Celebrex 100 mg capsules, hard

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Celecoxib
Available from:
Pfizer Healthcare Ireland
ATC code:
M01AH; M01AH01
INN (International Name):
Celecoxib
Dosage:
100 milligram(s)
Pharmaceutical form:
Capsule, hard
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Coxibs; celecoxib
Authorization status:
Marketed
Authorization number:
PA0822/116/001
Authorization date:
2000-05-12

Page 1 of 10

2018-0040882

Package leaflet: Information for the user

Celebrex®

100 mg hard capsules

Celebrex® 200 mg hard capsules

Celecoxib

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

1.

What Celebrex is and what it is used for

2.

What you need to know before you take Celebrex

3.

How to take Celebrex

4.

Possible side effects

5.

How to store Celebrex

6.

Contents of the pack and other information

1. What Celebrex is and what it is used for

Celebrex is used in adults for the relief of signs and symptoms of rheumatoid arthritis,

osteoarthritis and ankylosing spondylitis.

Celebrex belongs to a group of medicines called nonsteroidal anti-inflammatory drugs (NSAID),

and specifically a sub-group known as cyclooxygenase-2 (COX-2) inhibitors. Your body makes

prostaglandins that may cause pain and inflammation. In conditions such as rheumatoid arthritis

and osteoarthritis your body makes more of these. Celebrex acts by reducing the production of

prostaglandins, thereby reducing the pain and inflammation.

You should expect your medicine to start working within hours of taking the first dose, but you

may not experience a full effect for several days.

2. What you need to know before you take Celebrex

You have been prescribed Celebrex by your doctor. The following information will help you get

the best results with Celebrex. If you have any further questions please ask your doctor or

pharmacist.

Do not take Celebrex

Page 2 of 10

2018-0040882

Tell your doctor if any of the following are true for you as patients with these conditions

should not take Celebrex.

if you are allergic to celecoxib or any of the other ingredients of this medicine (listed in

section 6)

if you have had an allergic reaction to a group of medicines called “sulfonamides” (e.g.

some antibiotics used to treat infections)

if you currently have an ulcer in your stomach or intestines, or bleeding in your

stomach or intestines

if as a result of taking acetylsalicylic acid or any other anti-inflammatory and pain-

relieving

medicine

(NSAID)

have

asthma,

nose

polyps,

severe

nose

congestion, or an allergic reaction such as an itchy skin rash, swelling of the face, lips,

tongue or throat, breathing difficulties or wheezing

if you are pregnant. If you can become pregnant during ongoing treatment you should

discuss methods of contraception with your doctor

if you are breast-feeding

if you have severe liver disease

if you have severe kidney disease

if you have an inflammatory disease of the intestines such as ulcerative colitis or

Crohn’s disease

if you have heart failure, established ischaemic heart disease, or cerebrovascular

disease, e.g. you have been diagnosed with a heart attack, stroke, or transient ischaemic

attack (temporary reduction of blood flow to the brain; also known as “mini-stroke”),

angina, or blockages of blood vessels to the heart or brain

if you have or have had problems with your blood circulation (peripheral arterial

disease) or if you have had surgery on the arteries of your legs

Warnings and precautions

Talk to your doctor or pharmacist before taking Celebrex:

if you have previously had an ulcer or bleeding in your stomach or intestines.

(Do not take Celebrex if you currently have an ulcer or bleeding in your stomach or

intestine)

if you are taking acetylsalicylic acid (even at low dose for heart protective purposes)

if you are taking antiplatelet therapies

if you use medicines to reduce blood clotting (e.g. warfarin/warfarin like anticoagulants

or novel oral anti-clotting medicines, e.g. apixaban)

if you use medicines called corticosteroids (e.g. prednisone)

if you are using Celebrex at the same time as other non-acetylsalicylic NSAIDs such as

ibuprofen or diclofenac. The use of these medicines together should be avoided

if you smoke, have diabetes, raised blood pressure or raised cholesterol

if your heart, liver or kidneys are not working well your doctor may want to keep a

regular check on you

if you have fluid retention (such as swollen ankles and feet)

if you are dehydrated, for instance due to sickness, diarrhoea or the use of diuretics

(used to treat excess fluid in the body)

if you have had a serious allergic reaction or a serious skin reaction to any medicines

if you feel ill due to an infection or think you have an infection, as Celebrex may mask

a fever or other signs of infection and inflammation

if you are over 65 years of age your doctor will want to monitor you regularly

Page 3 of 10

2018-0040882

the consumption of alcohol and NSAIDs may increase the risk of gastrointestinal

problems

As with other NSAIDs (e.g. ibuprofen or diclofenac) this medicine may lead to an increase in

blood pressure, and so your doctor may ask to monitor your blood pressure on a regular basis.

Some cases of severe liver reactions, including severe liver inflammation, liver damage, liver

failure (some with fatal outcome or requiring liver transplant), have been reported with celecoxib.

Of the cases that reported time to onset, most severe liver reactions occurred within one month of

start of treatment.

Celebrex may make it more difficult to become pregnant. You should inform your doctor if you

are planning to become pregnant or if you have problems to become pregnant (see section on

Pregnancy and breast-feeding).

Other medicines and Celebrex

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

medicines:

Dextromethorphan (used to treat coughs)

ACE inhibitors, angiotensin II antagonists, beta blockers and diuretics (used for high

blood pressure and heart failure)

Fluconazole and rifampicin (used to treat fungal and bacterial infections)

Warfarin or other warfarin like medicines (blood-thinning” agents that reduce blood

clotting) including newer medicines like apixaban

Lithium (used to treat some types of depression)

Other medicines to treat depression, sleep disorders, high blood pressure or an irregular

heartbeat

Neuroleptics (used to treat some mental disorders)

Methotrexate (used to treat rheumatoid arthritis, psoriasis and leukaemia)

Carbamazepine (used to treat epilepsy/seizures and some forms of pain or depression)

Barbiturates (used to treat epilepsy/seizures and some sleep disorders)

Ciclosporin and tacrolimus (used for immune system suppression e.g. after transplants)

Celebrex can be taken with low dose acetylsalicylic acid (75 mg or less daily). Ask your doctor

for advice before taking both medicines together.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby,

ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Celebrex must not be used by women who are pregnant or can become pregnant (i.e. women of

child bearing potential who are not using adequate contraception) during ongoing treatment. If

you become pregnant during treatment with Celebrex you should discontinue the treatment and

contact your doctor for alternative treatment.

Breast-feeding

Celebrex must not be used during breast-feeding.

Page 4 of 10

2018-0040882

Fertility

NSAIDs, including Celebrex, may make it more difficult to become pregnant. You should tell

your doctor if you are planning to become pregnant or if you have problems becoming pregnant.

Driving and using machines

You should be aware of how you react to Celebrex before you drive or operate machinery. If you

feel dizzy or drowsy after taking Celebrex, do not drive or operate machinery until these effects

wear off.

Celebrex contains lactose

Celebrex contains lactose (a type of sugar). If you have been told by your doctor that you have an

intolerance to some sugars, contact your doctor before taking this medicinal product.

