ARCOXIA 60 MG TABLETS

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
ETORICOXIB
Available from:
MERCK SHARP & DOHME ISRAEL LTD
ATC code:
M01AH05
Pharmaceutical form:
TABLETS
Composition:
ETORICOXIB 60 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
MERCK SHARP & DOHME CORP., USA
Therapeutic group:
ETORICOXIB
Therapeutic area:
ETORICOXIB
Therapeutic indications:
Arcoxia 60 mg tablets are indicated for the symptomatic relief of osteoarthritis (OA), rheumatoid arthritis (RA) and ankylosing spondylitis.
Authorization number:
129 42 30786 11
Authorization date:
2013-10-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

17-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

04-09-2017

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS REGULATIONS

(PREPARATIONS) 1986

This medicine can be sold under doctor's prescription only

ARCOXIA

®

ARCOXIA

®

ARCOXIA

®

ARCOXIA

®

30 mg

60 mg

90 mg

120 mg

Tablets Tablets Tablets

Tablets

Each tablet contains:

Etoricoxib 30 mg

Etoricoxib 60 mg

Etoricoxib 90 mg

Etoricoxib 120 mg

For a list of inactive ingredients please refer to section 6.

Read all of this leaflet carefully before you start using this medicine.

This leaflet contains concise information about ARCOXIA. If you have any further questions, ask your

doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their

ailment seems similar to yours.

This medicine is not intended for children and adolescents under 16 years of age.

1. WHAT ARCOXIA IS AND WHAT IT IS USED FOR?

1.1 What is ARCOXIA?

THERAPEUTIC GROUP: ARCOXIA 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).

1.2 What is ARCOXIA used for?

ARCOXIA 30 mg helps to reduce the pain and swelling (inflammation) in the joints and muscles of people

who suffer from osteoarthrirtis.

ARCOXIA 60 mg helps to reduce the pain and swelling (inflammation) in the joints and muscles of people

who suffer from osteoarthrirtis, rheumatoid arthritis and ankylosing spondylitis.

ARCOXIA 90 mg helps to reduce the pain and swelling (inflammation) in the joints and muscles of people

who suffer from rheumatoid arthritis and ankylosing spondylitis. ARCOXIA 90 mg is also used for the short

term treatment of moderate pain after dental surgery.

ARCOXIA 120 mg helps to reduce the pain and swelling (inflammation) in the joints and muscles of people

who suffer from gout.

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 of the joints. It is

caused by deposits of mineral crystals in the joints.

What is ankylosing spondylitis?

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

2. BEFORE YOU TAKE ARCOXIA

2.1 Do not take ARCOXIA if you:

are allergic (hypersensitive) to etoricoxib or any of the other ingredients of this medicine ( detailed

in section 6)

are allergic to non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and COX-2

inhibitors (see "Side Effects”, section 4)

have a current stomach ulcer or bleeding in your stomach or intestines.

have serious liver disease

have serious kidney disease

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

fertility”, section 2.5)

are under 16 years of age

have inflammatory bowel disease, such as Crohn’s Disease, Ulcerative Colitis, or Colitis

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)

you suffer from heart problems including heart failure (moderate or severe) , angina (chest pain)

you suffer from ischemic heart disease, have had a heart attack or bypass surgery or peripheral

vascular disease (poor circulation in the legs or feet due to narrowing or blocked arteries)

you have had any kind of stroke (including mini-stroke, transient ischaemic attack or TIA).

Etoricoxib may slightly increase the risk of heart attack and stroke and this is why it should not be

used in patients 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.

2.2 Special warnings concerning use of ARCOXIA

Talk to your doctor or pharmacist before taking ARCOXIA if:

You have a history of stomach bleeding or ulcers.

You are dehydrated, for example by a prolonged bout of vomiting or 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. ARCOXIA 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 a history of liver or kidney disease.

You are being treated for an infection. ARCOXIA 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 ARCOXIA to see if

this medicine is suitable for you.

ARCOXIA 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.

2.3 Taking other medicines

If you are taking or have recently taken other medicines, including non-prescription medicines and

nutritional supplements, you should inform the attending doctor or pharmacist.

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, after starting the treatment with ARCOXIA:

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 treat high blood pressure and heart failure called ACE inhibitors and

angiotensin receptor blockers, examples include enalapril, ramipril, 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 ARCOXIA with aspirin.

aspirin for prevention of heart attacks or stroke:

ARCOXIA can be taken with low-dosages of aspirin. If you are currently taking a low-dose of

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 ARCOXIA.

2.4 Taking ARCOXIA with food and drink

ARCOXIA tablets may be taken with or without food. The onset of the effect of ARCOXIA may be faster

when taken without food.

2.5 Pregnancy, breast-feeding and fertility

Pregnancy

ARCOXIA 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

them and consult your doctor. Consult your doctor if you are unsure or need more advice.

Breast-feeding

It is not known if ARCOXIA is excreted in human milk. If you are breast-feeding, or planning to breast-feed,

consult your doctor before taking ARCOXIA. If you are using ARCOXIA, you must not breast-feed.

Fertility

ARCOXIA is not recommended in women attempting to become pregnant.

2.6 Driving and using machines

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

Do not drive if you experience dizziness or sleepiness.

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

2.7 Important information about some of the ingredients of ARCOXIA

ARCOXIA contains lactose. If you have been told by your doctor that you are unable to tolerate some

sugars, contact your doctor before taking this medicinal product.

