95% CI)

Rate

+

(95% CI)

Relative risk (95%

CI)

Confirmed Thrombotic Cardiovascular Serious Adverse Event

Per- protocol

1.24 (1.11, 1.38)

1.30 (1.17, 1.45)

0.95 (0.81, 1.11)

Intent-to treat

1.25 (1.14, 1.36)

1.19 (1.08, 1.30)

1.05 (0.93, 1.19)

Confirmed Cardiac Events

Per- protocol

0.71 (0.61, 0.82)

0.78 (0.68, 0.90)

0.90 (0.74, 1.10)

Intent-to treat

0.69 (0.61, 0.78)

0.70 (0.62, 0.79)

0.99 (0.84, 1.17)

Confirmed Cerebrovascular Events

Per- protocol

0.34 (0.28, 0.42)

0.32 (0.25, 0.40)

1.08 (0.80, 1.46)

Intent-to treat

0.33 (0.28, 0.39)

0.29 (0.24, 0.35)

1.12 (0.87, 1.44)

Confirmed Peripheral Vascular Events

Per- protocol

0.20 (0.15, 0.27)

0.22 (0.17, 0.29)

0.92 (0.63, 1.35)

Intent-to treat

0.24 (0.20, 0.30)

0.23 (0.18, 0.28)

1.08 (0.81, 1.44)

Events per 100 Patient-Years; CI=confidence interval

N=total number of patients included in Per-protocol population

Per-protocol: all events on study therapy or within 14 days of discontinuation

(excluded: patients who took < 75% of their study medication or took non-study

NSAIDs >10% of the time).

Intent-to-treat: all confirmed events up to the end of the trial (included patients

potentially exposed to non-study interventions following discontinuation of

study medication). Total number of patients randomised, n= 17412 on etoricoxib

and 17289 on diclofenac.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

1

1

The cardio renal 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 nonserious.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

1

2

Additional Thrombotic Cardiovascular Safety Data

In clinical studies excluding the MEDAL Programme Studies, approximately 3100 patients were treated with

etoricoxib

60 mg daily for 12 weeks or longer. There was no discernible difference in the rate of confirmed serious

thrombotic cardiovascular events between patients receiving etoricoxib

60 mg, placebo, or non-naproxen NSAIDs.

However, the rate of these events was higher in patients receiving etoricoxib compared with those receiving naproxen

500 mg twice daily. The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and selective

COX-2 inhibitors may be of clinical significance in patients at risk of thrombo-embolic events. Selective COX-2

inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet

thromboxane. The clinical relevance of these observations has not been established.

Additional Gastrointestinal Safety Data

In two 12-week double-blind endoscopy studies, the cumulative incidence of gastroduodenal ulceration was

significantly lower in patients treated with etoricoxib 120 mg once daily than in patients treated with either naproxen

500 mg twice daily or ibuprofen 800 mg three times daily. Etoricoxib had a higher incidence of ulceration as compared

to placebo.

Renal Function Study in the Elderly

A randomized, double-blind, placebo-controlled, parallel-group study evaluated the effects of 15 days of treatment of

etoricoxib (90 mg), celecoxib (200 mg bid), naproxen (500 mg bid) and placebo on urinary sodium excretion, blood

pressure, and other renal function parameters in subjects 60 to 85 years of age on a 200-mEq/day sodium diet.

Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion over the 2 weeks of treatment. All

active comparators showed an increase relative to placebo with respect to systolic blood pressures; however, etoricoxib

was associated with a statistically significant increase at Day 14 when compared to celecoxib and naproxen (mean

change from baseline for systolic blood pressure: etoricoxib 7.7 mmHg, celecoxib 2.4 mmHg, naproxen 3.6 mmHg).

5.2 Pharmacokinetic properties

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 µghr/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 120 l in humans.