3. How to take Celebrex

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

doctor or pharmacist if you are not sure. If you think or feel that the effect of Celebrex is too

strong or too weak, talk to your doctor or pharmacist.

Your doctor will tell you what dose you should take. As the risk of side effects associated with

heart problems may increase with dose and duration of use, it is important that you use the lowest

dose that controls your pain and you should not take Celebrex for longer than necessary to control

symptoms.

Method of administration:

Celebrex is for oral use. The capsules can be taken at any time of the day, with or without food.

However, try to take each dose of Celebrex at the same time each day.

If you have difficulty swallowing capsules: The entire capsule contents can be sprinkled onto a

level teaspoon of semi-solid food (such as cool or room temperature applesauce, rice gruel,

yogurt or mashed banana) and swallowed immediately with a drink approximately 240 ml of

water.

To open the capsule, hold upright to contain the granules at the bottom then gently squeeze the

top and twist to remove, taking care not to spill the contents. Do not chew or crush the

granules.

Contact your doctor within two weeks of starting treatment if you do not experience any benefit.

The recommended dose is:

For osteoarthritis the recommended dose is 200 mg each day, increased by your doctor to a

maximum of 400 mg, if needed.

The dose is usually:

one 200 mg capsule once a day; or

one 100 mg capsule twice a day.

Page 5 of 10

2018-0040882

For rheumatoid arthritis the recommended dose is 200 mg each day, increased by your doctor

to a maximum of 400 mg, if needed.

The dose is usually:

one 100 mg capsule twice a day.

For ankylosing spondylitis the recommended dose is 200 mg each day, increased by your doctor

to a maximum of 400 mg, if needed.

The dose is usually:

one 200 mg capsule once a day; or

one 100 mg capsule twice a day.

Kidney or liver problems: make sure your doctor knows if you have liver or kidney problems as

you may need a lower dose.

The elderly, especially those with a weight less than 50 kg: if you are over 65 years of age and

especially if you weigh less than 50 kg, your doctor may want to monitor you more closely.

You should not take more than 400 mg per day.

Use in children

Celebrex is for adults only, it is not for use in children.

If you take more Celebrex than you should

You should not take more capsules than your doctor tells you to. If you take too many capsules

contact your doctor, pharmacist or hospital and take your medicine with you.

If you forget to take Celebrex

If you forget to take a capsule, take it as soon as you remember. Do not take a double dose to

make up for a forgotten dose.

If you stop taking Celebrex

Suddenly stopping your treatment with Celebrex may lead to your symptoms getting worse. Do

not stop taking Celebrex unless your doctor tells you to. Your doctor may tell you to reduce the

dose over a few days before stopping completely.

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

4. Possible side effects

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

The side effects listed below were observed in arthritis patients who took Celebrex. Side

effects marked with an asterisk (*) are listed below at the higher frequencies that occurred

in patients who took Celebrex to prevent colon polyps. Patients in these studies took

Celebrex at high doses and for a long duration.

If any of the following happen, stop taking Celebrex and tell your doctor immediately:

If you have:

Page 6 of 10

2018-0040882

an allergic reaction such as skin rash, swelling of the face, wheezing or difficulty

breathing

heart problems such as pain in the chest

severe stomach pain or any sign of bleeding in the stomach or intestines, such as

passing black or bloodstained stools, or vomiting blood

a skin reaction such as rash, blistering or peeling of the skin

liver failure (symptoms may include nausea (feeling sick), diarrhoea, jaundice (your

skin or the whites of your eyes look yellow))

Very common: may affect more than 1 in 10 people

High blood pressure, including worsening of existing high blood pressure *

Common: may affect up to 1 in 10 people

Heart attack*

Fluid build up with swollen ankles, legs and/or hands

Urinary infections

Shortness of breath*, sinusitis (sinus inflammation, sinus infection,

blocked or painful

sinuses), blocked or runny nose, sore throat, coughs, colds, flu-like symptoms

Dizziness, difficulty sleeping

Vomiting*, stomach ache, diarrhoea, indigestion, wind

Rash, itching

Muscle stiffness

Difficulty swallowing*

Headache

Nausea (feeling sick)

Painful joints

Worsening of existing allergies

Accidental injury

Uncommon: may affect up to 1 in 100 people

Stroke*

Heart failure, palpitations (awareness of heart beat), fast heart rate

Abnormalities in liver-related blood tests

Abnormalities in kidney-related blood tests

Anaemia (changes in red blood cells that can cause fatigue and breathlessness)

Anxiety, depression, tiredness, drowsiness, tingling sensations (pins and needles)

High levels of potassium in blood test results (can cause nausea (feeling sick), fatigue, muscle

weakness or palpitations)

Impaired or blurred vision, ringing in the ears, mouth pain and sores, difficulty hearing*

Constipation,

burping,

stomach

inflammation

(indigestion,

stomach

ache

vomiting),

worsening of inflammation of the stomach or intestine

Leg cramps

Raised itchy rash (hives)

Eye inflammation

Difficulty breathing

Skin discolouration (bruising)

Page 7 of 10

2018-0040882

Chest pain (generalised pain not related to the heart)

Face swelling

Rare: may affect up to 1 in 1,000 people

Ulcers (bleeding) in the stomach, gullet or intestines; or rupture of the intestine (can cause

stomach

ache,

fever,

nausea,

vomiting,

intestinal

blockage),

dark

black

stools,

inflammation

pancreas

(can

lead

stomach

pain),

inflammation

gullet

(oesophagus)

Low levels of sodium in the blood (a condition known as hyponatraemia)

Reduced number of white blood cells (which help to protect the body from infection) or

blood platelets (increased chance of bleeding or bruising)

Difficulty coordinating muscular movements

Feeling confused, changes in the way things taste

Increased sensitivity to light

Loss of hair

Hallucinations

Bleeding in the eye

Acute reaction that may lead to lung inflammation

Irregular heartbeat

Flushing

Blood clot in the blood vessels in the lungs. Symptoms may include sudden breathlessness,

sharp pains when you breathe or collapse

Bleeding of the stomach or intestines (can lead to bloody stools or vomiting), inflammation of

the intestine or colon

Severe liver inflammation (hepatitis). Symptoms may include nausea (feeling sick),

diarrhoea, jaundice (yellow discolouration of the skin or eyes), dark urine, pale stools,

bleeding easily, itching or chills

Acute kidney failure

Menstrual disturbances

Swelling of the face, lips, mouth, tongue or throat, or difficulty swallowing

Very rare: may affect up to 1 in 10,000 people

Serious allergic reactions (including potentially fatal anaphylactic shock)

Serious skin conditions such as Stevens-Johnson syndrome, exfoliative dermatitis and toxic

epidermal necrolysis (can cause rash, blistering or peeling of the skin) and acute generalised

exanthematous pustulosis (symptoms include the skin becoming red with swollen areas

covered in numerous small pustules)

A delayed allergic reaction with possible symptoms such as rash, swelling of the face, fever,

swollen glands, and abnormal test results (e.g., liver, blood cell (eosinophilia, a type of raised

white blood cell count))