2.8 Children and adolescents

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

3. HOW DO YOU USE ARCOXIA?

Always take ARCOXIA exactly as your doctor has told you. You should check with your doctor or

pharmacist if you are not sure.

The dosage and treatment will only be determined by the physician.

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 ARCOXIA 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 usually recommended dosage is:

Osteoarthritis

The recommended dosage is 30 mg once a day, may be increased to a maximum of 60 mg once a day if

needed.

Rheumatoid arthritis

The recommended dosage is 60 mg once a day, may be increased to a maximum of 90 mg once a day if

needed.

Ankylosing spondylitis

The recommended dosage is 60 mg once a day, may be increased to a maximum of 90 mg once a day if

needed.

For acute gouty arthritis and postoperative dental surgery pain, etoricoxib should be used only for the acute

symptomatic period.

Gout

The recommended dosage is 120 mg once a day, which should only be used in the acute period of the

pain, limited to a maximum of 8 days treatment.

Postoperative dental surgery pain

The recommended dosage 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.

Do not exceed the recommended dose.

Use in children and adolescents

ARCOXIA should not be given to children or adolescents under 16 years of age.

Elderly

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

exercised in elderly patients.

Method of administration

ARCOXIA is for oral use. Take the tablets once a day. ARCOXIA can be taken with or without food.

Swallow the medicine with a small amount of water.

No information is available with regards to crushing/splitting/chewing the tablets.

If you take more ARCOXIA than you should

You should never take more tablets than the doctor has recommended. If you do take too many ARCOXIA

tablets, you should seek medical attention immediately.

If you have taken an overdose, or if a child has accidentally swallowed the medicine, proceed immediately

to a hospital emergency room and bring the package of the medicine with you.

If you forgot to take ARCOXIA

It is important to take ARCOXIA as your doctor has prescribed. If you missed a dose, take the next tablet

at the regular time the following day. Do not take a double dose to make up for the forgotten tablet.

Complete the full course of treatment as instructed by the doctor.

Even if there is an improvement in your health, do not discontinue use of this medicine before consulting

your doctor.

Do not take medicines in the dark! Check the label and the dose each time you take your medicine. Wear

glasses if you need them.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. SIDE EFFECTS

Like all medicines, ARCOXIA can cause side effects, in some of the users.

Do not be alarmed by reading the list of side effects, you may not suffer from any of them.

If you develop any of these signs you should stop ARCOXIA and talk to your doctor immediately

(see “Before you take ARCOXIA”, 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

The frequency of possible side effects listed below is defined using the following convention:

Very common (affects more than 1 user in 10)

Common (affects 1 to 10 users in 100)

Uncommon (affects 1 to 10 users in 1,000)

Rare (affects 1 to 10 users in 10,000)

Very rare (affects less than 1 user in 10,000)

The following side effects can occur during treatment with ARCOXIA:

Very Common

stomach pain

Common:

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 (arrythmia)

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:

gastroenteritis (inflammation of the gastrointestinal tract that involves both the stomach and small

intestine/stomach flu), upper respiratory infection, urinary tract infection

changes in laboratory values (decreased number of red blood cells, 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 kidneys,

serious kidney problems

chest pain

Rare:

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

cause difficulty in breathing or swallowing, and 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

If a side effect appears, if any of the side effects gets serious or if you notice a side effect not mentioned in

this leaflet, consult the doctor.

Side effects can be reported to the Ministry of Health by using the link "Reporting side effects due to

medicinal treatment" at the home page of the Ministry of Health's web site (www.health.gov.il

) which refers

to the online side effects reporting form, or by using the link:

https://sideeffects.health.gov.il

5. HOW TO STORE ARCOXIA?

Avoid Poisoning! This medicine, as all other medicines, must be stored in a safe place out of the reach and

sight of children and/or infants, in order to avoid poisoning. Do not induce vomiting unless explicitly

instructed to do so by a doctor!

Do not use ARCOXIA after the expiry date (exp. date) which is stated on pack. The expiry date refers to the

last day of the indicated month.

Store below 30°C. Store in the original package in order to protect from moisture.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to

dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

6.1 What ARCOXIA contains

The active substance is etoricoxib. Each film coated tablet contains 30, 60, 90 or 120 mg of etoricoxib.

The other ingredients are:

Core: microcrystalline cellulose, calcium hydrogen phosphate (anhydrous), croscarmellose sodium,

magnesium stearate.

Tablet coating: carnauba wax, lactose monohydrate, hypromellose, titanium dioxide, glycerol triacetate.

ARCOXIA 30, 60 and 120 mg tablets also contain:

Iron oxide yellow and indigo carmine lake (E132 colouring agent).

ARCOXIA tablets contain lactose:

ARCOXIA 30 mg tablets contain 1.3 mg of lactose (as lactose monohydrate).

ARCOXIA 60 mg tablets contain 2.7 mg of lactose (as lactose monohydrate).

ARCOXIA 90 mg tablets contain 4.0 mg of lactose (as lactose monohydrate).

ARCOXIA 120 mg tablets contain 5.3 mg of lactose (as lactose monohydrate).

6.2 What ARCOXIA looks like and contents of the pack

ARCOXIA tablets are available in four strengths:

ARCOXIA 30 mg blue-green, apple-shaped, biconvex film coated tablets marked ‘ACX 30’ on one side and

‘101’ on the other.

ARCOXIA 60 mg dark green, apple-shaped, biconvex film coated tablets marked ‘ARCOXIA 60’ on one

side and ‘200’ on the other.