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

Biotransformation

Etoricoxib is extensively metabolised with <1% of a dose recovered in urine as the parent drug. The major route of

metabolism to form the 6'-hydroxymethyl derivative is catalyzed by CYP enzymes. CYP3A4 appears to contribute to

the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can

catalyse the main metabolic pathway, but their quantitative roles in vivo have not been studied.

Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid derivative of etoricoxib

formed by further oxidation of the 6'-hydroxymethyl derivative. These principal metabolites either demonstrate no

measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.

Elimination

Following administration of a single 25-mg radiolabeled intravenous dose of etoricoxib to healthy subjects, 70% of

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

1

3

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 is 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).

5.3 Preclinical safety data

In preclinical studies, etoricoxib has been demonstrated not to be genotoxic. Etoricoxib was not carcinogenic in mice.

Rats developed hepatocellular and thyroid follicular cell adenomas at >2-times the daily human dose [90 mg] based on

systemic exposure when dosed daily for approximately two years. Hepatocellular and thyroid follicular cell adenomas

observed in rats are considered to be a consequence of rat-specific mechanism related to hepatic CYP enzyme

induction. Etoricoxib has not been shown to cause hepatic CYP3A enzyme induction in humans.

In the rat, gastrointestinal toxicity of etoricoxib increased with dose and exposure time. In the 14-week toxicity study

etoricoxib caused gastrointestinal ulcers at exposures greater than those seen in man at the therapeutic dose. In the 53-

and 106-week toxicity study, gastrointestinal ulcers were also seen at exposures comparable to those seen in man at the

therapeutic dose. In dogs, renal and gastrointestinal abnormalities were seen at high exposures.

Etoricoxib was not teratogenic in reproductive toxicity studies conducted in rats at 15 mg/kg/day (this represents

approximately 1.5 times the daily human dose [90 mg] based on systemic exposure). In rabbits, a treatment related

increase in cardiovascular malformations was observed at exposure levels below the clinical exposure at the daily

human dose (90mg). However no treatment-related external or skeletal foetal malformations were observed. In rats and

rabbits, there was a dose dependent increase in post implantation loss at exposures greater than or equal to 1.5 times the

human exposure (see sections 4.3 and 4.6).

Etoricoxib is excreted in the milk of lactating rats at concentrations approximately two-fold those in plasma. There was

a decrease in pup body weight following exposure of pups to milk from dams administered etoricoxib during lactation.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

1

4

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Calcium phosphate dibasic anhydrous

Microcrystalline cellulose

Croscarmellose sodium

Hydroxy propyl cellulose

Magnesium stearate

Silica

Tablet coat

Hypromellose

Lactose monohydrate

Titanium dioxide (E171)

Triacetin

Indigo Carmine Aluminium Lake (E132)

Iron Oxide Yellow (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

Bottles: Use within 90 days of first opening

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

OPA/Alu/PVC-Alu blister or PVC/PVDC blister or Triplex (PVC/PE/PVDC) packs containing 2, 5, 7, 10, 14, 20, 28,

30, 49, 50, 84, 100 tablets or multipacks containing 98 (2 packs of 49) tablets.

OPA/Alu/PVC-Alu blisters (unit doses) in packs of 5, 50 or 100 tablets.

White opaque HDPE round bottle sealed with induction seal & with white polypropylene screw cap containing 30 and

90 tablets and two 1-gram desiccant containers.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

1

5

7 MARKETING AUTHORISATION HOLDER

Bristol Laboratories Ltd.

Unit 3, Canalside

Northbridge Road

Berkhamsted HP4 1EG

8 MARKETING AUTHORISATION NUMBER

PA1240/026/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16

June 2017

10 DATE OF REVISION OF THE TEXT

March 2018

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

2

3

/

0

3

/

2

0

1

8

C

R

N

2

2

0

1

8

7

5

p

a

g

e

n

u

m

b

e

r

:

1

6

Similar products

Search alerts related to this product

View documents history

Share this information