Bleeding within the brain causing death

Meningitis (inflammation of the membrane around the brain and spinal cord)

Liver failure, liver damage and severe liver inflammation (fulminant hepatitis) (sometimes

fatal or requiring liver transplant). Symptoms may include nausea (feeling sick), diarrhoea,

jaundice (yellow discolouration of the skin or eyes), dark urine, pale stools, bleeding easily,

itching or chills

Page 8 of 10

2018-0040882

Liver problems (such as cholestasis and cholestatic hepatitis, which may be accompanied by

symptoms such as discoloured stools, nausea and yellowing of the skin or eyes)

Inflammation of the kidneys and other kidney problems (such as nephrotic syndrome and

minimal change disease, which may be accompanied by symptoms such as water retention

(oedema), foamy urine, fatigue and a loss of appetite)

Worsening of epilepsy (possible more frequent and/or severe seizures)

Blockage of an artery or vein in the eye leading to partial or complete loss of vision

Inflamed blood vessels (can cause fever, aches, purple blotches on the skin)

A reduction in the number of red and white blood cells and platelets (may cause tiredness,

easy bruising, frequent nose bleeds and increased risk of infections)

Muscle pain and weakness

Impaired sense of smell

Loss of taste

Not known: frequency cannot be estimated from the available data

Decreased fertility in females, which is usually reversible on discontinuation of the medicine

In clinical studies not associated with arthritis or other arthritic conditions, where Celebrex

was taken at doses of 400 mg per day for up to 3 years, the following additional side effects

have been observed:

Common: may affect up to 1 in 10 people

Heart problems: angina (chest pain)

Stomach

problems:

irritable

bowel

syndrome

(can

include

stomach

ache,

diarrhoea,

indigestion, wind)

Kidney stones (which may lead to stomach or back pain, blood in urine), difficulty passing

urine

Weight gain

Uncommon: may affect up to 1 in 100 people

Deep vein thrombosis (blood clot usually in the leg, which may cause pain, swelling or

redness of the calf or breathing problems)

Stomach problems: stomach infection (which can cause irritation and ulcers of the stomach

and intestines)

Lower limb fracture

Shingles, skin infection, eczema (dry itchy rash), pneumonia (chest infection (possible cough,

fever, difficulty breathing))

Floaters in the eye causing blurred or impaired vision, vertigo due to inner ear troubles, sore,

inflamed or bleeding gums, mouth sores

Excessive urination at night, bleeding from piles/ haemorrhoids, frequent bowel movements

Fatty lumps in skin or elsewhere, ganglion cyst (harmless swellings on or around joints and

tendons in the hand or foot), difficulty speaking, abnormal or very heavy bleeding from the

vagina, breast pain

High levels of sodium in blood test results

Reporting of side effects

Page 9 of 10

2018-0040882

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

effects

listed

this

leaflet.

also

report

side

effects

directly

HPRA

Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1

6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. By reporting side effects you can

help provide more information on the safety of this medicine.

5. How to store Celebrex

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

Do not use this medicine after the expiry date which is stated on the blister and carton. The

expiry date refers to the last day of that month.

Do not store Celebrex above 30

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how

to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Celebrex contains

The active substance is celecoxib.

1 capsule contains 100 mg or 200 mg celecoxib.

The other ingredients are:

Lactose monohydrate, sodium laurilsulfate, povidone, croscarmellose sodium, magnesium

stearate. Capsule shells contain gelatin, titanium dioxide E171, sodium laurilsulfate and sorbitan

monolaurate. Printing ink contains shellac, propylene glycol, indigotine E132 (100 mg capsule),

iron oxide E172 (200 mg capsule).

What Celebrex looks like and contents of the pack

Celebrex is available as hard capsules.

Opaque, white with two blue bands marked 7767 and 100 (Celebrex 100 mg).

Opaque, white with two gold bands marked 7767 and 200 (Celebrex 200 mg).

The capsules are packaged in clear or opaque PVC/aluminium blisters.

Celebrex is contained in packs of 2, 5, 6, 10, 20, 30, 40, 50, 60, 100, 10x10, 10x30, 10x50, 1x50

unit dose, 1x100 unit dose, 5x(10x10).

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Page 10 of 10

2018-0040882

Pfizer Healthcare Ireland

9 Riverwalk

National Digital Park

Citywest Business Campus

Dublin 24

Manufacturer

R-Pharm Germany GmbH

Heinrich-Mack-Str. 35

89257 Illertissen

Germany

Pfizer Manufacturing Deutschland GmbH

Betriebsstätte Freiburg Mooswaldallee 1,

79090 Freiburg

Germany

For any information about this medicine, please contact:

Medical Information

Pfizer Ltd

Walton Oaks

Dorking Road

Tadworth

Surrey

KT20 7NS

Telephone: 1800 633 363

This medicinal product is authorised in the Member States of the EEA under the following

names:

Name

Country

Celebra

Denmark, Finland, Iceland, Norway, Sweden

Celebrex

Austria, Belgium, France, Germany, Greece,

Ireland, Italy, Luxembourg, Netherlands,

Portugal, Spain, UK

This leaflet was last revised in 11/2019.

Ref: CB 24_0

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 1 of 15

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Celebrex 100 mg capsules, hard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 100 mg celecoxib.

Excipient with known effect

Lactose (each capsule contains 149.7 mg lactose monohydrate; see section 4.4).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, hard.

Opaque, white with two blue bands marked 7767 and 100.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Celebrex is indicated in adults for the symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing

spondylitis.

The decision to prescribe a selective cyclooxygenase-2 (COX-2) inhibitor should be based on an assessment of the individual

patient's overall risks (see sections 4.3 and 4.4).

4.2 Posology and method of administration

Posology

As the cardiovascular (CV) risks of celecoxib 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 usual recommended daily dose is 200 mg taken once daily or in two divided doses. In some patients, with insufficient

relief from symptoms, an increased dose of 200 mg twice daily may increase efficacy. In the absence of an increase in

therapeutic benefit after two weeks, other therapeutic options should be considered.

Rheumatoid arthritis

The initial recommended daily dose is 200 mg taken in two divided doses. The dose may, if needed, later be increased to

200 mg twice daily. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be

considered.

Ankylosing spondylitis

The recommended daily dose is 200 mg taken once daily or in two divided doses. In a few patients, with insufficient relief from

symptoms, an increased dose of 400 mg once daily or in two divided doses may increase efficacy. In the absence of an

increase in therapeutic benefit after two weeks, other therapeutic options should be considered.

The maximum recommended daily dose is 400 mg for all indications.

Special populations

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 2 of 15

Elderly

As in younger adults, 200 mg per day should be used initially. The dose may, if needed, later be increased to 200 mg twice

daily. Particular caution should be exercised in elderly with a body weight less than 50 kg (see sections 4.4 and 5.2).

Paediatric population

Celecoxib is not indicated for use in children.

CYP2C9 poor metabolisers

Patients who are known, or suspected to be CYP2C9 poor metabolisers based on genotyping or previous history/experience

with other CYP2C9 substrates should be administered celecoxib with caution as the risk of dose-dependent adverse effects is

increased. Consider reducing the dose to half the lowest recommended dose (see section 5.2).