ARCOXIA 90 mg white, apple-shaped, biconvex film coated tablets marked ‘ARCOXIA 90’ on one side and

‘202’ on the other.

ARCOXIA 120 mg pale-green, apple-shaped, biconvex film coated tablets marked ‘ARCOXIA 120’ on one

side and ‘204’ on the other.

Pack sizes:

30 mg: Pack sizes of 2, 7, 28 tablets in blisters.

60, 90, 120 mg: Pack sizes of 2, 5, 7, 10, 14, 30 tablets in blisters.

Not all pack sizes may be marketed.

Manufacturer:

Arcoxia 60 mg, 90 mg and 120 mg tablets: Merck Sharp & Dohme Corp., NJ, USA.

Arcoxia 30 mg tablets: Merck Sharp & Dohme B.V. Haarlem, Holland.

Marketing authorization holder:

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121, Petah-Tikva 49170.

Revised on August 2020.

Drug registration no. listed in the official registry of the Ministry of Health:

ARCOXIA 30 mg Tablets:

141.86.31986

ARCOXIA 60 mg Tablets:

129.42.30786

ARCOXIA 90 mg Tablets:

129.43.30787

ARCOXIA 120 mg Tablets:

129.44.30788

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

ARCOXIA

®

30 mg Tablets

ARCOXIA

®

60 mg Tablets

ARCOXIA

®

90 mg Tablets

ARCOXIA

®

120 mg Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 30, 60, 90 or 120 mg of etoricoxib.

Excipients with known effect:

30 mg tablet: 1.3 mg lactose (as monohydrate)

60 mg tablet: 2.7 mg lactose (as monohydrate)

90 mg tablet: 4.0 mg lactose (as monohydrate)

120 mg tablet: 5.3 mg lactose (as monohydrate)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablets (tablets).

30 mg tablets: Blue-green, apple-shaped biconvex tablets debossed ‘101’ on one side and

‘ACX 30’ on the other side.

60 mg tablets: Dark green, apple-shaped, biconvex tablets debossed ‘200’ on one side

and ‘ARCOXIA 60’ on the other side.

90 mg tablets: White, apple-shaped, biconvex tablets debossed ‘202’ on one side and

‘ARCOXIA 90’ on the other side.

120 mg tablets: Pale-green, apple-shaped, biconvex tablets debossed ‘204’ on one side

and ‘ARCOXIA 120’ on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

ARCOXIA

30 mg

for the symptomatic relief of osteoarthritis (OA).

ARCOXIA

60 mg

for the symptomatic relief of osteoarthritis (OA), rheumatoid arthritis (RA) and ankylosing

spondylitis (AS).

ARCOXIA

90 mg

for the symptomatic relief of rheumatoid arthritis (RA) and ankylosing spondylitis (AS).

For the short-term treatment of moderate pain associated with dental surgery.

ARCOXIA

120 mg

for the symptomatic relief of the pain and signs of inflammation associated with acute

gouty arthritis.

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

considered.

For acute gouty arthritis and postoperative dental surgery pain, 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 ARCOXIA 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

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

effect of the medicinal product may be faster when ARCOXIA 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).

Estimated renal creatinine clearance <30 ml/min.

Children and adolescents under 16 years of age.

Inflammatory bowel disease.

Congestive heart failure (NYHA II-IV).

Patients with hypertension whose blood pressure is persistently elevated above

140/90 mmHg and has not been adequately controlled.

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

cerebrovascular disease.

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 Antiinflammatory Drugs (NSAIDs), including etoricoxib, can be associated

with new onset or recurrent congestive heart failure.

For information regarding a dose related response for etoricoxib see section 5.1. Caution

should be exercised in patients with a history of cardiac failure, left ventricular dysfunction,

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

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

including discontinuation of etoricoxib should be taken.

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

other NSAIDs and selective COX-2 inhibitors, particularly at high doses. Therefore,

hypertension should be controlled before treatment with etoricoxib (see section 4.3) and

special attention should be paid to blood pressure monitoring during treatment with

etoricoxib. Blood pressure should be monitored within two weeks after initiation of

treatment and periodically thereafter. If blood pressure rises significantly, alternative

treatment should be considered.

Hepatic effects

Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)

(approximately three or more times the upper limit of normal) have been reported in

approximately 1% of patients in clinical trials treated for up to one year with etoricoxib 30,

60 and 90 mg daily.

Any patients with symptoms and/or signs suggesting liver dysfunction, or in whom an

abnormal liver function test has occurred, should be monitored. If signs of hepatic

insufficiency occur, or if persistently abnormal liver function tests (three times the upper

limit of normal) are detected, etoricoxib should be discontinued.

General

If during treatment, patients deteriorate in any of the organ system functions described

above, appropriate measures should be taken and discontinuation of etoricoxib therapy

should be considered. Medically appropriate supervision should be maintained when using

etoricoxib in the elderly and in patients with renal, hepatic, or cardiac dysfunction.

Caution should be used when initiating treatment with etoricoxib in patients with

dehydration. It is advisable to rehydrate patients prior to starting therapy with etoricoxib.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-

Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in

association with the use of NSAIDs and some selective COX-2 inhibitors during post-

marketing surveillance (see section 4.8). Patients appear to be at highest risk for these

reactions early in the course of therapy with the onset of the reaction occurring in the

majority of cases within the first month of treatment. Serious hypersensitivity reactions

(such as anaphylaxis and angioedema) have been reported in patients receiving etoricoxib

(see section 4.8). Some selective COX-2 inhibitors have been associated with an

increased risk of skin reactions in patients with a history of any drug allergy. Etoricoxib

should be discontinued at the first appearance of skin rash, mucosal lesions, or any other

sign of hypersensitivity.

Etoricoxib may mask fever and other signs of inflammation.

Caution should be exercised when co-administering etoricoxib with warfarin or other oral

anticoagulants (see section 4.5).

The use of etoricoxib, as with any medicinal product known to inhibit cyclooxygenase /

prostaglandin synthesis, is not recommended in women attempting to conceive (see

sections 4.6, 5.1, and 5.3).

ARCOXIA tablets contain lactose. Patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not

take this medicine.

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 ACE inhibitors or angiotensin II antagonists.

Therefore, the combination should be administered with caution, especially in the elderly.

Patients should be adequately hydrated and consideration should be given to monitoring

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

Acetylsalicylic Acid: In a study in healthy subjects, at steady state, etoricoxib 120 mg once

daily had no effect on the anti-platelet activity of acetylsalicylic acid (81 mg once daily).

Etoricoxib can be used concomitantly with acetylsalicylic acid at doses used for

cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant

administration of low-dose acetylsalicylic acid with etoricoxib may result in an increased

rate of GI ulceration or other complications compared to use of etoricoxib alone.

Concomitant administration of etoricoxib with doses of acetylsalicylic acid above those for

cardiovascular prophylaxis or with other NSAIDs is not recommended (see sections 5.1

and 4.4.).

Cyclosporin and tacrolimus: Although this interaction has not been studied with etoricoxib,

coadministration of cyclosporin or tacrolimus with any NSAID may increase the

nephrotoxic effect of cyclosporin or tacrolimus. Renal function should be monitored when

etoricoxib and either of these drugs is used in combination.

Pharmacokinetic interactions

The effect of etoricoxib on the pharmacokinetics of other drugs

Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma

levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the

combination is being taken and when the NSAID is withdrawn.

Methotrexate: Two studies investigated the effects of etoricoxib 60, 90 or 120 mg

administered once daily for seven days in patients receiving once-weekly methotrexate

doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on

methotrexate plasma concentrations or renal clearance. In one study, etoricoxib 120 mg

had no effect, but in the other study, etoricoxib 120 mg increased methotrexate plasma

concentrations by 28% and reduced renal clearance of methotrexate by 13%. Adequate

monitoring for methotrexate-related toxicity is recommended when etoricoxib and

methotrexate are administered concomitantly.

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

containing 35 micrograms ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days

increased the steady state AUC

0-24hr

of EE by 37%. Etoricoxib 120 mg given with the same

oral contraceptive concomitantly or separated by 12 hours, increased the steady state

0-24hr

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 PREMARIN

) for 28

days, increased the mean steady state AUC

0-24hr

of unconjugated estrone (41%), equilin

(76%), and 17-β-estradiol (22%). The effect of the recommended chronic doses of

etoricoxib (30, 60, and 90 mg) has not been studied. The effects of etoricoxib 120 mg on

the exposure (AUC

0-24hr

) 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 AUC

0-24hr

or renal elimination of digoxin. There was an

increase in digoxin C

(approximately 33%). This increase is not generally important for

most patients. However, patients at high risk of digoxin toxicity should be monitored for this

when etoricoxib and digoxin are administered concomitantly.

Effect of etoricoxib on drugs metabolised by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and has

been shown to increase the serum concentrations of ethinyl estradiol. While knowledge

about effects of multiple sulfotransferases is presently limited and the clinical

consequences for many drugs are still being examined, it may be prudent to exercise care

when administering etoricoxib concurrently with other drugs primarily metabolised by

human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolised by CYP isoenzymes

Based on in vitro studies, etoricoxib is not expected to inhibit cytochromes P450 (CYP)

1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study in healthy subjects, daily administration of

etoricoxib 120 mg did not alter hepatic CYP3A4 activity as assessed by the erythromycin

breath test.

Effects of other drugs on the pharmacokinetics of etoricoxib

The main pathway of etoricoxib metabolism is dependent on CYP enzymes. CYP3A4

appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that

CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic

pathway, but their quantitative roles have not been studied in vivo.

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

for 11 days to healthy volunteers, did not have any clinically important effect on the single-

dose pharmacokinetics of 60 mg etoricoxib (43% increase in AUC).

Voriconazole and Miconazole: Co-administration of either oral voriconazole or topical

miconazole oral gel, strong CYP3A4 inhibitors, with etoricoxib caused a slight increase in

exposure to etoricoxib, but is not considered to be clinically meaningful based on

published data.

Rifampicin: Co-administration of etoricoxib with rifampicin, a potent inducer of CYP

enzymes, produced a 65% decrease in etoricoxib plasma concentrations. This interaction

may result in recurrence of symptoms when etoricoxib is co-administered with rifampicin.

While this information may suggest an increase in dose, doses of etoricoxib greater than

those listed for each indication have not been studied in combination with rifampicin and

are therefore not recommended (see section 4.2).

Antacids: Antacids do not affect the pharmacokinetics of etoricoxib to a clinically relevant

extent.