Hepatic impairment

Treatment should be initiated at half the recommended dosein patients with establishedmoderate liver impairment with a

serumalbumin of25-35 g/l. Experience in such patients is limited to cirrhotic patients (see sections 4.3, 4.4 and 5.2).

Renal impairment

Experience with celecoxib in patients with mild or moderate renal impairment is limited, therefore such patients should be

treated with caution (see sections 4.3, 4.4 and 5.2).

Method of administration

Oral use

Celebrex may be taken with or without food. For patients who have difficulty swallowing capsules, the contents of a celecoxib

capsule can be added to applesauce, rice gruel, yogurt or mashed banana. To do so, the entire capsule contents must be

carefully emptied onto a level teaspoon of cool or room temperature applesauce, rice gruel, yogurt or mashed banana and

should be ingested immediately with 240 ml of water. The sprinkled capsule contents on applesauce, rice gruel or yogurt are

stable for up to 6 hours under refrigerated conditions (2‑8°C). The sprinkled capsule contents on mashed banana should not

be stored under refrigerated conditions and should be ingested immediately.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Known hypersensitivity to sulfonamides.

Active peptic ulceration or gastrointestinal (GI) bleeding.

Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type

reactions after taking acetylsalicylic acid (aspirin) or other non‑steroidal anti-inflammatory drugs (NSAIDs) including COX-2

inhibitors.

In pregnancy and in women of childbearing potential unless using an effective method of contraception (see section 4.6).

Celecoxib has been shown to cause malformations in the two animal species studied (see sections 4.6 and 5.3). The potential

for human risk in pregnancy is unknown, but cannot be excluded.

Breast-feeding (see sections 4.6 and 5.3).

Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥10).

Patients with estimated creatinine clearance <30 ml/min.

Inflammatory bowel disease.

Congestive heart failure (NYHA II-IV).

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 3 of 15

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

4.4 Special warnings and precautions for use

Gastrointestinal (GI) effects

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

outcome, have occurred in patients treated with celecoxib. 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 antiplatelet drugs (such

acetylsalicylic

acid)

glucocorticoids

concomitantly,

patients

using

alcohol,

patients

with

prior

history

gastrointestinal disease, such as ulceration and GI bleeding.

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

gastrointestinal complications), when celecoxib 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).

Concomitant NSAID use

The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.

Cardiovascular effects

Increased number of serious cardiovascular (CV) events, mainly myocardial infarction, has been found in a long-term

placebo-controlled study in subjects with sporadic adenomatous polyps treated with celecoxib at doses of 200 mg BID and

400 mg BID compared to placebo (see section 5.1).

As the cardiovascular risks of celecoxib may increase with dose and duration of exposure, the shortest duration possible and

the lowest effective daily dose should be used. NSAIDs, including COX-2 selective inhibitors, have been associated with

increased risk of cardiovascular and thrombotic adverse events when taken long term. The exact magnitude of the risk

associated with a single dose has not been determined, nor has the exact duration of therapy associated with increased risk.

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 celecoxib 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 effects. Therefore, antiplatelet therapies should not be discontinued (see section

5.1).

Fluid retention and oedema

As with other medicinal products known to inhibit prostaglandin synthesis fluid retention and oedema have been observed in

patients taking celecoxib. Therefore, celecoxib should be used with caution in patients with history of cardiac failure, left

ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason, since prostaglandin

inhibition may result in deterioration of renal function and fluid retention. Caution is also required in patients taking diuretic

treatment or otherwise at risk of hypovolaemia.

Hypertension

As with all NSAIDS, celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of

which may contribute to the increased incidence of cardiovascular events. Therefore, blood pressure should be monitored

closely during the initiation of therapy with celecoxib and throughout the course of therapy.

Hepatic and renal effects

Compromised renal or hepatic function and especially cardiac dysfunction are more likely in the elderly and therefore medically

appropriate supervision should be maintained.

NSAIDs, including celecoxib, may cause renal toxicity.

Clinical trials with celecoxib have shown renal effects similar to those

observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 4 of 15

failure, liver dysfunction, those taking diuretics, angiotensin converting enzyme (ACE)-inhibitors, angiotensin II receptor

antagonists, and the elderly (see section 4.5). Such patients should be carefully monitored while receiving treatment with

celecoxib.

Some cases of severe hepatic reactions, including fulminant hepatitis (some with fatal outcome), liver necrosis and, hepatic

failure (some with fatal outcome or requiring liver transplant), have been reported with celecoxib. Among the cases that

reported time to onset, most of the severe adverse hepatic events developed within one month after initiation of celecoxib

treatment (see section 4.8).

If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should

be taken and discontinuation of celecoxib therapy should be considered.

CYP2D6 inhibition

Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction may be necessary for

individually dose-titrated medicinal products that are metabolised by CYP2D6 (see section 4.5).

CYP2C9 poor metabolisers

Patients known to be CYP2C9 poor metabolisers should be treated with caution (see section 5.2).

Skin and systemic hypersensitivity reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal

necrolysis, have been reported very rarely in association with the use of celecoxib (see section 4.8). Patients appear to be at

highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within

the first month of treatment. Serious hypersensitivity reactions (including anaphylaxis, angioedema and drug rash with

eosinophilia and systemic symptoms (DRESS), or hypersensitivity syndrome), have been reported in patients receiving celecoxib

(see section 4.8). Patients with a history of sulfonamide allergy or any drug allergy may be at greater risk of serious skin

reactions or hypersensitivity reactions (see section 4.3). Celecoxib should be discontinued at the first appearance of skin rash,

mucosal lesions, or any other sign of hypersensitivity.

General

Celecoxib may mask fever and other signs of inflammation.

Use with oral anticoagulants

In patients on concurrent therapy with warfarin, serious bleeding events, some of them fatal, have been reported. Increased

prothrombin time (INR) with concurrent therapy has been reported. Therefore, this should be closely monitored in patients

receiving warfarin/coumarin‑type oral anticoagulants, particularly when therapy with celecoxib is initiated or celecoxib dose is

changed (see section 4.5). Concomitant use of anticoagulants with NSAIDS may increase the risk of bleeding. Caution should

be exercised when combining celecoxib with warfarin or other oral anticoagulants, including novel anticoagulants (e.g.

apixaban, dabigatran, and rivaroxaban).

Excipients

Celebrex 100 mg and 200 mg capsules contain lactose (149.7 mg and 49.8 mg, respectively). 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 interactions

Pharmacodynamic interactions

Anticoagulants

Anticoagulant activity should be monitored particularly in the first few days after initiating or changing the dose of celecoxib in

patients receiving warfarin or other anticoagulants since these patients have an increased risk of bleeding complications.

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

first few days when therapy with celecoxib is initiated or the dose of celecoxib is changed (see section 4.4). Bleeding events in

association with increases in prothrombin time have been reported, predominantly in the elderly, in patients receiving

celecoxib concurrently with warfarin, some of them fatal.