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

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 program 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

program 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 Program 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‡ ß

Uncommon

angioedema/anaphylactic

/anaphylactoid reactions including

shock

Rare

Metabolism and nutrition

disorders

oedema/fluid retention

Common

appetite increase or decrease,

weight gain

Uncommon

Psychiatric disorders

anxiety, depression, mental acuity

decreased, hallucinations

Uncommon

confusion

, restlessness

Rare

Nervous system disorders

dizziness, headache

Common

dysgeusia, insomnia,

paresthaesia/hypaesthesia,

somnolence

Uncommon

Eye disorders

blurred vision, conjunctivitis

Uncommon

Ear and labyrinth disorders

tinnitus, vertigo

Uncommon

Cardiac disorders

palpitations, arrhythmia

Common

atrial fibrillation, tachycardia

,

congestive heart failure, non-

specific ECG changes, angina

pectoris

, myocardial infarction

Uncommon

Vascular disorders

hypertension

Common

flushing, cerebrovascular

accident

, transient ischaemic

attack, hypertensive crisis

,

vasculitis

Uncommon

Respiratory, thoracic and

mediastinal disorders

bronchospasm

Common

cough, dyspnoea, epistaxis

Uncommon

Gastrointestinal disorders

abdominal pain

Very common

Constipation, flatulence, gastritis,

heartburn/acid reflux, diarrhea,

dyspepsia/epigastric discomfort,

nausea, vomiting, oesophagitis,

oral ulcer

Common

abdominal distention, bowel

movement pattern change, dry

mouth, gastroduodenal ulcer,

peptic ulcers including

gastrointestinal perforation and

bleeding, irritable bowel syndrome,

pancreatitis

Uncommon

Hepatobiliary disorders

ALT increased, AST increased

Common

hepatitis

Rare

hepatic failure

, jaundice

Rare

Skin and subcutaneous

tissue disorders

ecchymosis

Common

facial oedema, pruritus, rash,

erythema

, urticaria

Uncommon

Stevens-Johnson syndrome

, toxic

epidermal necrolysis

, fixed drug

eruption

Rare

Musculoskeletal and

connective tissue disorders

muscular cramp/spasm,

musculoskeletal pain/stiffness

Uncommon

Renal and urinary disorders

proteinuria, serum creatinine

increased, renal failure/renal

insufficiency

(see section 4.4)

Uncommon

General disorders and

administration site

conditions

asthenia/fatigue, flu-like disease

Common

chest pain

Uncommon

Investigations

blood urea nitrogen increased,

creatine phosphokinase increased,

hyperkalaemia, uric acid increased

Uncommon

blood sodium decreased

Rare

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

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

Very Rare (<1/10,000).

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

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

The frequency category of “Rare” was defined per the Summary of Product Characteristics (SmPC) guidance (rev. 2,

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

subjects treated with ARCOXIA 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".

Based on analyses of long-term placebo and active controlled clinical trials, selective COX-2 inhibitors have been

associated with an increased risk of serious thrombotic arterial events, including myocardial infarction and stroke. The

absolute risk increase for such events is unlikely to exceed 1% per year based on existing data (uncommon).

The following serious undesirable effects have been reported in association with the use of

NSAIDs and cannot be ruled out for etoricoxib: nephrotoxicity including interstitial nephritis

and nephrotic syndrome.

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Any suspected adverse events should be reported to the Ministry of Health

according to the National Regulation by using an online form:

https://sideeffects.health.gov.il

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 overdosage with etoricoxib, although adverse experiences were not

reported in the majority of cases. The most frequently observed adverse experiences were

consistent with the safety profile for etoricoxib (e.g. gastrointestinal events, cardiorenal

events).

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

remove unabsorbed material from the GI tract, employ clinical monitoring, and institute

supportive therapy, if required.

Etoricoxib is not dialysable by haemodialysis; it is not known whether etoricoxib is

dialysable by peritoneal dialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

coxibs, ATC code: M01 AH05

Mechanism of Action

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

range.

Across clinical pharmacology studies, ARCOXIA produced dose-dependent inhibition of

COX-2 without inhibition of COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit

gastric prostaglandin synthesis and had no effect on platelet function.

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

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

be induced by pro-inflammatory stimuli and has been postulated to be primarily

responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever.

COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus,

regulation of renal function, and central nervous system functions (fever induction, pain

perception and cognitive function). It may also play a role in ulcer healing. COX-2 has

been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has

not been established.

Clinical efficacy and safety

Efficacy

In patients with osteoarthritis (OA), etoricoxib 60 mg once daily provided significant

improvements in pain and patient assessments of disease status. These beneficial effects

were observed as early as the second day of therapy and maintained for up to 52 weeks.

Studies with etoricoxib 30 mg once daily demonstrated efficacy superior to placebo over a

12 week treatment period (using similar assessments as the above studies). In a dose

ranging study, etoricoxib 60 mg demonstrated significantly greater improvement than 30

mg for all 3 primary endpoints over 6 weeks of treatment. The 30 mg dose has not been

studied in osteoarthritis of hands.

In patients with rheumatoid arthritis (RA), etoricoxib 60 mg and 90 mg once daily both

provided significant improvements in pain, inflammation, and mobility.

In studies

evaluating the 60 mg and 90 mg dose, these beneficial effects were maintained over the

12- week treatment periods.

In a study evaluating the 60 mg dose compared to the 90 mg

dose, etoricoxib 60 mg once daily and 90 mg once daily were both more effective than

placebo. The 90 mg dose was superior to the 60 mg dose for Patient Global Assessment

of Pain (0-100mm visual analogue scale), with an average improvement of -2.71 mm (95%

CI: -4.98 mm, -0.45 mm).