Anti-hypertensives

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 5 of 15

NSAIDs may reduce the effect of anti-hypertensive medicinal products including ACE‑inhibitors, angiotensin II receptor

antagonists,

diuretics and beta-blockers. As for NSAIDs, the risk of acute renal insufficiency, which is usually reversible, may be

increased in some patients with compromised renal function (e.g. dehydrated patients, patients on diuretics, or elderly patients)

when ACE-inhibitors, angiotensin II receptor antagonists, and/or diuretics are combined with NSAIDs, including celecoxib (see

section 4.4). 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.

In a 28-day clinical study in patients with lisinopril-controlled Stage I and II hypertension, administration of celecoxib

200 mg BID resulted in no clinically significant increases, when compared to placebo treatment, in mean daily systolic or

diastolic blood pressure as determined using 24-hour ambulatory blood pressure monitoring. Among patients treated with

celecoxib 200 mg BID, 48% were considered unresponsive to lisinopril at the final clinic visit (defined as either cuff diastolic

blood pressure >90 mmHg or cuff diastolic blood pressure increased >10 % compared to baseline), compared to 27% of

patients treated with placebo; this difference was statistically significant.

Ciclosporin and tacrolimus

Co-administration of NSAIDs and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin or tacrolimus,

respectively. Renal function should be monitored when celecoxib and any of these medicinal products are combined.

Acetylsalicylic acid

Celecoxib can be used with low-dose acetylsalicylic acid but is not a substitute for acetylsalicylic acid for CV prophylaxis. In the

submitted studies, as with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications

compared to use of celecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid (see section 5.1).

Pharmacokinetic interactions

Effects of celecoxib on other medicinal products

CYP2D6 inhibition

Celecoxib is an inhibitor of CYP2D6. The plasma concentrations of medicinal products that are substrates of this enzyme may

be increased when celecoxib is used concomitantly. Examples of medicinal products which are metabolised by CYP2D6 are

antidepressants

(tricyclics

SSRIs),

neuroleptics,

anti-arrhythmic

medicinal

products,

etc.

dose

individually

dose-titrated CYP2D6 substrates may need to be reduced when treatment with celecoxib is initiated or increased if treatment

with celecoxib is terminated.

Concomitant

administration

celecoxib

200 mg

twice

daily

resulted

2.6-fold

1.5-fold

increases

plasma

concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to celecoxib

inhibition of the CYP2D6 substrate metabolism.

CYP2C19 inhibition

In vitro

studies have shown some potential for celecoxib to inhibit CYP2C19 catalysed metabolism. The clinical significance of

this in vitro

finding is unknown. Examples of medicinal products which are metabolised by CYP2C19 are diazepam, citalopram

and imipramine.

Methotrexate

In patients with rheumatoid arthritis celecoxib had no statistically significant effect on the pharmacokinetics (plasma or renal

clearance) of methotrexate (in rheumatologic doses). However, adequate monitoring for methotrexate-related toxicity should

be considered when combining these two medicinal products.

Lithium

In healthy subjects, co-administration of celecoxib 200 mg twice daily with 450 mg twice daily of lithium resulted in a mean

increase in C

of 16% and in area under the curve (AUC) of 18% of lithium. Therefore, patients on lithium treatment should be

closely monitored when celecoxib is introduced or withdrawn.

Oral contraceptives

In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral contraceptives (1 mg

norethisterone /35 micrograms ethinylestradiol).

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 6 of 15

Glibenclamide/tolbutamide

Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide to a clinically relevant

extent.

Effects of other medicinal products on celecoxib

CYP2C9 poor metabolisers

In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to celecoxib, concomitant

treatment

with

CYP2C9

inhibitors

such

fluconazole

could

result

further

increases

celecoxib

exposure.

Such

combinations should be avoided in known CYP2C9 poor metabolisers (see sections 4.2 and 5.2).

CYP2C9 inhibitors and inducers

Since celecoxib is predominantly metabolised by CYP2C9 it should be used at half the recommended dose in patients receiving

fluconazole. Concomitant use of 200 mg single dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9

inhibitor, resulted in a mean increase in celecoxib C

of 60% and in AUC of 130%. Concomitant use of inducers of CYP2C9

such as rifampicin, carbamazepine and barbiturates may reduce plasma concentrations of celecoxib.

Ketoconazole and antacids

Ketoconazole or antacids have not been observed to affect the pharmacokinetics of celecoxib.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

Studies in animals (rats and rabbits) have shown reproductive toxicity, including malformations (see sections 4.3 and 5.3).

Inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an

increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. The potential for

human risk in pregnancy is unknown, but cannot be excluded. Celecoxib, as with other medicinal products inhibiting

prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester.

During the second or third trimester of pregnancy, NSAIDs including celecoxib may cause fetal renal dysfunction which may

result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment

initiation and are usually reversible.

Celecoxib is contraindicated in pregnancy and in women who can become pregnant (see sections 4.3 and 4.4). If a woman

becomes pregnant during treatment, celecoxib should be discontinued.

Breast-feeding

Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Administration of celecoxib to a

limited number of lactating women has shown a very low transfer of celecoxib into breast milk.Women who take Celebrex

should not breastfeed.

Fertility

Based on the mechanism of action, the use of NSAIDs, including celecoxib, may delay or prevent rupture of ovarian follicles,

which has been associated with reversible infertility in some women.

4.7 Effects on ability to drive and use machines

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

machinery.

4.8 Undesirable effects

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 7 of 15

Adverse reactions are listed by system organ class and ranked by frequency in Table 1, reflecting data from the following

sources:

Adverse reactions reported in osteoarthritis patients and rheumatoid arthritis patients at incidence rates greater

than 0.01 % and greater than those reported for placebo during 12 placebo- and/or active-controlled clinical trials

of duration up to 12 weeks at celecoxib daily doses from 100 mg up to 800 mg. In additional studies using

non-selective NSAID comparators, approximately 7400 arthritis patients have been treated with celecoxib at daily

doses up to 800 mg, including approximately 2300 patients treated for 1 year or longer. The adverse reactions

observed with celecoxib in these additional studies were consistent with those for osteoarthritis and rheumatoid

arthritis patients listed in Table 1.

Adverse reactions reported at incidence rates greater than placebo for subjects treated with celecoxib 400 mg daily

in long-term polyp prevention trials of duration up to 3 years (the Adenoma Prevention with Celecoxib (APC) and

Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials; see section 5.1, Cardiovascular safety

–long‑term studies involving patients with sporadic adenomatous polyps).

Adverse drug reactions from post-marketing surveillance as spontaneously reported during a period in which an

estimated >70 million patients were treated with celecoxib (various doses, durations, and indications). Even

though these were identified as reactions from post-marketing reports, trial data was consulted to estimate

frequency. Frequencies are based on a cumulative meta-analysis with pooling of trials representing exposure in

38102 patients.

Table 1. Adverse drug reactions in celecoxib clinical trials and surveillance experience (MedDRA preferred terms)

1,2

Adverse Drug Reaction Frequency

System Organ

Class

Very

Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to

<1/100)

Rare

(≥1/10,000 to

<1/1,000)

Very Rare

(<1/10,000)

Frequency

Not

Known

(cannot be

estimated

from

available

data)

Infections and

infestations

Sinusitis, upper

respiratory tract

infection,

pharyngitis, urinary

tract infection

Blood and

lymphatic

system disorders

Anaemia

Leukopenia,

thrombo-cyto

penia

Pancytopenia

Immune system

disorders

Hyper-sensitivity

Anaphylactic

shock

anaphylactic

reaction

Metabolism and

nutrition

disorders

Hyperkalaemia

Psychiatric

disorders

Insomnia

Anxiety,

depression,

fatigue

Confusional

state,

hallucinations

Nervous system

disorders

Dizziness,

hypertonia,

headache

Cerebral

infarction

paraesthesia,

somnolence

Ataxia,

dysgeusia

Haemorrhage

intracranial

(including fatal

intracranial

haemorrhage)

meningitis aseptic

epilepsy (including

aggravated

epilepsy)

ageusia

, anosmia

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 8 of 15

Adverse Drug Reaction Frequency

System Organ

Class

Very

Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to

<1/100)

Rare

(≥1/10,000 to

<1/1,000)

Very Rare

(<1/10,000)

Frequency

Not

Known

(cannot be

estimated

from

available

data)

Eye disorders

Vision blurred,

conjunctivitis

haemorrhage

Retinal artery

occlusion

, retinal

vein occlusion

Ear and

labyrinth

disorders

Tinnitus,

hypoacusis

Cardiac

disorders

Myocardial

infarction

Cardiac failure,

palpitations,

tachycardia

Arrhythmia

Vascular

disorders

Hyper-tensi

(including

aggravated

hyper-tensi

Pulmonary

embolism

flushing

Vasculitis

Respiratory,

thoracic, and

mediastinal

disorders

Rhinitis, cough,

dyspnoea

Bronchospasm

Pneumonitis

Gastrointestinal

disorders

Nausea

, abdominal

pain, diarrhoea,

dyspepsia,

flatulence,

vomiting

,dysphagia

Constipation,

gastritis,

stomatitis,

gastrointestinal

inflammation

(including

aggravation of

gastrointestinal

inflammation),

eructation

Gastro-intesti

haemorrhage

duodenal

ulcer, gastric

ulcer,

oesophageal

ulcer,

intestinal ulcer,

large intestinal

ulcer,

intestinal

perforation,

oesophagitis,

melaena,

pancreatitis,

colitis

Hepatobiliary

disorders

Hepatic

function

abnormal,

hepatic enzyme

increased

(including

increased SGOT

and SGPT)

Hepatitis

Hepatic failure

(sometimes fatal or

requiring liver

transplant),

hepatitis fulminant

(some with fatal

outcome), hepatic

necrosis

cholestasis

hepatitis

cholestatic

jaundice

Skin and

subcutaneous

Rash, pruritus

(includes pruritus

Urticaria,

ecchymosis

Angioedema

alopecia,

Dermatitis

exfoliative

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 9 of 15

Adverse Drug Reaction Frequency

System Organ

Class

Very

Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to

<1/100)

Rare

(≥1/10,000 to

<1/1,000)

Very Rare

(<1/10,000)

Frequency

Not

Known

(cannot be

estimated

from

available

data)

tissue disorders

generalised)

photo-sensitiv

erythema

multiforme

Stevens-Johnson

syndrome

, toxic

epidermal

necrolysis

, drug

reaction with

eosinophilia and

systemic symptoms

(DRESS)

, acute

generalised

exanthematous

pustulosis (AGEP)

dermatitis bullous

Musculoskeletal

and connective

tissue disorders

Arthralgia

Muscle spasms

(leg cramps)

Myositis

Renal and

urinary

disorders

Blood

creatinine

increased,

blood urea

increased

Renal failure

acute

hypo-natraem

Tubulointerstitial

nephritis

nephrotic

syndrome

glomerulonephritis

minimal lesion

Reproductive

system and

breast disorders

Menstrual

disorder

Infertility

female

(female

fertility

decreased)

General

disorders and

administrative

site conditions

Influenza-like illness,

oedema peripheral/

fluid retention

Face oedema,

chest pain

Injury,

poisoning and

procedural

complications

Injury (accidental

injury)

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 10 of 15

Adverse Drug Reaction Frequency

System Organ

Class

Very

Common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to

<1/100)

Rare

(≥1/10,000 to

<1/1,000)

Very Rare

(<1/10,000)

Frequency

Not

Known

(cannot be

estimated

from

available

data)

Adverse drug reactions that occurred in polyp prevention trials, representing subjects treated with

celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials). The adverse

drug reactions listed above for the polyp prevention trials are only those that have been previously

recognised in the post-marketing surveillance experience, or have occurred more frequently than in the

arthritis trials.

Furthermore, the following previously unknown adverse reactions occurred in polyp prevention trials,

representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the

APC and PreSAP trials):

Common: angina pectoris, irritable bowel syndrome, nephrolithiasis, blood creatinine increased, benign

prostatic hyperplasia, weight increased. Uncommon: helicobacter infection, herpes zoster, erysipelas,

bronchopneumonia, labyrinthitis, gingival infection, lipoma, vitreous floaters, conjunctival haemorrhage,

deep vein thrombosis, dysphonia, haemorrhoidal haemorrhage, frequent bowel movements, mouth

ulceration, allergic dermatitis, ganglion, nocturia, vaginal haemorrhage, breast tenderness, lower limb

fracture, blood sodium increased.

Women intending to become pregnant are excluded from all trials, thus consultation of the trial database

for the frequency of this event was not reasonable.

Frequencies are based on cumulative meta-analysis with pooling of trials representing exposure in 38102

patients.

In final data (adjudicated) from the APC and PreSAP trials in patients treated with celecoxib 400 mg daily for up to 3 years

(pooled data from both trials; see section 5.1 for results from individual trials), the excess rate over placebo for myocardial

infarction was 7.6 events per 1,000 patients (uncommon) and there was no excess rate for stroke (types not differentiated) over

placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected

adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

There is no clinical experience of overdose. Single doses up to 1200 mg and multiple doses up to 1200 mg twice daily have

been administered to healthy subjects for nine days without clinically significant adverse effects. In the event of suspected

overdose, appropriate supportive medical care should be provided e.g. by eliminating the gastric contents, clinical supervision

and, if necessary, the institution of symptomatic treatment. Dialysis is unlikely to be an efficient method of medicinal product

removal due to high protein binding.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic drugs, NSAIDs, Coxibs, ATC code: M01AH01.

Mechanism of action

Celecoxib is an oral, selective, COX-2 inhibitor within the clinical dose range (200-400 mg daily). No statistically significant

inhibition of COX-1 (assessed as ex vivo

inhibition of thromboxane B

[TxB

] formation) was observed in this dose range in

healthy volunteers.

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 11 of 15

Pharmacodynamic effects

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 humans but its relevance to ulcer healing has not been established.

The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical

significance in patients at risk of thrombo-embolic reactions. COX-2 selective inhibitors reduce the formation of systemic (and

therefore possibly endothelial) prostacyclin without affecting platelet thromboxane.