In patients experiencing attacks of acute gouty arthritis, etoricoxib 120 mg once daily over

an eight-day treatment period, relieved moderate to extreme joint pain and inflammation

comparable to indomethacin 50 mg three times daily. Pain relief was observed as early as

four hours after initiation of treatment.

In patients with ankylosing spondylitis, etoricoxib 90 mg once daily provided significant

improvements in spine pain, inflammation, stiffness and function. The clinical benefit of

etoricoxib was observed as early as the second day of therapy after initiation of treatment

and was maintained throughout the 52-week treatment period.

In a second study

evaluating the 60 mg dose compared to the 90 mg dose, etoricoxib 60 mg daily and 90 mg

daily demonstrated similar efficacy compared to naproxen 1000 mg daily. Among

inadequate responders to 60 mg daily for 6 weeks, dose escalation to 90 mg daily

improved spinal pain intensity score (0-100mm 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) Program

The MEDAL Program was a prospectively designed Cardiovascular (CV) Safety Outcomes

Program of pooled data from three randomized, double-blind active comparator controlled

trials, the MEDAL study, EDGE II and EDGE.

The MEDAL Study, was an endpoint driven CV Outcomes study in 17,804 OA and 5,700

RA patients treated with etoricoxib 60 (OA) or 90 mg (OA and RA) or diclofenac 150 mg

daily for a mean period of 20.3 months (maximum of 42.3 months, median 21.3 months).

In this trial, only serious adverse events and discontinuations due to any adverse events

were recorded.

The EDGE and EDGE II studies compared the gastrointestinal tolerability of etoricoxib

versus diclofenac.

The EDGE study included 7,111 OA patients treated with a dose of etoricoxib 90 mg daily

(1.5 times the dose recommended for OA) or diclofenac 150 mg daily for a mean period of

9.1 months (maximum 16.6 months, median 11.4 months). The EDGE II study included

4,086 RA patients treated with etoricoxib 90 mg daily or diclofenac 150 mg daily for a

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

In the pooled MEDAL Program, 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

Program had a wide range of cardiovascular and gastrointestinal risk factors at baseline.

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

percutaneous coronary intervention within 6 months preceding enrollment were excluded.

Use of gastroprotective agents and low dose aspirin were permitted in the studies.

Overall Safety:

There was no significant difference between etoricoxib and diclofenac in the rate of

cardiovascular thrombotic events. Cardiorenal adverse events were observed more

frequently with etoricoxib than with diclofenac, and this effect was dose-dependent (see

specific results below). Gastrointestinal and hepatic adverse events were observed

significantly more frequently with diclofenac than etoricoxib. The incidence of adverse

experiences in EDGE and EDGE II and of adverse experiences considered serious or

resulting in discontinuation in the MEDAL study was higher with etoricoxib than diclofenac.

Cardiovascular safety results:

The rate of confirmed thrombotic cardiovascular serious adverse events (consisting of

cardiac, cerebrovascular, and peripheral vascular events) was comparable between

etoricoxib and diclofenac, and data are summarized in the table below. There were no

statistically significant differences in thrombotic event rates between etoricoxib and

diclofenac across all subgroups analyzed including patient categories across a range of

baseline cardiovascular risk. When considered separately, the relative risks for confirmed

thrombotic cardiovascular serious adverse events with etoricoxib 60 mg or 90 mg

compared with diclofenac 150 mg were similar.

Table 2: Rates of Confirmed Thrombotic CV Events (Pooled MEDAL Program)

Etoricoxib

(N=16,819)

25,836 Patient-

Years

Diclofenac

(N=16,483)

24,766 Patient-

Years

Between

Treatment

Comparison

Rate

(95% CI)

Rate

(95% CI)

Relative Risk

(95% CI)

Confirmed Thrombotic Cardiovascular Serious Adverse Events

Per-protocol

1.24 (1.11, 1.38)

1.30 (1.17, 1.45)

0.95 (0.81, 1.11)

Intent-to-treat

1.25 (1.14, 1.36)

1.19 (1.08, 1.30)

1.05 (0.93, 1.19)

Confirmed Cardiac Events

Per-protocol

0.71 (0.61, 0.82)

0.78 (0.68, 0.90)

0.90 (0.74, 1.10)

Intent-to-treat

0.69 (0.61, 0.78)

0.70 (0.62, 0.79)

0.99 (0.84, 1.17)

Confirmed Cerebrovascular Events

Per-protocol

0.34 (0.28, 0.42)

0.32 (0.25, 0.40)

1.08 (0.80, 1.46)

Intent-to-treat

0.33 (0.28, 0.39)

0.29 (0.24, 0.35)

1.12 (0.87, 1.44)

Confirmed Peripheral Vascular Events

Per-protocol

0.20 (0.15, 0.27)

0.22 (0.17, 0.29)

0.92 (0.63, 1.35)

Intent-to-treat

0.24 (0.20, 0.30)

0.23 (0.18, 0.28)

1.08 (0.81, 1.44)

Events per 100 Patient-Years; CI=confidence interval

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

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

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

NSAIDs >10% of the time).

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

potentially exposed to non-study interventions following discontinuation of study

medication). Total number of patients randomised, n= 17,412 on etoricoxib and

17,289 on diclofenac.

CV mortality, as well as overall mortality, was similar between the etoricoxib and

diclofenac treatment groups.

Cardiorenal Events:

Approximately 50% of patients enrolled in the MEDAL study had a history of hypertension

at baseline.