Celecoxib is a diaryl-substituted pyrazole, chemically similar to other non-arylamine sulfonamides (e.g. thiazides, furosemide)

but differs from arylamine sulfonamides (e.g. sulfamethoxizole and other sulfonamide antibiotics).

A dose-dependent effect on TxB

formation has been observed after high doses of celecoxib. However, in healthy subjects, in

small multiple dose studies with 600 mg BID (three times the highest recommended dose) celecoxib had no effect on platelet

aggregation and bleeding time compared to placebo.

Clinical efficacy and safety

Several clinical studies have been performed confirming efficacy and safety in osteoarthritis, rheumatoid arthritis and

ankylosing spondylitis. Celecoxib was evaluated for the treatment of the inflammation and pain of osteoarthritis of the knee

and hip in approximately 4200 patients in placebo and active controlled trials of up to 12 weeks duration. It was also evaluated

for treatment of the inflammation and pain of rheumatoid arthritis in approximately 2100 patients in placebo and active

controlled trials of up to 24 weeks duration. Celecoxib at daily doses of 200 mg – 400 mg provided pain relief within 24 hours

of dosing. Celecoxib was evaluated for the symptomatic treatment of ankylosing spondylitis in 896 patients in placebo and

active controlled trials of up to 12 weeks duration. Celecoxib at doses of 100 mg BID, 200 mg QD, 200 mg BID and 400 mg QD

in these studies demonstrated significant improvement in pain, global disease activity and function in ankylosing spondylitis.

Five randomised double-blind controlled studies have been conducted including scheduled upper gastrointestinal endoscopy

in approximately 4500 patients free from initial ulceration (celecoxib doses from 50 mg – 400 mg BID). In twelve week

endoscopy studies celecoxib (100 – 800 mg per day) was associated with a significantly lower risk of gastroduodenal ulcers

compared with naproxen (1000 mg per day) and ibuprofen (2400 mg per day). The data were inconsistent in comparison with

diclofenac (150 mg per day). In two of the 12-week studies the percentage of patients with endoscopic gastroduodenal

ulceration was not significantly different between placebo and celecoxib 200 mg BID and 400 mg BID.

prospective

long-term

safety

outcome

study

15 month

duration,

CLASS

study),

5,800 osteoarthritis

200 rheumatoid arthritis patients received celecoxib 400 mg BID (4-fold and 2-fold the recommended osteoarthritis and

rheumatoid

arthritis

doses,

respectively),

ibuprofen

800 mg

diclofenac

75 mg

(both

therapeutic

doses).

Twenty-two percent of enrolled patients took concomitant low-dose acetylsalicylic acid (≤325 mg/day), primarily for CV

prophylaxis. For the primary endpoint complicated ulcers (defined as gastrointestinal bleeding, perforation or obstruction)

celecoxib was not significantly different than either ibuprofen or diclofenac individually. Also for the combined NSAID group

there was no statistically significant difference for complicated ulcers (relative risk 0.77, 95 % CI 0.41-1.46, based on entire

study duration). For the combined endpoint, complicated and symptomatic ulcers, the incidence was significantly lower in the

celecoxib group compared to the NSAID group, relative risk 0.66, 95 % CI 0.45-0.97 but not between celecoxib and diclofenac.

Those patients on celecoxib and concomitant low-dose acetylsalicylic acid experienced 4-fold higher rates of complicated

ulcers as compared to those on celecoxib alone. The incidence of clinically significant decreases in haemoglobin (>2 g/dL),

confirmed by repeat testing, was significantly lower in patients on celecoxib compared to the NSAID group, relative risk 0.29,

95 % CI 0.17- 0.48. The significantly lower incidence of this event with celecoxib was maintained with or without acetylsalicylic

acid use.

In a prospective randomised 24 week safety study in patients who were aged

≥60 years or had a history of gastroduodenal

ulcers (users of ASA excluded), the percentages of patients with decreases in haemoglobin (

≥2 g/dL) and/or haematocrit

( ≥10%) of defined or presumed GI origin were lower in patients treated with celecoxib 200 mg twice daily (N=2238) compared

to patients treated with diclofenac SR 75 mg twice daily plus omeprazole 20 mg once daily (N=2246) (0.2% vs. 1.1% for defined

GI origin, p= 0.004; 0.4% vs. 2.4% for presumed GI origin, p = 0.0001). The rates of clinically manifest GI complications such as

perforation, obstruction or haemorrhage were very low with no differences between the treatment groups (4-5 per group).

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 12 of 15

Cardiovascular safety – long-term studies involving subjects with sporadic adenomatous polyps

Two studies involving subjects with sporadic adenomatous polyps were conducted with celecoxib i.e., the APC trial (Adenoma

Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a

dose-related increase in the composite endpoint of CV death, myocardial infarction, or stroke (adjudicated) with celecoxib

compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk

for the same composite endpoint.

In the APC trial, the relative risks compared to placebo for a composite endpoint (adjudicated) of CV death, myocardial

infarction, or stroke were 3.4 (95 % CI 1.4 - 8.5) with celecoxib 400 mg twice daily and 2.8 (95 % CI 1.1 ‑ 7.2) with celecoxib

200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0 % (20/671 subjects) and 2.5% (17/685

subjects), respectively, compared to 0.9% (6/679 subjects) for placebo. The increases for both celecoxib dose groups versus

placebo were mainly due to an increased incidence of myocardial infarction.

In the PreSAP trial, the relative risk compared to placebo for this same composite endpoint (adjudicated) was 1.2 (95 % CI 0.6 ‑

2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were

2.3 % (21/933 subjects) and 1.9 % (12/628 subjects), respectively. The incidence of myocardial infarction (adjudicated) was 1.0 %

(9/933 subjects) with celecoxib 400 mg once daily and 0.6 % (4/628 subjects) with placebo.

Data from a third long-term study, ADAPT (The Alzheimer's Disease Anti-inflammatory Prevention Trial), did not show a

significantly increased CV risk with celecoxib 200 mg BID compared to placebo. The relative risk compared to placebo for a

similar composite endpoint (CV death, myocardial infarction, stroke) was 1.14 (95 % CI 0.61 ‑ 2.15) with celecoxib 200 mg twice

daily. The incidence of myocardial infarction was 1.1 % (8/717 patients) with celecoxib 200 mg twice daily and 1.2 % (13/1070

patients) with placebo.

Prospective Randomised Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION)

The PRECISION study was a double-blind study of cardiovascular safety in OA or RA patients with or at high risk for

cardiovascular disease comparing Celecoxib (200-400 mg daily) with Naproxen (750-1000 mg daily) and Ibuprofen (1800-2400

mg daily). The primary endpoint, Antiplatelet Trialists Collaboration (APTC), was an independently adjudicated composite of

cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction or non-fatal stroke. The study was planned

with 80% power to evaluate non‑inferiority. All patients were prescribed open-label esomeprazole (20-40 mg) for gastro

protection. Patients who were taking low-dose aspirin were permitted to continue therapy, at baseline nearly half of the

subjects were on aspirin. Secondary and tertiary endpoints included cardiovascular, gastrointestinal and renal outcomes. The

Average Dose dispensed was 209±37 mg/day for Celecoxib, 2045±246 for Ibuprofen and 852±103 for Naproxen.

Regarding the primary endpoint, Celecoxib, as compared with either naproxen or ibuprofen, met all four pre-specified

non-inferiority requirements, see Table 2.

Other

independently

adjudicated

secondary

tertiary

endpoints

included

cardiovascular,

gastrointestinal

renal

outcomes. Additionally, there was a 4-month substudy focusing on the effects of the three drugs on blood pressure as

measured by ambulatory monitoring (ABPM).

Table 2. Primary Analysis of the Adjudicated APTC Composite Endpoint

Intent-To-Treat Analysis (ITT, through month 30)

​ ​

Celecoxib 100-200 mg bid

Ibuprofen 600-800 mg tid

Naproxen 375-500 mg bid

8,072

8,040

7,969

Subjects with Events

188 (2.3%)

218 (2.7%)

201 (2.5%)

Pairwise Comparison

Celecoxib vs. Naproxen

Celecoxib vs. Ibuprofen

Ibuprofen vs. Naproxen

HR (95% CI)

0.93 (0.76, 1.13)

0.86 (0.70, 1.04)

1.08 (0.89, 1.31)

Modified Intent-To-Treat Analysis (mITT, on treatment through month 43)

Celecoxib 100-200 mg bid

Ibuprofen 600-800 mg tid

Naproxen 375-500 mg bid

8,030

7,990

7,933

Subjects with Events

134 (1.7%)

155 (1.9%)

144 (1.8%)

Pairwise Comparison

Celecoxib vs. Naproxen

Celecoxib vs. Ibuprofen

Ibuprofen vs. Naproxen

HR (95% CI)

0.90 (0.72, 1.14)

0.81 (0.64, 1.02)

1.12 (0.889, 1.40)

The results were overall numerically similar in the celecoxib and comparator groups for the secondary and tertiary endpoints

and there were overall no unexpected safety findings.

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 13 of 15

Taken together the PRECISION study indicates that celecoxib at the lowest approved dose of 100 mg twice daily is non-inferior

to ibuprofen dosed in the range of 600 mg - 800 mg three times daily or naproxen dosed in the range of 375 mg - 500 mg

twice daily with respect to cardiovascular adverse effects. The cardiovascular risks of the NSAID class, including coxibs, are

dose-dependent, therefore, the results for celecoxib 200 mg daily on the composite cardiovascular endpoint cannot be

extrapolated to dosing regimens using the higher doses of celecoxib.

5.2 Pharmacokinetic properties

Absorption

Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Dosing with food (high fat

meal) delays absorption of celecoxib by about 1 hour resulting in a T

of about 4 hours and increases bioavailability by about

20%.

In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered

as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in C

or T

after

administration of capsule contents on applesauce.

Distribution

Plasma protein binding is about 97 % at therapeutic plasma concentrations and the medicinal product is not preferentially

bound to erythrocytes.

Biotransformation

Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, inactive as COX-1 or COX-2

inhibitors, have been identified in human plasma i.e., a primary alcohol, the corresponding carboxylic acid and its glucuronide

conjugate.

Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such

as those homozygous for the CYP2C9*3 polymorphism.

In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers, genotyped as either

CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median C

and AUC

0-24

of celecoxib on day 7 were approximately 4-fold

and 7-fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other genotypes. In three separate single dose

studies, involving a total of 5 subjects genotyped as CYP2C9*3/*3, single-dose AUC

0-24

increased by approximately 3-fold

compared to normal metabolisers. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3-1.0% among

different ethnic groups.

Patients who are known, or suspected to be CYP2C9 poor metabolisers based on previous history/experience with other

CYP2C9 substrates should be administered celecoxib with caution (see section 4.2).

No clinically significant differences were found in PK parameters of celecoxib between elderly African-Americans and

Caucasians.

The plasma concentration of celecoxib is approximately 100% increased in elderly women (>65 years).

Compared to subjects with normal hepatic function, patients with mild hepatic impairment had a mean increase in C

of 53%

and in AUC of 26% of celecoxib. The corresponding values in patients with moderate hepatic impairment were 41% and 146%

respectively. The metabolic capacity in patients with mild to moderate impairment was best correlated to their albumin values.

Treatment should be initiated at half the recommended dose in patients with moderate liver impairment (with serum albumin

25-35 g/l). Patients with severe hepatic impairment (serum albumin <25 g/l) have not been studied and celecoxib is

contraindicated in this patient group.

There is little experience of celecoxib in renal impairment. The pharmacokinetics of celecoxib has not been studied in patients

with renal impairment but is unlikely to be markedly changed in these patients. Thus caution is advised when treating patients

with renal impairment. Severe renal impairment is contraindicated.

Elimination

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 14 of 15

Celecoxib is mainly eliminated by metabolism. Less than 1 % of the dose is excreted unchanged in urine. The inter-subject

variability in the exposure of celecoxib is about 10-fold. Celecoxib exhibits dose- and time-independent pharmacokinetics in

the therapeutic dose range. Elimination half-life is 8-12 hours. Steady state plasma concentrations are reached within5 days of

treatment.

5.3 Preclinical safety data

Non-clinical safety data revealed no special hazard for humans based on conventional studies of repeated dose toxicity,

mutagenicity or carcinogenicity beyond those addressed in section 4.4, 4.6, and 5.1 of the SmPC.

Celecoxib at oral doses ≥150 mg/kg/day (approximately 2‑fold human exposure at 200 mg twice daily as measured by

0-24

), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused,

sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose‑dependent increase

in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6‑fold

human exposure based on the AUC

0-24

at 200 mg twice daily) throughout organogenesis. These effects are expected following

inhibition of prostaglandin synthesis. In rats, exposure to celecoxib during early embryonic development resulted in

pre‑implantation and post‑implantation losses, and reduced embryo/fetal survival.

Celecoxib was excreted in rat milk. In a peri-post natal study in rats, pup toxicity was observed.

In a 2 year toxicity study an increase in nonadrenal thrombosis was observed in male rat at high doses.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsules content:

lactose monohydrate

sodium laurilsulfate

povidone

croscarmellose sodium

magnesium stearate

Capsule shells:

gelatin

titanium dioxide E171

sodium laurilsulfate

sorbitan monolaurate

Printing ink:

indigotine E132

shellac

propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30

6.5 Nature and contents of container

Health Products Regulatory Authority

11 December 2019

CRN008RLM

Page 15 of 15

Clear or opaque PVC/aluminium blisters. Pack of 2, 5, 6, 10, 20, 30, 40, 50, 60, 100, 10x10, 10x30, 10x50, 1x50 unit dose, 1x100

unit dose, 5x(10x10).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Pfizer Healthcare Ireland

9 Riverwalk

National Digital Park

Citywest Business Campus

Dublin 24

Ireland

8 MARKETING AUTHORISATION NUMBER

PA0822/116/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 May 2000

Date of last renewal: 03 December 2009

10 DATE OF REVISION OF THE TEXT

December 2019

Similar products

Search alerts related to this product

View documents history

Share this information