In the study, the incidence of discontinuations due to hypertension-related adverse events

was statistically significantly higher for etoricoxib than for diclofenac. The incidence of

congestive heart failure adverse events (discontinuations and serious events) occurred at

similar rates on etoricoxib 60 mg compared to diclofenac 150 mg but was higher for

etoricoxib 90 mg compared to diclofenac 150 mg (statistically significant for 90 mg

etoricoxib vs. 150 mg diclofenac in MEDAL OA cohort). The incidence of confirmed

congestive heart failure adverse events (events that were serious and resulted in

hospitalisation or a visit to an emergency department) was non-significantly higher with

etoricoxib than diclofenac 150 mg, and this effect was dose-dependent. The incidence of

discontinuations due to oedema-related adverse events was higher for etoricoxib than

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

etoricoxib 90 mg, but not for etoricoxib 60 mg).

The cardiorenal results for EDGE and EDGE II were consistent with those described for

the MEDAL Study.

In the individual MEDAL Program 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 Program 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 Program. 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 Program 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 hemorrhage 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 hemorrhage, (POBs)) were not significantly different between etoricoxib

and diclofenac.

MEDAL Program 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 Program,

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 Program were non-serious.

Additional Thrombotic Cardiovascular Safety Data

In clinical studies excluding the MEDAL Program Studies

approximately 3,100 patients

were treated with etoricoxib ≥60 mg daily for 12 weeks or longer. There was no discernible

difference in the rate of confirmed serious thrombotic cardiovascular events between

patients receiving etoricoxib ≥60 mg, placebo, or non-naproxen NSAIDs. However, the

rate of these events was higher in patients receiving etoricoxib compared with those

receiving naproxen 500 mg twice daily. The difference in antiplatelet activity between

some COX-1 inhibiting NSAIDs and selective COX-2 inhibitors may be of clinical

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

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

affecting platelet thromboxane. The clinical relevance of these observations has not been

established.

Additional Gastrointestinal Safety Data

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

gastroduodenal ulceration was significantly lower in patients treated with etoricoxib 120 mg

once daily than in patients treated with either naproxen 500 mg twice daily or ibuprofen

800 mg three times daily. Etoricoxib had a higher incidence of ulceration as compared to

placebo.

Renal Function Study in the Elderly

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

of 15 days of treatment of etoricoxib (90 mg), celecoxib (200 mg bid), naproxen (500 mg

bid) and placebo on urinary sodium excretion, blood pressure, and other renal function

parameters in subjects 60 to 85 years of age on a 200-mEq/day sodium diet. Etoricoxib,

celecoxib, and naproxen had similar effects on urinary sodium excretion over the 2 weeks

of treatment. All active comparators showed an increase relative to placebo with respect to

systolic blood pressures; however, etoricoxib was associated with a statistically significant

increase at Day 14 when compared to celecoxib and naproxen (mean change from

baseline for systolic blood pressure: etoricoxib 7.7 mmHg, celecoxib 2.4 mmHg, naproxen

3.6 mmHg).

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 C

= 3.6 μg/ml) was observed at approximately 1

hour (T

) after administration to fasted adults. The geometric mean area under the curve

(AUC

0-24hr

) 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 C

and an increase in T

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 (V

) was

approximately 120 l in humans.

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

Biotransformation

Etoricoxib is extensively metabolised with <1% of a dose recovered in urine as the parent

drug. The major route of metabolism to form the 6’-hydroxymethyl derivative is catalyzed

by CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In

vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse

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

Five metabolites have been identified in man. The principal metabolite is the 6’-carboxylic

acid derivative of etoricoxib formed by further oxidation of the 6’-hydroxymethyl derivative.

These principal metabolites either demonstrate no measurable activity or are only weakly

active as COX-2 inhibitors. None of these metabolites inhibit COX-1.

Elimination

Following administration of a single 25-mg radiolabeled intravenous dose of etoricoxib to

healthy subjects, 70% of radioactivity was recovered in urine and 20% in faeces, mostly as

metabolites. Less than 2% was recovered as unchanged drug.

Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal

excretion. Steady state concentrations of etoricoxib are reached within seven days of once

daily administration of 120 mg, with an accumulation ratio of approximately 2,

corresponding to a half-life of approximately 22 hours. The plasma clearance after a 25-

mg intravenous dose is estimated to be approximately 50 ml/min.

Characteristics in patients

Elderly patients: Pharmacokinetics in the elderly (65 years of age and older) are similar to

those in the young.

Gender: The pharmacokinetics of etoricoxib are similar between men and women.

Hepatic impairment: Patients with mild hepatic dysfunction (Child-Pugh score 5-6)

administered etoricoxib 60 mg once daily had an approximately 16% higher mean AUC as

compared to healthy subjects given the same regimen. Patients with moderate hepatic

dysfunction (Child-Pugh score 7-9) administered etoricoxib 60 mg every other day had

similar mean AUC to the healthy subjects given etoricoxib 60 mg once daily; etoricoxib 30

mg once daily has not been studied in this population. There are no clinical or

pharmacokinetic data in patients with severe hepatic dysfunction (Child-Pugh score ≥10).

(See sections 4.2 and 4.3.)

Renal impairment: The pharmacokinetics of a single dose of etoricoxib 120 mg in patients

with moderate to severe renal insufficiency and patients with end-stage renal disease on

hemodialysis were not significantly different from those in healthy subjects. Hemodialysis

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 (90 mg). However no treatment-related external or skeletal foetal

malformations were observed. In rats and rabbits, there was a dose dependent increase in

post implantation loss at exposures greater than or equal to 1.5 times the human exposure

(see sections 4.3 and 4.6).

Etoricoxib is excreted in the milk of lactating rats at concentrations approximately two-fold

those in plasma. There was a decrease in pup body weight following exposure of pups to

milk from dams administered etoricoxib during lactation.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core:

Microcrystalline cellulose

Calcium hydrogen phosphate (anhydrous)

Croscarmellose sodium

Magnesium stearate

Tablet coating:

Carnauba wax

Lactose monohydrate

Hypromellose

Titanium dioxide

Glycerol triacetate

The 30-, 60- and 120-mg tablets also contain indigo carmine lake (E132) and

iron oxide

yellow.

6.2 Incompatibilities

Not applicable.

6.3 Shelf-life

3 years.

6.4 Special precautions for storage

Store below 30

Store in the original package in order to protect from moisture

6.5 Nature and contents of container

30 mg

Push through Aluminum/aluminium blisters in packs containing 2, 7, 28 tablets.

60, 90 and 120 mg

Push through Aluminum/aluminium blisters in packs containing 2, 5, 7, 10, 14, 30 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme (Israel – 1996) Company Ltd., POB. 7121, Petah-Tiqva 49170

Manufacturer:

Arcoxia 60 mg, 90 mg and 120 mg tablets: Merck Sharp & Dohme Corp., NJ, USA

Arcoxia 30 mg tablets: Merck Sharp & Dohme B.V. Haarlem, Holland

8. MARKETING AUTHORISATION NUMBER

ARCOXIA

30 mg Tablets:

141.86.31986

ARCOXIA

60 mg Tablets: 129.42.30786

ARCOXIA

90 mg Tablets: 129.43.30787

ARCOXIA

120 mg Tablets: 129.44.30788

Revised on August 2020

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

)תוחיטב )תוחיטב :ךיראת

21.10.12

םש

רישכת

:תילגנאב

Arcoxia 30, 60, 90, 120 mg Tablets

רפסמ

:םושיר

31986

,

30786

,

30787

,

30788

םש

לעב

:םושירה

Merck, Sharp & Dohme (Israel-1996) Company Ltd

.

םייונישה

ןולעב

םינמוסמ

לע

עקר

בוהצ ןולעב ןולעב

ל

ל

אפור אפור םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Posology and

method of

administration

Hepatic insufficiency

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 60 mg every other day should

not be exceeded; administration of 30 mg

once daily can also be considered.

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).

Hepatic insufficiency

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 60 30 mg every other day

once daily should not be exceeded.;

administration of 30 mg once daily can

also be considered.

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).

Interaction with

other medicinal

products and other

forms of interaction

______

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

Undesirable effects

Infections and infestations:

Common: alveolar osteitis

Undesirable effects

Vascular disorders:

Common: hypertension.

Uncommon: flushing, cerebrovascular

accident

, transient ischaemic attack.

Very rare: hypertensive crisis.

Not known: vasculitis

ןכרצל ןולעב ןכרצל ןולעב םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח ךיא

שמתשת ?היסקוקראב דבכ תויעב םע םישנא ,הלק דבכ תלחמ ךל שי םא -מ רתוי לוטיל ןיא

ג"מ .םויב םעפ דבכ תויעב םע םישנא

לוטיל ןיא ,הלק דבכ תלחמ ךל שי םא -מ רתוי

.םויב םעפ ג"מ ךל שי םא דבכ תלחמ הנותמ -מ רתוי לוטיל ןיא ,

30

םויב םעפ ג"מ

תועפות

יאוול תוירשפא תוחיכש

:

תופייעו השלוח

תרוחרחס

תייומד הלחמ ,שאר באכ תעפש

לושלש

םיזג

,הליחב )היספפסיד( לוכיע יישק

באכ ןטבב תוחונ רסוח וא ןטב

תברצ

םד תוקידבב םייוניש ל תורושקה לש תוחפנתה ,דבכ םיילגרה תופכ וא/ו םיילגרה תובקעב תריצא םילזונ )תקצב(

,םדה ץחלב היילע תויצטיפלפ )בל תוקיפד(

תולבח

תוחיכש

:

תופייעו השלוח

תרוחרחס

הלחמ ,שאר באכ תעפש תייומד

לושלש

םיזג

יישק ,הליחב )היספפסיד( לוכיע

תוחונ רסוח וא ןטב באכ ןטבב

תברצ

םד תוקידבב םייוניש תורושקה

תופכ וא/ו םיילגרה לש תוחפנתה ,דבכ

תובקעב םיילגרה תריצא )תקצב( םילזונ

תויצטיפלפ ,םדה ץחלב היילע )בל תוקיפד(

תולבח

רחאל באכו תקלד( השבי תישתכמ .)ןש תריקע תועפות

יאוול תוירשפא עודי אל

:

םייניעהו רועה לש הבהצה ,)תבהצ(

בצק ,בלבלב תקלד ריהמ בל ליגר-אל בל בצק , טקש-יא ,)הימתירא(

עודי אל

:

,)תבהצ(

םייניעהו

רועה לש הבהצה דבכ תקיפס-יא

בל בצק ,בלבלב תקלד ריהמ ,)הימתירא(

רידס-אל בל בצק

,טקש-יא םדה ילכ לש תקלד

Similar products

Search alerts related to this product

View documents history

Share this information